What do we know about #COVID19 to date - a #Tweetorial (disclaimer....I'm a surgeon...) #meded #medtwitter #coronavirusuk #coronavirus #CoronavirusUSA #covid #covid_19
I put these notes together really to help myself learn about this virus. It’s obviously only just some key points. I thought I might as well put them in this tweetorial as I’ve never done one before. All info is from peer-reviewed journals and can hopefully be digested by anyone.
COVID-19 is the name given to 'severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)' by the WHO on the 11th Feb. It is the 3rd Coronavirus (CoV) to cause a pandemic along with SARS CoV and MERS CoV. All 3 are 'zoonoses' – i.e. have crossed into humans from animals
As of the 17th April, there have been 2,176,164 positive cases, 145,304 deaths and 546,437 patients have recovered
Four CoVs - α, β, γ, δ have been identified so far, with human CoVs detected in the α and β genera. In late December 2019, patients presenting with cough, fever, and shortness of breath due to an unidentified infection were reported in Wuhan, China. They went on to develop ARDS.
Viral genomic sequencing of 5 patients revealed the presence of a previously unknown β-CoV strain in all of them. This isolated novel β-CoV shows 88% identity to the sequence of two bat-derived SARS-like CoVs, bat-SL-CoVZC45 and bat-SL-CoVZXC21, and 50% identity to MERS-CoV.
Similar to SARS-CoV, SARS-CoV-2 enters the body via the lungs and/or mucous membranes. The virus enters the cell using the ACE2 receptor and mutations, genetic recombination and natural selection have enabled SARS-CoV-2 to bind to the receptor more effectively than SARS-CoV.
There are 3 potential stages; 1-asymptomatic incubation period with or without detectable virus; 2-non-severe symptomatic period (some or all of cough, fever, myalgia, anosmia) with the presence of virus; 3 - severe respiratory symptomatic stage with high viral load
Symptoms can include fever, myalgia, headache, cough, SOB, tight chest, sore throat, anosmia, N&V, diarrhoea. Bacterial secondary infection is rare. 95% of patients will develop symptoms within 2-7 days, 97% within 5-14 – this is the reasoning behind a 14 day quarantine period.
Common lab findings include lymphopenia (reduced CD4+ and CD8+ T cells, 80% of patients), low platelets (severe thrombocytopenia is a poor prognostic sign), procalcitonin is usually normal, CRP is elevated and tracks severity and prognosis. D-dimer is usually elevated.
Stage 3, characterised by severe respiratory distress is similar to an ARDS-type picture - rapid deterioration and profound hypoxia. This appears to be an atypical ARDS with a dissociation between relatively well preserved lung mechanics and the severity of hypoxemia.
This clinical picture may be explained by histological findings which include bilateral diffuse alveolar damage with foci of haemorrhage & a lymphocytic infiltrate (CD4+ and CD8+).
Small vessels contain platelets and small fibrin thrombi. Megakaryocytes are seen actively producing platelets within alveolar capillaries. These findings raise the question of the need for anticoagulation and/or antiplatelet therapy.
Risk factors for ICU admission include age > 60, male sex, obesity, CV disease, DM & HTN. Raised troponins and NP are prognostic, especially with dynamic increases. Myocardial inflamm can result in myocarditis, HF, arrhythmias, ACS, rapid deterioration and sudden death.
Immune responses in SARS-CoV-2 are 2-phased - a specific adaptive immune response is required to eliminate the virus and prevent progression to clinical stage 3. Genetics and general health are important determinants of whether a patient will develop a protective immune response.
If a protective immune response is impaired and a patient progresses to stage 3, the virus propagates and destruction of tissues occur, especially in organs that have high ACE2 receptor expression (lungs, intestines, kidney).
A cytokine and chemokine storm (pro-inflammatory proteins) exacerbate the lung injury (mediated by pro-inflammatory macrophages and granulocytes). There is upregulation of pro-inflammatory cytokines in the blood, including interleukin (IL)-1, IL-6, TNF, and interferon γ
Major histocompatibility complex (MHC) are molecules that reside on the surface of different types of cells and present proteins that are part of a foreign entity (e.g. virus, bacteria) or as a result of its presence. These are then recognised by immune cells and dealt with.
The way in which this MHC system works is dictated by a series of genes called the Human Leukocyte Antigen complex (HLA). Like in transplantation or autoimmune conditions, a patient’s HLA type dictates their immune response and genetic susceptibility to contracting diseases.
It will be important to determine whether specific HLA genes are associated with the development of anti-SARS-CoV-2 immunity and identify the relevant alleles (class I or II) that demonstrate induction of protective immunity.
This phenomenon may explain differences in mortality rates between countries and will also determine how efficacious vaccination programmes will be.
Novel SARS-CoV-2 surface glycoproteins combine with the porphyrin within the haem molecule of haemoglobin in red blood cells to form a complex. At the same time transcribed non-structural proteins can attack the haem on the 1-beta chain of haemoglobin to dissociate the iron.
These processes lead to less haemoglobin to carry oxygen and carbon dioxide. This exacerbates respiratory distress. Diabetic patients and older people have higher levels of glycosylated haemoglobin, and if this is disrupted it causes unstable blood sugars.
Remdesivir is an investigational prodrug of an adenosine analogue that binds to RNA-dependent RNA polymerase and terminates the RNA chain. It displays potent in-vitro activity against SARS-CoV-2. There are 4 clinical trials currently recruiting in the US
Chloroquine, an antimalarial drug with anti-inflammatory and immunomodulatory properties, shows potent in vitro activity against SARS-CoV-2 (consistent with previous in vitro findings against SARS-CoV-1 and MERS-CoV), but not in animal models.
These findings support the clinical use of chloroquine but high quality evidence is lacking from clinical trials and dosing of chloroquine has not been validated. Supply issues and concerns regarding cardiovascular toxicity also limit its use.
Hydroxychloroquine, another antimalarial agent has also garnered interest and has been shown to be more potent against SARS-CoV-2 in in-vitro models. Clinically it has been shown to improve viral clearance but knowledge about clinical endpoints are lacking.
The data for corticosteroids are inconsistent, subject to bias and inconclusive. There will be a cohort of patients (e.g. cytokine-related lung injury) that may benefit from corticosteroid therapy but clinicians need to weigh the risks and benefits on an individual patient level
The take home message for all therapies is that so far, quality clinical evidence is lacking. Clinicians are encouraged to closely follow subsequent peer-reviewed publications because of the concerns raised by some over the discordance between in-vitro and in-vivo findings.
That’s enough for this Tweetorial, you’ll all be bored now. I think I will do another one soon that is transplant related and one for general surgery.
