Coronavirus Disease 2019 (COVID-19) – The Available Evidence

Joseph Grillo, M.D., J.D. (2020)

There is currently a large amount of information being circulated on the COVID-19 viral pandemic. Much of it is inaccurate and some is hysteria – often fostered by the mainstream media. In my view, the best way to combat this virus is by having evidence-based information and acting accordingly. There is a significant amount of accurate information currently known, but there is also considerable information that remains unknown at this time. Presented below is a discussion of both. Please feel free to contact me with questions at jfgrillo1@gmail.com

At the end of 2019, a new coronavirus was identified as the cause of a cluster of pneumonia cases in the Chinese city Wuhan. The World Health Organization (WHO) designated it coronavirus disease 2019 (COVID-19; initially called 2019-nCoV). The COVID-19 outbreak subsequently spread to become a global pandemic [1-3]. The illness is characterized primarily by upper respiratory symptoms – including fever, cough, and bilateral infiltrates on chest imaging. The possibility of COVID-19 should be considered primarily in patients with fever and/or respiratory tract symptoms who reside in or have recently traveled to areas with community transmission (eg, China, South Korea, Iran, most of Europe [including Italy], Japan) or who have had close contact with a confirmed or suspected case of COVID-19.

Understanding of COVID-19 is evolving. Interim guidance has been issued by the World Health Organization and by the United States Centers for Disease Control and Prevention.

Geographic distribution — Since the first reports of cases from Wuhan, a city in the Hubei Province of China, at the end of 2019, more than 80,000 COVID-19 cases have been reported in China; these include all laboratory-confirmed cases as well as clinically diagnosed cases in the Hubei Province. A joint World Health Organization (WHO)-China fact-finding mission estimated that the epidemic in China peaked between late January and early February 2020 [4].

Increasing numbers of cases have also been reported in other countries across all continents except Antarctica, and the rate of new cases outside of China has outpaced the rate in China. These cases initially occurred mainly among travelers from China and those who have had contact with travelers from China [5-9]. However, ongoing local transmission has driven smaller outbreaks in some locations outside of China, including South Korea, Italy, Iran, and Japan, and infections elsewhere have been identified in travelers from those countries [10].

In the United States, several clusters of COVID-19 with local transmission have been identified throughout the country.

Transmission — Understanding of the transmission risk is incomplete. As the outbreak progressed, person-to-person spread became the main mode of transmission.

Person-to-person spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is thought to occur mainly via respiratory droplets, resembling the spread of influenza. With droplet transmission, virus released in the respiratory secretions when a person with infection coughs, sneezes, or talks can infect another person if it makes direct contact with the mucous membranes; infection can also occur if a person touches an infected surface and then touches his or her eyes, nose, or mouth. Droplets typically do not travel more than six feet and do not linger in the air. However, given the current uncertainty regarding transmission mechanisms, airborne precautions are recommended routinely in some countries and in the setting of certain high-risk procedures in others.

The reported rates of transmission from an individual with symptomatic infection vary by location and infection control interventions. According to a joint WHO-China report, the rate of secondary COVID-19 ranged from 1 to 5 percent among tens of thousands of close contacts of confirmed patients in China [11]. In the United States, the symptomatic secondary attack rate was 0.45 percent among 445 close contacts of 10 confirmed patients [12].

Incubation period — The incubation period for COVID-19 is thought to be within 14 days following exposure, with most cases occurring approximately four to five days after exposure [13-16]. In a study of 1099 patients with confirmed symptomatic COVID-19, the median incubation period was four days (interquartile range two to seven days) [17].

Spectrum of illness severity — The spectrum of symptomatic infection ranges from mild to critical; most infections are not severe [18-20]. Specifically, in a report from the Chinese Center for Disease Control and Prevention that included approximately 44,500 confirmed infections with an estimation of disease severity [21]:

  • Mild (no or mild pneumonia) was reported in 81 percent.
  • Severe disease (eg, with dyspnea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours) was reported in 14 percent.
  • Critical disease (eg, with respiratory failure, shock, or multiorgan dysfunction) was reported in 5 percent.
  • The overall case fatality rate was 2.3 percent; no deaths were reported among noncritical cases.

Most of the fatal cases have occurred in patients with advanced age or underlying medical comorbidities (including cardiovascular disease, diabetes mellitus, chronic lung disease, hypertension, and cancer) [22,23].

Symptomatic infection in children appears to be uncommon; when it occurs, it is usually mild, although severe cases have been reported

Asymptomatic infections — Asymptomatic infections have also been described [48-50], but their frequency is unknown.

In a COVID-19 outbreak on a cruise ship where nearly all passengers and staff were screened for SARS-CoV-2, approximately 17 percent of the population on board tested positive as of February 20; about half of the 619 confirmed COVID-19 cases were asymptomatic at the time of diagnosis [24].

