Types of COVID-19 antibody tests

Hi everyone! 

In this post, I will go over in very short the different types of  COVID-19 antibody tests.

The Moderna Vaccine: End of Pandemic?

 

The Moderna (mRNA-1273) SARS-CoV-2 vaccine is the second vaccine to receive emergency use authorisation (EUA) by the FDA. Like the Pfizer vaccine, it is also a lipid nanoparticle encapsulated mRNA vaccine, and therefore has the same mechanism of action. Please read about the brief mechanism from the Pfizer vaccine article: https://www.medicowesome.com/2020/12/the-bnt162b2-covid-19-vaccine-pfizer.html I will try to avoid big numbers and statistics in this article. 

Both Moderna and Pfizer vaccines start protecting their recipients 10 days after the first dose, with maximum protection two weeks after the second dose. They both have efficacy ranging from 94-95% in protecting against symptomatic Covid-19. However, studies haven't yet evaluated their role in preventing asymptomatic Covid-19, a substantial missing link. 

Can Covid-19 vaccines mitigate the pandemic? 

People picture vaccines as a way back to normalcy, as before the pandemic; unless these mRNA vaccines' role in controlling asymptomatic SARS-CoV-2 infection is studied, normalcy is out of our reach. The other issues concerning the above question are -

1. Since the phase 3 studies of these vaccines are relatively 'young', we don't have sufficient knowledge about the nature and duration of immunological protection. Animal studies have shown that neutralizing antibodies confer protection and CD4 and CD8 T cells also amplify the immunological response. We don't know how long will the neutralizing antibodies last in our plasma after receiving the vaccine. 

2. With both these vaccines, there is an inevitable study flaw. Vaccine recipients faced more systemic adverse events, such as fever, fatigue, headache, myalgia than the placebo group. These symptoms can also occur with Covid-19. Therefore, it is not unlikely that vaccine recipients could have designated their symptoms to the 'shot', and hesitated to refer themselves to be tested for Covid-19.

3. The third issue is quite popular in the daily news. What if the virus mutates and renders itself 'immune' to the vaccine? Some new strains have come up worldwide, and expectedly, the diaspora has started panicking. People need answers quickly while science takes time. So we cannot rule out the possibility that the virus devises a way to escape from the vaccine-induced immunological response. 

4. Vaccine-associated enhanced disease (VAED). Earlier preclinical studies with SARS and MERS have demonstrated that low-level neutralizing antibodies in the plasma can trigger a severe form of the disease. Both the Moderna and Pfizer vaccines are 100% effective in protecting against severe Covid-19, notwithstanding this fact, the regulatory authorities should monitor these and other vaccine candidates for this adverse event. 

5. Anti-Vaxxers! The anti-vaccine sentiment is appalling, and there have been 'anti-vaccine' protests in many parts of the world, including the US, Germany, Poland, and others. There are numerous fake news and misinformation in social media platforms that misguide people and tarnish their perspective about the vaccines. And this phenomenon has even affected the medical professionals. The healthcare authorities have an onerous task to incite confidence in the general public and safeguard them from misinformation. 

Safety

The adverse effect profile of both the vaccines is similar, with the most common being local injection-site reactions. Systemic side effects are more common in the vaccine group and comprise mainly of fatigue and headache. Bell's palsy occurred in three (out of 15,210) vaccine recipients within 28 days of administration. This anecdotal risk would be studied in the planned two-year follow-up. 

Being a physician in the Indian subcontinent, there are various reasons to mistrust this vaccine. Both the mRNA vaccines have been studied primarily in the US population (mainly whites), and we don't have any data on its long-term effects. Recently, I have come across various tweets and posts in my social media feed with the headline - " Doctors and nurses are declining the vaccine." I am unaware of these posts' credibility; however, this isn't false in my experience. Well for what it's worth, we haven't seen a whole lot of polio, diphtheria or smallpox recently. 

Thanks for reading!

-VM

 

 

The BNT162b2 Covid-19 Vaccine: Pfizer-BioNTech Vaccine

 

The BNT162b2 mRNA Covid-19 vaccine, popularly known as the Pfizer vaccine is the first Covid-19 vaccine to receive authorization for use in the general public. The first jab was given to a 90-year old lady in the UK on December 8, 2020; a monumental event that brought hope to billions of people all across the globe. In this article, I will discuss this vaccine’s clinical trial and potential future implications.

 

How does it act?

