Introduction & History of virus
In today’s world, emerging infectious diseases such as Severe Acute Respiratory Syndrome (SARS) and Zika virus disease, present a major risk to public health. Despite intense research and studies, how, when and from where novel diseases appear is still a source of great uncertainty. Just last December, we faced a catastrophic outbreak of novel coronavirus. Four months later, the whole world is still in pandemic mode, with many countries having imposed lockdowns and are following self-isolation & social distancing rules.
Coronaviruses were first discovered in domestic poultry in the 1930s. It was a few decades later that the first human coronaviruses were identified in the 1960s, which were causing respiratory, gastrointestinal, liver, and neurologic diseases in animals. Only 7 coronaviruses have been acknowledged to cause diseases in humans. These coronaviruses which cause severe respiratory infections are zoonotic pathogens, which are present in infected animals and are transmitted from them to people.
Four of the 7 coronaviruses are endemic i.e., regularly found among particular people or in a certain area and most regularly cause symptoms similar to the common cold. Coronaviruses 229E and OC43 cause the common cold and the serotypes NL63 and HUK1 also have been associated with the common cold. Rarely, severe lower respiratory tract infections, such as pneumonia, can occur, typically in infants, older people, and the immunocompromised.
Three of the seven coronaviruses cause intense, severe, and sometimes fatal respiratory infections in humans than the other coronaviruses and have already caused major outbreaks of deadly pneumonia in the 21st century:
- MERS-CoV The first case of the Middle East respiratory syndrome (MERS) occurred in Saudi Arabia in 2012. There were two further MERS outbreaks: South Korea in 2015 and Saudi Arabia in 2018. There are a handful of MERS cases every year, but the outbreaks are usually well contained.
- SARS-CoV was identified in 2002 as the cause of an outbreak of extreme acute respiratory syndrome. The cause of this outbreak wasn’t confirmed until 2003 when the genome of the virus was identified by Canada’s National Microbiology Laboratory.
- SARS-CoV2 is a novel coronavirus identified as the cause of coronavirus disease 2019 (COVID-19) which began in Wuhan, China in late 2019 and spread worldwide.
In a timeline that reaches the present day, an epidemic of cases with unexplained respiratory infections detected in Wuhan, in China, were first reported to the WHO Country Office in China, on December 31, 2019. According to early epidemiological investigations, Patient Zero was a worker at a local indoor wet market. The Patient started to develop symptoms on 20th December and was then admitted to the Central Hospital of Wuhan on 26th Dec 2019. The patient was experiencing symptoms of severe respiratory distress syndrome that included fever, dizziness and cough. As they were unable to identify the causative agent, these first cases were classified as “pneumonia of unknown etymology.”
Later, metagenomics RNA sequencing of a sample of Bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’).
Phylogenetic analysis of its complete genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Beta coronavirus, subgenus Sarbecovirus) that had previously been found in bats in China.
On February 11, 2020, WHO, announced that the disease caused by this Novell CoV was “COVID-19”. SARS-CoV-2 is highly contagious and evolved into an international health risk within weeks. As on 8th May 2020 2 pm, there have been 38,45,607 confirmed cases & 2,69,564 registered deaths in 208 countries caused due to it.
Coronavirus genome structure and life cycle
COVID-19 is a spherical or pleomorphic enveloped particles containing a single-stranded (positive-sense) RNA, associated with a nucleoprotein within a capsid comprised of matrix protein. The envelope bears club-shaped glycoprotein projections. Some coronaviruses also contain a hemagglutinin-esterase protein (HE).
Coronaviruses possess the largest genomes (26.4–31.7 kb) among all known RNA viruses, with G + C contents varying from 32% to 43%. Variable numbers of small ORFs(Open Reading Frame) are present between the various conserved genes (ORF1ab, spike, envelope, membrane and nucleocapsid) and, downstream to the nucleocapsid gene in different coronavirus lineages. The viral genome contains distinctive features, including a unique N-terminal fragment within the spike protein. Genes for the major structural proteins in all coronaviruses occur in the 5′–3′ order as S, E, M, and N.
