key: cord-0801110-w9a4tpsu
authors: McArthur, L.; Sakthivel, D.; Ataide, R.; Chan, F.; Richards, J. S.; Narh, C. A.
title: COVID-19; Systematic and literature review of transmission, case definitions, clinical management and clinical trials.
date: 2020-05-20
journal: nan
DOI: 10.1101/2020.05.14.20102475
sha: 2987b58218c15f55d7a7daff6a19499632877f9c
doc_id: 801110
cord_uid: w9a4tpsu

Background: SARS-CoV-2, the viral agent responsible for coronavirus disease 2019 (COVID-19) was identified in Wuhan, China at the end of December 2019. It rapidly spread to the rest of the world, and was declared a Public Health Emergency of International Concern on the 30th of January 2020. Our understanding of the virus, it is clinical manifestations and treatment options continues to evolve at an unparalleled pace. Objective: This review sought to summarise the key literature regarding transmission, case definitions, clinical management and trials, and performed a systematic review of reported clinical data on COVID-19. Synthesis methods: Two reviewers selected all the literature independently, and extracted information according to pre-defined topics. Results: COVID-19 is pandemic with ~4 million cases and 270,000 deaths in 210 countries as of 8 May 2020. Our review of reports showed that SARS-CoV-2 was mainly transmitted via inhalation of respiratory droplets containing the virus and had an incubation period of four to six days. The commonly reported symptoms were fever (80%) and cough (60%) across the spectrum of clinical disease - mild, moderate, severe and critical. Categorization of these cases for home care or hospital management need to be well defined considering the age of the patient and the presence of underlying co-morbidities. The case definitions we reviewed varied among affected countries, which could have contributed to the differences observed in the mean case fatality rates among continents: Oceania (1%), Asia (3%), Africa (4%), South America (5%), North America (6%) and Europe (10%). Asymptomatic cases, which constituted an estimated 80% of COVID-19 cases are a huge threat to control efforts. Conclusion: The presence of fever and cough may be sufficient to warrant a COVID-19 testing but using these symptoms in isolation will miss a proportion of cases. A clear definition of a COVID-19 case is important for managing, treating and tracking clinical illness. While several treatments are in development or in clinical trials for COVID-19, home care of mild/moderate cases and hospital care for severe and critical cases remain the recommended management for the disease. Quarantine measures and social distancing can help control the spread of SARS-CoV-2.

were similar to the Severe Acute Respiratory Syndrome (SARS) outbreak that occurred in 2003 52 (3) (4) (5) . COVID-19 is the third coronavirus disease to cause public health outbreaks and has spread 53 more rapidly and widely than SARS and Middle East Respiratory Syndrome (MERS). As of 8 th 54

May 2020, there were ~4 million confirmed cases and ~270,000 deaths in 210 countries and 55

territories. This review provides a discussion of the disease transmission, clinical presentations, 56 variability of case definitions and review of the clinical management and clinical trials of drugs 57

for 59

Methods 60

This study was conducted following the PRISMA recommended guidelines (see Supplementary  62 data for PRISMA check list version 2009) where relevant. Literature search for articles relevant 63

for the topics discussed in this review was performed using OVID Medline, PubMed and Google 64

Scholar. The search terms included "SARS-CoV-2 and Wuhan", "Transmission and reproductive 65 number and SARS-CoV-2", "SARS-CoV-2 and COVID-19", "COVID-19 and case definitions", 66

"COVID-19 and symptoms and clinical", "COVID-19 and asymptomatic", "COVID-19 and risk 67 factors", "COVID-19 and treatments and hospital" and "COVID-19 and adults or children". 68

Furthermore, references within the articles that were returned by the search engines were also 69 retrieved and reviewed if they contained relevant information for this current review. Medical 70 review sites including BMJ Best Practice and UpToDate were reviewed periodically to provide 71 background and to get updates on COVID-19. For case definitions, the WHO criteria and those 72 published by individual countries in the six continents were obtained. For case management, the 73 NIH Clinical Trials database (https://clinicaltrials.gov/) was reviewed. The list of drugs and 74 treatments in development and clinical trials for COVID-19 were obtained through periodic 75 searches of News articles, Press releases and reports in the medical journals. Relevant Preprints on 76 biorxiv and Medrxiv were included only affect they were critically evaluated by two independent 77 reviewers. 78 79

Data collection and analysis 80

To determine the commonly reported symptoms for COVID-19, data was extracted from 15 81 studies that involved COVID-19 patients including children and adults (6-20) ( Figure S1 ). For 82 each study, the proportion of patients who reported or were observed to have a particular symptom 83 was recorded in an excel table. For each symptom, the average proportion of the number of patients 84

with that symptom was estimated and plotted with the upper standard error using Microsoft Excel. 85

