COVID19 Pandemic
Coronaviruses are a large family of enveloped, non-segmented, single-stranded, positive-sense RNA viruses that circulate among animals including camels, cats and bats. Coronaviruses derive their name from their electron microscopic image which resembles a crown or corona.
Six strains of coronavirus have infected humans. Three global coronavirus outbreaks have occurred in the past two decades. Severe Acute Respiratory Syndrome, caused by SARS-CoV, started in 2003 in Guangdong, China, and spread to many countries in Southeast Asia, North America, Europe, and South Africa. Early cases were linked to human and animal contact at live game markets. Bats are the natural hosts of SARS-CoV while palm civets and racoon dogs are intermediate hosts. Transmission occurred person to person through droplets produced by coughing or sneezing, through personal contact and by touching contaminated surfaces. Peak viral shedding occurs approximately 10 days after the onset of illness, when many patients are hospitalized. This explains why health care professionals have a particularly high risk of becoming infected. SARS-CoV infected 8,069 persons and caused 774 deaths. SARS-CoV has a R0 of 4 and a case fatality rate of 9.5%. The last known case of SARS-CoV was detected in September 2003
Nine years later in 2012, MERS-CoV emerged in Saudi Arabia and caused Middle Eastern Respiratory syndrome pandemic. MERS is characterized by sporadic zoonotic transmission from camels and limited episodes of person to person transmission. Explosive nosocomial transmission has been linked to single super-spreaders of infection. Almost all cases have been linked to persons in or near the Arabian Peninsula.
Symptoms of MERS-CoV are nonspecific, but many patients develop atypical pneumonia and severe acute respiratory distress. Up to 80% of patients with MERS require mechanical ventilation. Patients with MERS often have prominent GI symptoms and acute kidney failure. This constellation of symptoms is due to the binding of MERS-CoV S glycoprotein to dipeptidyl peptidase 4 (DPPT4), which is present in the lower respiratory tract, gastrointestinal tract and kidney.
Like SARS-CoV, health professionals are at higher risk of acquiring the disease. MERS is still circulating and has infected approximately 2,500 people and caused 850 deaths. The main factor that controlled spread of MERS-CoV is its very low R0 of 1, meaning that each person with the disease only transmits the disease to only one other person. However, the case fatality rate is very high, at 35%.
In December 30, 2019, a cluster of patients with pneumonia of unknown etiology was observed in Wuhan, China, and reported to the World Health Organization (WHO) China bureau in Beijing. On January 7, 2020, a new coronavirus (SARS-CoV-2) was isolated from these patients. This virus was initially referred to as novel coronavirus 2019 (2019-nCoV) by the WHO but was later given the official name of of SARS-CoV-2 by the International Committee on Taxonomy of Viruses on February 11, 2020. Two factors facilitated the rapid spread of this virus in Wuhan: a population of 11,000,000 inhabitants increased the chance of person to person contact and its busy transportation hub increased the likelihood of exporting cases to other locations. Despite Chinese containment measures, cases of COVID19 have already been reported in more than 100 other countries as of March 2020. According to Johns Hopkins CSSE, as of March 8, 2020, there have been 109,609 confirmed cases of COVID-19 and 3800 deaths worldwide.
SARS-CoV-2 is a Betacoronovirus that shares 79% genetic sequence with SARS-CoV and 96% homology to two coronaviruses in chrysanthemum bats. The pangolin is thought to the intermediate host between bats and humans. The virus uses a densely glycosylated spike (S) protein to bind with high affinity to the angiotensin-converting enzyme 2 (ACE2) receptor on human alveolar type II cells, similar to SARS-CoV.
The virus appears to be transmitted primarily through large droplets, but it has also been found in stool and blood, raising questions about other potential modes of transmission.The incubation period was originally thought to range from 1 to 14 days with a median of 5 to 6 days, but recent case reports suggest that it may be as long as 24 days. Patients with the COVID-19 infection have a median age of 59 years. They present with fever, dry cough, fatigue, myalgia and shortness of breath. Patients may develop pneumonia towards the end of the first week of infection. The mean interval from onset of illness to hospitalization is between 9.1 to 12.5 days. Approximately 25% of patients have a severe course requiring intensive care, and approximately 10% required mechanical ventilation. The most severe cases develop pneumonia and ARDS. Children and younger adults have more benign disease.
Abnormal laboratory findings have included lymphopenia (70%), prolonged prothrombin time (58%), and elevated lactate dehydrogenase (40%). Chest radiographs are characterized by bilateral patchy infiltrates and chest CT scans demonstrate ground-glass infiltrates.
At this time, the R0 is estimated to be 2.0 to 3.5, indicating that one patient can transmit the disease to two to three other people. The case fatality rate is between 2% and 3% but is higher in patients with comorbid conditions.If one assumes that the number of asymptomatic or minimally symptomatic cases is several times as high as the number of reported cases, the case fatality rate may be less than 1%.Even though its case fatality rate is lower than MERS-CoV, SARS-CoV-2 will cause many more deaths, because there have been so many more cases. As with other coronaviruses, health care–associated transmission appears to be a major mode of infection.