A typical CoV contains at least six ORFs in its genome. All the structural and accessory proteins are translated from the sgRNAs of CoVs. Four main structural proteins contain spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins are encoded by ORFs 10, 11 on the one-third of the genome near the 3′-terminus. Besides these four main structural proteins, different CoVs encode special structural and accessory proteins, such as HE protein, 3a/b protein, and 4a/b protein. These mature proteins are responsible for several important functions in genome maintenance and virus replication.
There are three or four viral proteins in the coronavirus membrane. The most abundant structural protein is the membrane (M) glycoprotein and it spans the membrane bilayer three times leaving a short amino-terminal outside the virus and a long -COOH terminus inside the virion.
The spike protein (S) as a type I membrane glycoprotein constitutes the peplomers. In fact, the main inducer of neutralizing antibodies is the S protein. Between the envelope proteins exist a molecular interaction that probably determines the formation and composition of the coronaviral membrane.
M plays a predominant role in the intracellular formation of virus particles without requiring S. In the presence of tunicamycin coronavirus grows and produces spikeless, noninfectious virions that contain M but devoid of S.
The latest study has presented three main transmission routes for the COVID-19:
1) Droplets Transmission
2) Contact transmission
3) Aerosol transmission:
In addition to those three routes, one Study also indicated the gastrointestinal system as a possible transmission route for COVID-19 infection. Since patients had abdominal discomfort and diarrhoea symptoms, researchers analysed four datasets with single-cell transcriptomes of biological process systems and found that ACE2 was extremely expressed in absorptive enterocytes from ileum and colon.
Treatment & Management
Currently, there is no specific medicine or vaccine for COVID-19 and no medicines or vaccines have been fully tested for safety and efficacy. At present, antiviral therapy is being used, as well as symptomatic and supportive treatment based on the clinical condition of the patient.
Supportive treatments include oxygen therapy, hydration, fever/pain control, and antibiotics in the presence of bacterial co-infection.
In cases of respiratory failure, refractory to oxygen therapy, mechanical ventilation may be necessary whereas for managing septic shock hemodynamic support is essential. When the disease results in complex clinical pictures of MOD, organ function support in addition to respiratory support is mandatory.
Extracorporeal membrane oxygenation (ECMO) for patients with refractory hypoxemia despite lung-protective ventilation should merit consideration after a case-by-case analysis. It can be suggested for those with poor results to prone position ventilation.
Intubation requires special precautions and should only be performed by an expert operator using full personal protective equipment (PPE). If required, rapid sequence intubation (RSI) should be performed. Preoxygenation (100% O2 for 5 minutes) should be performed via the continuous positive airway pressure (CPAP) method. Between the mask and the circuit of the fan or between the mask and the ventilation balloon Heat and moisture exchanger (HME) must be properly positioned.
Protective mechanical ventilation
Mechanical ventilation should be with lower tidal volumes (4 to 6 ml/kg predicted body weight, PBW) and lower inspiratory pressures, reaching a plateau pressure (Pplat) < 28 to 30 cm H2O. PEEP must be as high as possible to maintain the driving pressure (Pplat-PEEP) as low as possible (< 14 cmH2O). Moreover, disconnections from the ventilator must be avoided for preventing loss of PEEP and atelectasis.
Finally, the use of paralytics is not recommended unless PaO2/FiO2 < 150 mmHg. The prone ventilation for > 12 hours per day, and the use of a conservative fluid management strategy for ARDS patients without tissue hypoperfusion (strong recommendation) are emphasized.
Concerning HFNO or non-invasive ventilation (NIV), the experts’ panel, points out that these approaches performed by systems with good interface fitting do not create widespread dispersion of exhaled air, and their use can be considered at low risk of airborne transmission. Practically, non-invasive techniques can be used in non-severe forms of respiratory failure. However, if the scenario does not improve or even worsen within a short period of time (1–2 hours) the mechanical ventilation must be preferred.
Individuals who are in the senior age groups i.e., 60+years and those who are immunocompromised are at significant risk. All health care workers & front liners should understand the presentation of the disease, workup, support care & prevention. Further, health professionals &front liners should be well aware of the precautions necessary to avoid the contraction and spread of the disease.