For each country, data on the total number of cases and deaths reported since the outbreak began 86 till 8 th May 2020 were retrieved from Worldometer (21). The case fatality rate was estimated as a 87

percentage of the quotient of the total number of deaths reported and total number of cases reported 88

for each country. The total number of deaths and case fatality rates were plotted for countries with 89 ≥ 15 deaths reported. All mapping analyses were performed using QGIS 3.12.1- București 90 (http://qgis.osgeo.org). Shapefiles for country borders were downloaded from Natural Earth (Free 91 vector and raster map data at naturalearthdata.com). The data extracted from Worldometer (21) 92 was imported to Stata/SE 16.1 (StataCorp, TX, USA) and the country names were spelt to match 93 those of the country shapefile. The resulting database was exported as a csv file and imported to 94 QGIS where a join was performed using the MMQIS Plugin developed by Michael Minn 95 v.2020.1.16. http://michaelminn.com/linux/mmqgis/). 96 97 98

1. Human-to-human transmission routes of SARS-CoV-2 99 SARS-CoV-2 is transmitted between humans via respiratory droplets which are produced when 100 an infected individual talks, sneezes or coughs ( Figure 1 ). Droplet transmission can occur within 101 1-4 meters (15, 22, 23) . SARS-CoV-2 has been shown to survive in aerosolised form for more 102 than 3 hours under experimental conditions, but this mechanical generation of aerosols is unlikely 103

to mimic the true clinic scenario (24). Certain clinical procedures involving the upper airway, such 104 as obtaining a nose or throat swab, endotracheal intubation, manual ventilation or nebulisation are 105 capable of generating particles <5µm, allowing for airborne transmission in healthcare settings 106 (23). In particular, intensive care units (ICU) have been associated with a higher risk of infection 107 (22) . 108 109

Fomite transmission, transmission from contact with contaminated surfaces, is possible with high 110 rates of contamination of floors and the soles of healthcare staff as well as computer mice, 111 doorknobs and trash cans (22). The virus is viable for up to 72 hours on plastic and stainless steel, 112 24 hours on cardboard and 4 hours on copper. These survival times appear to be longer than that 113 of SARS-CoV under similar conditions and may contribute to the wider spread of SARS-CoV-2 114 than SARS-CoV (24). 115 116

Infection from direct contact with body fluids from infected individuals is likely to be another 117 possible route of transmission. SARS-CoV-2 has been detected in saliva, blood, urine, tears, faeces 118 and cerebrospinal fluid samples (25) (26) (27) (28) (29) 

The reported incubation period for SARS-CoV-2 has been variable between different studies, but 137 has generally ranged between 2-11 days, with an average of 4-6 days (34). In one study, the 138 incubation period was estimated at 4.9 days (95% CI 4.4-5.5) and was not significantly different 139 from that of SARS-CoV (4.7, 95% CI 4.3-5.1) and MERS-CoV (5.8, 95% CI 5.0-6.5) (35). 140 141

Symptomatic patients with COVID-19 develop a clinical syndrome similar to the influenza ( Figure  142 2). Our analysis of 15 studies involving COVID-19 patients showed that the majority of patients 143

with clinical disease had fever (80%) and cough (60%) and myalgia/fatigue (40%; Figure 2 ). Other 144 reported symptoms were less common and included dyspnoea, sore throat, diarrhoea, vomiting, 145 pharyngeal congestion, headache, sputum production, anorexia and chest pain (1, 36-39). The 146 majority of these symptoms appeared within 11 days post-infection but may vary depending on 147 age and co-morbidities (6, 30, 40, 41) . See section 6 for a review of factors associated with disease 148 severity. See Figure S1 for a detailed analysis of the reported symptoms for each of the 15 studies 149

were the clinical data in Figure 2 was obtained. 150 151

Where illness warrants hospitalisation, studies suggest that this usually occurs within five days of 152 symptom onset (30), with a mean time to hospitalisation of seven days (7 presentations being more common in elderly and immunosuppressed individuals (58). It appears 207 that fever is less characteristic of mild cases. In a Dutch study of patients identified through 208 screening, 53.5% had fever compared to 77-98.6% of hospitalised patients. Headache and 209 pharyngeal congestion were comparatively prominent with malaise, cough and myalgia being less 210 typical than in severe cases (7, 11, 12) . Although fatalities have been reported among children, 211 they seem more likely to experience a mild illness and the case fatality rate appears significantly 212 lower compared to adults (59 Other common symptoms include myalgia or fatigue, which appear early in the illness and seen in 224 around 18-32.1% of cases (8), sore throat (19) and dyspnoea (26). Fatigue may ultimately occur 225 in up to 69.6% of patients through the course of the illness but it is non-specific (47). Anosmia has 226 been reported as a commonly observed symptom and in a recent Italian study 33.9% of patients 227

reported a disturbance of smell or taste, with most experiencing this prior to their admission to 228

hospital. Less common are gastrointestinal symptoms such as diarrhoea and vomiting, as well as 229 chest pain and pharyngeal congestion. However, it is worth noting that while some symptoms are 230

common -with fever in particular being regarded as a defining symptom of the illness -they are 231 by no means necessary and will not always be present throughout the course of the disease. 232 233