Clinical manifestations

Initial presentation — Pneumonia appears to be the most frequent serious manifestation of infection, characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest imaging [25-27]. There are no specific clinical features that can yet reliably distinguish COVID-19 from other viral respiratory infections. In a study describing 138 patients with COVID-19 pneumonia in Wuhan, the most common clinical features at the onset of illness were [28]:

  • Fever in 99 percent
  • Fatigue in 70 percent
  • Dry cough in 59 percent
  • Anorexia in 40 percent
  • Myalgias in 35 percent
  • Dyspnea in 31 percent
  • Sputum production in 27 percent

In addition to respiratory symptoms, gastrointestinal symptoms (eg, nausea and diarrhea) have also been reported in some patients, but these are relatively uncommon [29].

Laboratory findings — In patients with COVID-19, the white blood cell count can vary. Leukopenia, leukocytosis, and lymphopenia have been reported, although lymphopenia appears most common [31-32]. 

Management

Home care — Home management is appropriate for patients with mild infection who can be adequately isolated in the outpatient setting [33]. Management of such patients should focus on prevention of transmission to others, and monitoring for clinical deterioration, which should prompt hospitalization.

Outpatients with COVID-19 should stay at home and try to separate themselves from other people and animals in the household. They should wear a facemask when in the same room (or vehicle) as other people and when presenting to health care settings. Disinfection of frequently touched surfaces is also important, as discussed elsewhere.

Hospital care — Some patients with suspected or documented COVID-19 have severe disease that warrants hospital care.

Investigational agents — A number of investigational agents are being explored for antiviral treatment of COVID-19, and enrollment in clinical trials should be discussed with patients or their proxies. A registry of international clinical trials can be found on the WHO website and at clinicaltrials.gov.

Certain investigational agents have been described in observational series or are being used anecdotally based on in vitro or extrapolated evidence. It is important to acknowledge that there are no controlled data supporting the use of any of these agents, and their efficacy for COVID-19 is unknown.

Remdesivir– Several randomized trials are underway to evaluate the efficacy of remdesivir for moderate or severe COVID-19 [34]. Remdesivir is a novel nucleotide analogue that has activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and related coronaviruses (including SARS and MERS-CoV) both in vitro and in animal studies [72,73]. The compassionate use of remdesivir through an investigational new drug application was described in a case report of one of the first patients with COVID-19 in the United States [74]. Any clinical impact of remdesivir on COVID-19 remains unknown.

Chloroquine/hydroxychloroquine– Both chloroquine and hydroxychloroquine inhibit SARS-CoV-2 in vitro, although hydroxychloroquine appears to have more potent antiviral activity [75]. A number of clinical trials are underway in China to evaluate the use of chloroquine or hydroxychloroquine for COVID-19 [35,36].

Lopinavir-ritonavir– This combined protease inhibitor, which has primarily been used for HIV infection, has in vitro activity against the SARS-CoV [37] and appears to have some activity against MERS-CoV in animal studies [38]. The use of this agent for treatment of COVID-19 has been described in case reports [39], but its efficacy is unclear. In one report of five patients who were treated with lopinavir-ritonavir, three improved and two had clinical deterioration; four had gastrointestinal side effects. It is being evaluated in larger randomized trials.

Tocilizumab– Treatment guidelines from China’s National Health Commission include the IL-6 inhibitor tocilizumab for patients with severe COVID-19 and elevated IL-6 levels; the agent is being evaluated in a clinical trial [40].

Preventing exposure in the community — The following general measures are recommended to reduce transmission of infection:

  • Diligent hand washing, particularly after touching surfaces in public. Use of hand sanitizer that contains at least 60 percent alcohol is a reasonable alternative if the hands are not visibly dirty.
  • Respiratory hygiene (eg, covering the cough or sneeze).
  • Avoiding touching the face (in particular eyes, nose, and mouth).
  • Avoiding crowds (particularly in poorly ventilated spaces) if possible and avoiding close contact with ill individuals.
  • Cleaning and disinfecting objects and surfaces that are frequently touched. The CDC has issued guidance on disinfection in the home setting; a list of EPA-registered products can be found here.

In particular, older adults and individuals with chronic medical conditions should be encouraged to follow these measures.

COVID-19 testing not readily available — In some cases, testing for COVID-19 may not be accessible, particularly for individuals who have a compatible but mild illness that does not warrant hospitalization and do not have a known COVID-19 exposure or high-risk travel history.

In the United States, there is limited official guidance for this situation, and the approach may depend on the prevalence of COVID-19 in the area. If the clinician has sufficient concern for possible COVID-19 (eg, there is community transmission), it is reasonable to advise the patient to self-isolate at home (if hospitalization is not warranted) and alert the clinician about worsening symptoms.

Society Guidelines

The following is a listing of society and government-sponsored guidelines. These are the places to go to find the most current and accurate information.