The BNT162B2 is a lipid nanoparticle-formulated, nucleoside-modified mRNA that encodes the SARS-CoV-2 full-length spike protein, modified by two proline mutations to lock it in the prefusion conformation. This means that this is an mRNA that has been modified to resist disintegration by nucleases and that translates into the SARS-CoV-2 spike protein. However, this spike protein has also been modified to lock it into its pre-fusion conformation; so that it doesn’t fuse with the target cell’s plasma membrane and remain exposed to immunogenic stimulation.

 

Who is it for?

This primarily depends on the characteristics of the population included in the vaccine’s clinical trial. This trial randomised 43,458 persons from six countries: USA, Argentina, Brazil, South Africa, Germany, and Turkey. More than three-fourth of the study population (76.7%) belonged to the USA. Moving on to the representation of race or ethnicity in the study population - 82.9% were white, 27.9% were Hispanic, while African Americans, Asians, and Native Americans comprised 9.2%, 4.2%, and 0.5% of the study group. Males and females were almost equally included. The age range is from 16 years to 89 years in the intervention group. This trial did not evaluate the efficacy of the vaccine in children, adolescents, and pregnant women.  

 

Is it effective?

Define effective; it depends on the trial’s efficacy end points. The primary endpoint was the efficacy of the vaccine to prevent Covid-19 infection 7 days after the second dose in participants who had no serologic (antigen and antibodies) or virologic (RT-PCR) evidence of SARS-CoV-2 infection up to 7 days after the second dose; the second primary endpoint was to prevent infection in those with and without evidence of prior infection. Confirmed Covid-19 was defined as – the presence of at least one symptom (fever, new or worsened cough, new or worsened dyspnoea, chills, new or worsened muscle pain, new loss of taste or smell, sore throat, diarrhoea or vomiting combined with a positive RT-PCR test within 4 days).    

Efficacy End Point	BNT162b2 Group		Placebo Group		Vaccine efficacy, % (95% credible interval)
	Covid-19 Cases	N	Covid-19 Cases	N
1st Primary	8	18,198	162	18,325	95(90.3-97.6)
2nd Primary	9	19,965	169	20,172	94.6(89.9-97.3

 This trial showed that a two-dose regimen of BNT162b2 (30 micrograms per dose, given 21 days apart) was 95% effective in preventing symptomatic Covid-19 infection 7 days after its course. The efficacy was 52% after the first dose, and 91% in the first 7 days after the second dose.

However, the trial results did not show the efficacy in preventing asymptomatic infection. We don’t know if this vaccine can safeguard against transmissible asymptomatic infection; therefore, people who have taken the vaccine should not stop wearing masks for the sake of the people around them.

 

Is it safe?

The vaccine group reported more local reactions, such as pain, redness, and swelling at the injection site than the placebo group. In general, these were mild-to-moderate in severity and resolved within 1-2 days. The systemic adverse effects were also reported more in the intervention group, especially in the younger population (16 to 55 years of age), and more after the second dose. These included – fever (11%), fatigue (51%), headache (39%), chills (23%), muscle pain (29%), joint pain (19%), and 38% of the vaccine group needed to use antipyretic medication. These were generally mild and resolved within 1-2 days. Two deaths happened in the vaccine group, one from arteriosclerosis, and one from cardiac arrest. These deaths weren’t related to the vaccine or Covid-19. The investigators plan to continue the surveillance for adverse events for further 2 years.  

 

This study has importance beyond the efficacy of the BNT162b2 vaccine candidate. It demonstrates the utility of RNA-based vaccines, its speed of development, and its promising efficacy in preventing infectious diseases. The success of this clinical trial immensely improves our preparedness for a future pandemic.

Reference:

Polack, FP, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine. Dec 10, 2020. 10.1056/NEJMoa2034577. C4591001 Clinical Trial group

-Vinayak

COVID-19 Vaccine Development

The worldwide magnitude of the COVID-19 pandemic is ineffable; it is unsurprisingly compared to the Spanish flu pandemic, which ravaged the world during the First World War (adding fuel to the fire!). One of the pandemic's various positive impacts has been the unprecedented research collaboration and data sharing across the world. Such singular efforts made it possible to cut down the usual time to achieve an approved vaccine from 10⁺ years to less than a year.

To put things into perspective, it took 60 years from the time of the first polio outbreak to developing its vaccine; in the case of Ebola, it took 15 years. Vaccine candidates for SARS-CoV-1 and MERS did not receive the necessary impetus to advance into fruition. However, with SARS-CoV-2, the situation is very different. Global initiatives such as ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines), a public-private partnership comprising of bigwigs like CDC, FDA, EMA (European Medicines Agency), and numerous leading biopharmaceutical enterprises. Another project on a similar scale is Operation Warp Speed, which has invited comparison to the infamous Manhattan Project.