Severe 

Once patients have recovered, there is some suggestion they may still be able to transmit the virus, 263

with case reports of positive RT-PCR throat swabs 5-13 days after symptom resolution, and 264 potentially present in patients who have previously been swab-negative for SARS-CoV-2 (68). 265 Viral shedding has been observed for up to 37 days in survivors with a median duration of 20 days 266 (69). SARS-CoV-2 has also been detected in faecal specimens 18-30 days after illness onset in 267 children (19) , suggesting that prolonged shedding may still be possible during and after recovery. 268 269

To date, studies of vertical transmission of SARS-CoV-2 remain limited but as of yet there are no 270 definitive documented cases (70-72). While SARS-CoV-2 specific IgM has been detected in infant 271 sera of COVID-19 positive mothers, it is as yet uncertain whether this represents passive 272 immunization, such as through an altered placenta or disease transmission with infant immune 273 response (73). 274 275

Defining the scope of the COVID-19 pandemic has been affected by the need to refine case 277 definitions as the pandemic progressed and as clinical presentations become more clearly defined. 278

These case definitions have been used to determine whom to test and to guide case investigations 279 of possible contacts. By influencing testing algorithms, they have greatly impacted the confirmed 280 test outcomes. As an example, case definitions in China were changed on the 12 th February 2020, 281

to include clinically-diagnosed mild cases, resulting in an increase of >15,000 in a single day (74). 282

Thus, developing consistent case definitions, whenever possible, is necessary to track metrics of 283 the disease and its spread. 284 285 COVID-19 case definitions have been developed and modified in different jurisdictions according 286

to local circumstances and authorities (Table 1 ). In Canada, the definition of a probable case has 287 been widened to require only one symptom of illness in addition to an epidemiological risk factor; 288 and the definition of such a risk factor has also been expanded to encompass other sources of 289 exposure, such as laboratory materials. In Australia, where case definitions are used to determine 290 testing priorities, additional efforts have been devoted to defining high-risk settings such as 291 residential facilities and the nature of a close contact as it relates to in-person interactions and 292 proximity (Table 1) . These definitions are highly significant as they determine who receives testing 293 and which patients need to be regarded as at-risk for transmitting the virus. These precautions 294 require resources -including equipment and personnel -such that case definitions must balance 295 capturing possible COVID-19 infections against burdening the healthcare system with individuals 296 with a low probability of infection. 297 298

As of 8 th May 2020, ~4 million confirmed cases and 270,000 deaths due to COVID-19 were 300

reported from 210 countries and territories ( Figure 3A ) (21). In Asia, where the epidemic started, 301 ~620,000 cases and ~21,200 deaths were reported with estimated case mean case fatality of 3%. 302

Although the hardest hit countries in this region were Turkey (~134,000 cases: ~3,600 deaths; 3% 303 fatality rate), Iran (~103,000; ~6,500; 6%) and China (~82, 900; ~4,600; 6%), Indonesia and the 304

Philippines had the highest case fatality, ~7% ( Figure 3B ). It is worth noting that the case 305 definitions were not the same which may affect testing and management of cases. As the epidemic 306 spread farther outside Asia, Europe became the hotspot with ~1.6 million cases and ~150, 000 307

deaths with a mean case fatality of 10% ( Figure 3B ). The five hardest hit countries include Spain 308 (~256,900; ~26,100; 10%), Italy (~215,900; ~30,000; 14%), UK (~206,700; ~30,600; 15%), 309