International

United States

  1. World Health Organization. Director-General’s remarks at the media briefing on 2019-nCoV on 11 February 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 (Accessed on February 12, 2020).
  2. Centers for Disease Control and Prevention. 2019 Novel coronavirus, Wuhan, China. Information for Healthcare Professionals. https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html (Accessed on February 14, 2020).
  3. World Health Organization. Novel Coronavirus (2019-nCoV) technical guidance. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance (Accessed on February 14, 2020).
  4. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 24 February 2020 https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—24-february-2020 (Accessed on February 26, 2020).
  5. World Health Organization. WHO Disease outbreak news: Novel Coronavirus – Republic of Korea (ex-China). January 21, 2020. https://www.who.int/csr/don/21-january-2020-novel-coronavirus-republic-of-korea-ex-china/en/ (Accessed on January 21, 2020).
  6. Centers for Disease Control and Prevention. First travel-related case of 2019 novel coronavirus detected in United States, January 21, 2020. https://www.cdc.gov/media/releases/2020/p0121-novel-coronavirus-travel-case.html (Accessed on January 21, 2020).
  7. Centers for Disease Control and Prevention. Second travel-related case of 2019 novel coronavirus detected in United States, January 24, 2020. https://www.cdc.gov/media/releases/2020/p0124-second-travel-coronavirus.html (Accessed on January 24, 2020).
  8. European Centre for Disease Prevention and Control. Geographical distribution of 2019-nCov cases. https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases (Accessed on January 26, 2020).
  9. Centers for Disease Control and Prevention. 2019 Novel Coronavirus (2019-nCoV) in the US. https://www.cdc.gov/coronavirus/2019-ncov/cases-in-us.html (Accessed on February 10, 2020).
  10. World Health Organization. Novel coronavirus situation report -2. January 22, 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200122-sitrep-2-2019-ncov.pdf (Accessed on January 23, 2020).
  11. Kupferschmidt K. Study claiming new coronavirus can be transmitted by people without symptoms was flawed. Science. February 3, 2020. https://www.sciencemag.org/news/2020/02/paper-non-symptomatic-patient-transmitting-coronavirus-wrong (Accessed on February 04, 2020).
  12. Centers for Disease Control and Prevention. Interim Clinical Guidance for Management of Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) Infection, Updated February 12, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html (Accessed on February 14, 2020).
  13. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med 2020.
  14. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020.
  15. Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020; 395:514.
  16. Lauer S, Grantz KH, Bi Q, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med 2020.
  17. Bajema KL, Oster AM, McGovern OL, et al. Persons Evaluated for 2019 Novel Coronavirus – United States, January 2020. MMWR Morb Mortal Wkly Rep 2020; 69:166.
  18. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497.
  19. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395:507.
  20. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020.
  21. Liu K, Fang YY, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl) 2020.
  22. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020.
  23. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020.
  24. CDC, Updated Guidance on Evaluating and Testing Persons for COVID-19. HAN429. https://emergency.cdc.gov/han/2020/han00429.asp?deliveryName=USCDC_511-DM22015 (Accessed on March 09, 2020).
  25. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons Under Investigation (PUIs) for Coronavirus Disease 2019 (COVID-19). February 14, 2020 https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html (Accessed on March 15, 2020).
  26. Patel A, Jernigan DB, 2019-nCoV CDC Response Team. Initial Public Health Response and Interim Clinical Guidance for the 2019 Novel Coronavirus Outbreak – United States, December 31, 2019-February 4, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:140.
  27. WHO. Coronavirus disease (COVID-19) technical guidance: Surveillance and case definitions. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/surveillance-and-case-definitions (Accessed on February 28, 2020).
  28. World Health Organization. Novel Coronavirus (2019-nCoV) technical guidance: Patient management. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/patient-management (Accessed on February 02, 2020).
  29. Centers for Disease Control and Prevention. Interim guidance for persons who may have 2019 Novel Coronavirus (2019-nCoV) to prevent spread in homes and residential communities. https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-prevent-spread.html#First_heading (Accessed on February 06, 2020).
  30. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; 395:473.
  31. Gilead. Gilead Sciences Statement on the Company’s Ongoing Response to the 2019 Novel Coronavirus (2019-nCoV). https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-company-ongoing-response-to-the-2019-new-coronavirus (Accessed on February 02, 2020).
  32. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017; 9.
  33. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30:269.
  34. Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382:929.
  35. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020.
  36. Cortegiani A, Ingoglia G, Ippolito M, et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020.
  37. Groneberg DA, Poutanen SM, Low DE, et al. Treatment and vaccines for severe acute respiratory syndrome. Lancet Infect Dis 2005; 5:147.
  38. Chan JF, Yao Y, Yeung ML, et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis 2015; 212:1904.
  39. Lim J, Jeon S, Shin HY, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR. J Korean Med Sci 2020; 35:e79.
  40. Wang Z, Chen X, Lu Y, et al. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends 2020.
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