What is an "ideal" COVID-19 vaccine? There are three criteria from the immunological perspective: 1) It induces a robust humoral immune response that produces long-lasting neutralizing antibodies against SARS-CoV-2 antigens, 2) It generates a strong cell-mediated immunity that includes the production of memory T cells, 3) It should be free of any serious local or systemic adverse effects. Considering the logistics of vaccinating the entire world, there are three more criteria: 1) It should be easy to administer, preferably in one or two doses, 2) It should be easy to produce on a large-scale, 3) Its storage should be uncomplicated, ideally possible at room temperature.

 Source: Front. Pharmacol., 19 June 2020 | https://doi.org/10.3389/fphar.2020.00937

Let us discuss the vaccines that are currently in development. We all have heard about a few of them in the news and social media, namely, Pfizer, Moderna, Covaxin, Astra Zeneca, and so on. There are, impressively, 125⁺ SARS-CoV-2 vaccines in development globally. Broadly, there are six platforms currently being utilized for vaccine development –

1.   DNA

2.   mRNA (examples – Moderna, Pfizer)

3.   Protein (Subunit vaccines)

4.   Viral vector – replicating/non-replicating (examples - Oxford/Astra Zeneca, Johnson & Johnson)

5.   Live attenuated virus

6.   Inactivated virus

Almost all of the above models have targeted the spike glycoprotein, which is present on the surface of SARS-CoV-2, to interfere with the viral entry into a cell.

This article is an oversimplified summary of the vaccine development process. I haven't covered the vaccine platforms, molecular targets, and vaccine candidates in detail. With the advent of vaccine administration, whether it's Pfizer's or any other, there will be a massive surge in vaccine-related information. There will be challenges at every step, from distribution to underdeveloped areas of the world to alleviate the concerns of the skeptical anti-vaxxers. Let us hope that these vaccines start the end of the pandemic.

-Vinayak

About the Pfizer BioNTech COVID-19 Vaccine trial

Important things we know about the Pfizer BioNTech COVID-19 Vaccine

• From roughly 44000 participants, vaccine and placebo were administered 1:1 ratio, the vaccine participants demonstrated 95% efficacy in preventing COVID-19 in those without prior infection 7 days or more after the second dose.

• Partial protection from the vaccine candidate appeared as early as 12 days after the first dose.

• The vaccine has shown consistent results in people of different ages, races, BMI, and with various co-morbid conditions.

COVID-19 and the increased risk of Parkinson's disease

Hi!

Currently posted in psychiatry, I was reading articles on Parkinson's disease and came through this important finding in context with the coronavirus disease.

COVID-19 and Vasculopathy

Over the past few months, overwhelming evidence has accumulated suggesting the dysregulation of the coagulation pathways in COVID patients stemming from the altered immune and inflammatory response towards SARS-CoV2.

Observed coagulation abnormalities have multi-faceted pathogenesis. The most likely suspect is microvascular dysfunction secondary to cytokine storm-like state, tipping the balance towards thrombosis. Direct vascular injury is also likely with evidence of endothelial viral inclusions in some cases.

-Pulmonary Intravascular Thrombosis

Evidence suggests that starking discrepancy exists between hypoxemia onset and respiratory failure in COVID patients, with the former occurring fairly early in the disease course, pointing to the fact that it's not classic ARDS-like pathology that is responsible for the marked deterioration in the pulmonary gas exchange process. It is appropriately explained by the diffuse thrombosis affecting the pulmonary vasculature. In fact, it's so prominent that a whole new entity called "Pulmonary Intravascular Thrombosis" has been proposed as the framework for explaining this phenomenon.

Pulmonary Intravascular Thrombosis could be considered as lying along the spectrum of classic DIC with few important dissimilarities. It is usually localized to the pulmonary vascular bed at least initially and doesn't feature hypofibrinogenemia, consistent with the acute phase response driving continued fibrinogen production. D-dimers levels, however, are significantly elevated suggesting thrombus formation and ongoing hyperfibrinolysis.

-Pathogenesis

ACE2 is expressed in huge numbers on the alveolar epithelial cells, especially type 2 cells and also pulmonary endothelial cells. Hence, in contrast to patchy involvement classically seen in bronchopneumonia, in COVID, extensive involvement of the alveolo-capillary network is seen. This, in turn, results in florid interstitial inflammation resulting in efflux and activation of macrophages in the alveoli. It is so rampant that it has been likened to Macrophage Activation Syndrome (MAS) or sHLH like state. Activated epithelial cells and macrophages then orchestrate the cytokine storm leading to microvascular dysfunction and widespread thrombosis in the juxtaposed capillary network. Enhanced tissue factor and thrombin expression, coupled simultaneously with the reduced levels of PAI-1 drives thrombosis. Hypoxemia due to V/Q mismatch further exacerbates this process.