Russia (~177,200; 1,600; 1%) and France (~174,800; 26,000; 15%). In North America 310 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 20, 2020. . https://doi.org/10.1101/2020.05.14.20102475 doi: medRxiv preprint (~1,412,000; ~85,200; 6%), the United States (~1,300,000; ~76,900; 6%) was the hotspot, 311

contributing ~92% of the total cases from the region ( Figure 3A ). In South America (~267,900; 312 13,600; 5%), Brazil (~135,800; ~9,200; 7%), Peru (~58,500; ~1,600; 3%) and Ecuador (~30,300; 313 ~1,600; 5%) were the hardest hit ( Figure 3A ). In Africa, where ~55,400 cases were confirmed and 314 ~2,100 deaths occurred with a mean case fatality of 4%, South Africa (~8,200; 160; 2%), Egypt 315 (~8,000; 500; 6%), Morocco (5,500; 180; 3%) and Algeria (5,200; 500; 9%) were the hardest hit 316 ( Figure 3B ). Oceania had the lowest number of cases reported so far with ~8,500 cases and 120 317 deaths with a mean case fatality of 1%, with the hardest hit country being Australia (7,000; 100; 318 1%, Figure 3B ). As the pandemic continues, these figures and trends in cases and deaths may 319 change, and thus, it is important for countries to keep track to inform public health control efforts. 320 321

In different healthcare settings, the case fatality may vary. Studies of hospitalised patients have 322

reported varying fatality rates ranging from 1.4 to 14% (6, 41, 74). However, several of such 323 studies are likely underestimating true fatality rates in these patient groups given that the 324 percentage of patients recovered to discharge by the conclusion of the study often remains low -325 31% in the analysis by Chen et al, where case fatality rate was found to be 11% (10) illness in 40% of patients who fell critically ill (13). Other predictors of severe illness and death 356 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 20, 2020. . may include presentation with dyspnoea (present in 59.5-63.9% of ARDS cases, versus 19.6-357 25.6% of less severe illness) and anorexia (66.7% vs. 30.4%) (7, 64). Severe illness has also been 358 associated with smoking (6) For patients with severe or critical SARS-CoV-2, supportive care is the current mainstay of 391 treatment (Figure 1 ). This includes attention to fluids and electrolytes, monitoring for 392 complications, facilitating symptomatic management and providing respiratory support. 393

Respiratory support can be provided in a stepwise fashion as required, moving from oxygen 394 therapy through to non-invasive ventilation then intubation and mechanical ventilation. In ARDS, 395

there is some evidence that prone positioning of patients may improve oxygenation and it is 396 currently being recommended for critical care of COVID-19 patients (59). Extracorporeal 397 membranous oxygenation may be used if available for refractory hypoxia. It is important to note 398 that while respiratory support measures are integral to COVID-19 management, they also create 399

high-risk environments in which airborne transmission of the virus may be possible (23). These 400 measures include intubation, nebulised treatments, moving patients to prone position and positive-401 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) There are a range of drugs and treatments currently under investigation due to their potential to 414 modify some aspect of the COVID-19 disease course ( supporting its use has been released (100) but its efficacy has yet to be conclusively demonstrated 445

in clinical trials. A non-randomised control trial in France found that hydroxychloroquine reduced 446 nasal viral load six days post-treatment and had high efficacy when combined with azithromycin. 447 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 20, 2020. .

hydroxychloroquine among hospitalised patients, the drug improved clinical symptoms when 449 compared to standard of care but did not improve negative conversion rate of SARS-CoV-2 (102). 450

In another trial involving hospitalised patients in China (currently awaiting peer-review), the drug 451 reduced the time to recovery from fever, cough and pneumonia (18 suggested that a combination therapy of the two drugs is effective against MERS in animal models 465 (90) . This combination is being trialled in COVID-19 patients (104). While an early case report 466

showed that treatment with this therapy lead to a decrease in the viral load (105) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 20, 2020. . https://doi.org/10.1101/2020.05.14.20102475 doi: medRxiv preprint Nearly, every country in the world has been hit by this pandemic. It is important to note that the 492 definitions for COVID-19 cases vary slightly between countries and territories affected by the 493 disease and this in turn may have affected the public health response. When defining cases, it is 494 important that national guidelines factor in the presence of co-morbidities including cardiovascular 495 diseases, diabetes and cancer, which increase the risk of developing severe and/or critical disease 496 and increase the risk of fatality. Where transmission is still in the exponential phase of SARS-497

CoV-2 infections, it is critical that clinical cases are triaged to prioritize management and treatment 498 without overwhelming the healthcare system. 499 500

Several drugs are in clinical trials but it may take months before any become available for clinical 501 use. Hence, it is important that quarantine and isolation measures are strictly enforced to control 502 the disease outbreak. A major challenge though to controlling SARS-CoV-2 transmission is how 503 to identify the "silent spreaders" who are asymptomatic carriers of the infection. 504 505 506

Limitations of the study 507

During the review period, the data on COVID-19 constantly changed with increasing amounts of 508 literature both peer-reviewed and non-peer-reviewed. COVID-19 data was dependent on country 509

level definitions and testing rates. 510 511

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