One small study suggested that some patients may continue to be viral carriers after apparent recovery. Four Chinese medical professionals recovered from COVID19 and met the criteria for hospital discharge or discontinuation of quarantine. These criteria included absence of clinical symptoms, resolution of radiological abnormalities and 2 negative RT-PCR test results. All of these patients had repeat positive RT-PCR test results 5 to 13 days later.
One histopathological study of the lungs of a deceased patient reported the presence of hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, and multinucleated giant cells.
The BioFire Respiratory Viral Panel detects 4 coronavirus targets (HKU1, 229E, NL63, OC43). These human coronaviruses are common causes of mild to severe upper and lower respiratory illness. These 4 coronavirus targets do not cross-react with any of the epidemic coronaviruses (MERS-CoV, SARS-CoV, or SARS-CoV-2). Detection of a coronavirus with the RVP indicates infection with a seasonal human coronavirus. RVP should not be used to rule in/out infection with SARS-CoV-2.
At present, testing capabilities remain limited in the United States. CDC has published primers, probes, and protocols. The Food and Drug Administration (FDA) issued new guidance on February 29, 2020, for laboratories to be able to develop novel coronavirus (COVID-19) molecular diagnostics tests and begin use prior to obtaining Emergency Use Authorization (EUA). This permits laboratories that are CLIA certified to perform high complexity testing to offer SARS-CoV-2molecular diagnostic testing after completing method validation. Laboratories must receive FDA EUA approval within 15 business days of clinical use.
Primers and probes for the CD assay can be purchased from Integrated DNA Technologies (IDT)). All other reagents must be procured from other vendors. To remain in FDA compliance, labs must follow the exact specifications under which the EUA was received. Labs could purchase the IDT kit and run it on alternative platforms, but this would be considered a deviation from EUA clearance and require new EUA approval.
Currently, several reference labs have testing available or near available. Quest, LabCorp and Viracor have announced they will begin offering testing during the second week of March. Several IVD vendors (GenMark, Cepheid, Luminex, and BioFire) have assays in development and expect to submit for EUA approval in the next 1 to 2 weeks. Hopefully, FDA will expedite EUA for these assays. These assays will provide the best option for most hospital clinical laboratories.
Clinical laboratories should contact their state health departments for guidance if they have a suspected COVID-19 case specimen. Clinical laboratories should NOT attempt viral isolation from specimens collected from COVID-19 persons under investigation (PUIs). Nasopharyngeal swabs, not throat swabs, should be submitted for reverse-transcriptase polymerase chain reaction (RT-PCR) testing. Ideally, a lower respiratory tract sample such as induced sputum or bronchoalveolar lavage should also be submitted. Serum samples can also be sent. Viral cultures are not recommended. Additional tests, such as complete blood cell count and routine microbiology, including molecular testing for other respiratory viruses, can be handled using universal precautions in hospital laboratories.
The care of the patient with COVID-19 is similar to that of other viral pneumonias, primarily consisting of supportive care and oxygen supplementation when needed. Corticosteroids have not been recommended. Anecdotal evidence suggests that remdesivir, a nucleoside prodrug that is thought to act by inhibiting viral RNA transcription, may be useful and clinical trials are under way. Additionally, lopinavir/ritonavir has also been tried based on efficacy in animal models of MERS-CoV, but this may not be the case in humans with COVID-19. Recently China approved the use of favilavir, an antiviral drug used for influenza, as investigational therapy for COVID-19.
No vaccine against SARS-CoV-2 is currently available. More than 11 vaccine candidates are in development and a phase 1 study of an mRNA vaccine developed by the NIH is expected to begin in March 2020. None of these vaccines will be available to the public for at least a year.
CDC recommends that health care workers use personal protective equipment (PPE) and implement standard, contact, and airborne precautions including the use of eye protection. Health care workers should wear a gown, gloves, and either an N95 respirator plus a face shield or goggles or a powered, air-purifying respirator. Regular paper masks provide little protection.
The current outbreak has prompted a debate about the effectiveness of quarantines both in China and other countries. When executed properly, quarantines can reduce transmission, but human rights must be respected. In an age of global connectivity, it may be difficult if not impossible to implement effective quarantine measures.
For most people who get the virus, it will be a mild infection. Marc Lipsitch, an epidemiologist at Harvard, estimates that 20 to 60 percent of all adults may get infected. It is not known if SARS-COV-2 virus will continue spreading into the spring and summer, or if it will fade as other winter respiratory viruses do. If it ebbs, chances are it may return in the fall, perhaps even more voraciously.
References
Guarner J. Three Emerging Coronaviruses in Two Decades. Am J Clin Pathol. 2020; published online on Feb 19, 2020.
Carlos del Rio and Preeti N. Malani. COVID-19—New Insights on a Rapidly Changing Epidemic. JAMA February 28, 2020. doi:10.1001/jama.2020.3072
Lan L et al. Positive RT-PCR Test Results in Patients Recovered From COVID-19, Published on line February27,2020.doi:10.1001/jama.2020.2783
Johns Hopkins CSSE Dashboard https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6