Levels of ACE2 in alveoli initially decrease as the virus particles are internalized. ACE2, by virtue of its ability to convert AngII to anti-inflammatory Ang1-7 peptide, keeps excessive inflammation in check. Hence, reduced ACE2 expression compounds the thrombotic propensity in the vascular bed. Direct involvement of endothelial cells by virus leading to endothelitis/vasculitis has also been suggested, although endothelial activation due to inflammatory cytokines seems more likely.

Reduced type 1 interferon signaling pathways are another intriguing possibility contributing to hyperinflammation. The role of positive pressure ventilation in forcing the viral particles and cytokines in vasculature also merits consideration.

- Skin manifestations

A variety of skin manifestations ranging from pseudo-chilblains to livedoid lesions have been described in COVID patients. While some of the lesions, like acral vesicles and pustules, confer to the pattern of viral exanthem, livedoid lesions suggest the possibility of vascular injury. These vasculopathy eruptions are known as "toevids", appearing as violaceous plaque-like eruptions over toes. Upon molecular testing, such patients often are negative, suggesting that they have probably cleared the infection and vascular injury is perhaps immune-mediated.
Interestingly, papular gloves and socks syndrome, occasionally seen in association with viral infections, especially Parvovirus, bears substantial similarity to certain COVID lesions, both clinically and histologically, with some reports even documenting evidence of leukocytoclastic vasculitis in the former.



-Clinical Relevance

Significant elevations in pulmonary pressures due to diffuse thrombosis strains the right ventricle causing hemodynamic dysfunction. Elevated D-dimer, pro- BNP, and troponin levels have been proven to be poor prognostic markers consistently across various studies. The development of an overt DIC-like state certainly portends a dismal prognosis.

Troponinemia in COVID can be attributed to severe right ventricular strain in the setting of pulmonary embolism and/or Pulmonary Intravascular Thrombosis. Some evidence also exists regarding the possibility of myocarditis, however, without classic lymphocytic infiltration characteristic of viral myocarditis.



To summarize, the intricate interplay of diffuse pulmonary intravascular thrombosis and MAS-like state drives the severe and often fatal pulmonary microvascular dysfunction in COVID.

SARS-CoV2 infection--> diffuse alveolar damage--> interstitial inflammation--> MAS like state--> massive activation of macrophages--> local inflammatory cytokine milieu--> Microvascular dysfunction--> Pulmonary  Intravascular Thrombosis

-Kirtan Patolia


Reference:

1.) https://doi.org/10.1016/S2665-9913(20)30121-1
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30121-1/fulltext

2.) https://doi.org/10.1111/bjd.19163
https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.19163

Authors' diary: No visitors policy during the COVID-19 pandemic

COVID-19: Whose Virus Is It Anyway? Possible origins of SARS-CoV-2

It's only reasonable you may want to know about the origins of the COVID-19 pandemic. After all, our lives have been affected, one way or the other. But was it the bat? Was it the pangolin? Or was it a lab experiment gone wrong? Let's look at the two most definitive evidence we have at hand: virus genomics and structure.

Evidence #1

The receptor binding domain (RBD) in the spike protein is the most variable part of the coronavirus family genome. SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, and other species with high receptor homology. This RBD has six key amino acid residues.

Evidence #2

The second notable feature of SARS-CoV-2 is a polybasic cleavage site at the junction of S1 and S2, the two subunits of the spike. This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity and host range. Insertion of proline to this site and subsequent addition of O-linked glycans are unique to SARS-CoV-2.

Keeping these in mind, we have:

Theory #1
Natural selection in animal before zoonotic transfer

As many early cases of COVID-19 were linked to the Huanan market in Wuhan, it is possible that an animal source was present at this location.

Given the similarity of SARS-CoV-2 to bat SARS-CoV-like coronaviruses, it is likely that bats serve as reservoir hosts for its progenitor. This "bat virus" or more formally, RaTG13 is nearly 96% identical to SARS-CoV-2. Its spike diverges in the RBD, which suggests that it may not bind efficiently to human ACE2. 

Malayan pangolins illegally imported into Guangdong province contain coronaviruses similar to SARS-CoV-2. Some "pangolin coronavirus" exhibit strong similarity to SARS-CoV-2 in the RBD, including all six key RBD residues. This clearly shows that the SARS-CoV-2 spike protein optimised for binding to human-like ACE2 is the result of natural selection.

Neither the bat nor the pangolin coronavirus, however, has polybasic cleavage sites. This means, no animal coronavirus has been identified that is sufficiently similar to be the direct progenitor of SARS-CoV-2. That said, the diversity of coronaviruses in bats and other species is massively undersampled. Mutations, insertions and deletions can occur near the S1–S2 junction of coronaviruses, which shows that the polybasic cleavage site can arise by a natural evolutionary process. This perfectly sets us up for our next theory.

Theory #2
Natural selection in human after zoonotic transfer

It is possible that a progenitor of SARS-CoV-2 jumped into humans to acquire the genomic features described above through adaptation, during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off.

All SARS-CoV-2 genomes sequenced so far have the genomic features described above and are thus derived from a common ancestor that had them too. The "pangolin coronavirus" has an RBD very similar to that of SARS-CoV-2, by the process of natural selection. From this, we can infer the same happened with the virus that jumped to humans. So we can say, with some degree of confidence, the insertion of polybasic cleavage site occured during human-to-human transmission.

From what we know the first case of COVID-19 has been traced back to November 2019. This presumes a period of unrecognised human-to-human transmission, between the initial zoonotic event and the acquisition of the polybasic cleavage site.

Theory #3
Lab experiment gone wrong

Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and animal models has been ongoing for many years in biosafety level 2 laboratories across the world, and there are documented instances of laboratory escapes of SARS-CoV. In theory, it is possible that SARS-CoV-2 acquired RBD mutations during adaptation to passage in cell culture.

Having said that, the "pangolin coronavirus" with nearly identical RBDs, provides a much stronger explanation of how SARS-CoV-2 acquired these via recombination or mutation. The high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2.

The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios. New polygenic cleavage sites have only been observed after prolonged in-vivo passage whereas generating O-linked glycans likely involves an immune system.

Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for coronaviruses would probably have been used. However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone.

These are strong arguments that SARS-CoV-2 is not the product of purposeful manipulation.

Conclusion
Theory #2 seems most likely, given the information currently available, but more scientific data could swing the balance of evidence to favour one hypothesis over another. What's important is to further study the possible origins, not just for understanding the current zoonotic pandemic but also to prevent the potential future ones.

References
1. 'The proximal origin of SARS-CoV-2' by Andersen et al: www.nature.com/articles/s41591-020-0820-9
2. 'A pneumonia outbreak associated with a new coronavirus of probable bat origin' by Zhou et al: www.nature.com/articles/s41586-020-2012-7
3. 'A new coronavirus associated with human respiratory disease in China' by Wu et al: www.nature.com/articles/s41586-020-2008-3

- Ashish Singh

COVID-19: effects on reproduction

Hello

In this post, I will be talking about effects of SARS-CoV-2 on the male reproductive system, as evidenced from a recent study.

COVID-19: Whatsapp group

I created a COVID-19 Whatsapp group to strictly discuss the medical aspect of the disease, the latest research/community practices. Email me if interested: medicowesome@gmail.com

-IkaN

COVID-19: Neurological manifestations

Since the Chinese health authorities confirmed the first case of novel coronavirus infection, almost all of the clinical focus has been on the viral's prodromal symptoms and severe life-threatening adverse effects such as ARDS. However, neurologists all over the world have been reporting the neurological manifestations of COVID-19 such as, ataxia, encephalopathy, myelitis among others. One neurological symptom in particular received inordinate attention, anosmia, even though it barely has any diagnostic relevance. It is safe to say that the neurological deficits are ongoing in this pandemic without getting noticed appropriately. However, since we are in the early phases of understanding the clinical conundrum of the COVID-19, such relative blindness is expected.

How does SARS-CoV-2 enter the CNS?

Two pathways have been postulated:
1. Through the cribriform plate
2. Systemic circulatory dissemination after infecting the lungs.

Reported neurological manifestations:

1. Anosmia - Can be explained by the proximity of the olfactory bulb to the cribriform plate
2. Hypoguesia, dysguesia
3. Headache, malaise
4. Unstable walking or ataxia, dizziness
These four can occur in the early phase of the disease.

5. Cerebral hemorrhage - This has been hypothesized to be due to decrease in expression and function of ACE2 proteins, especially in hypertensive patients in whom the expression of ACE2 is already low. Given that ACE2 signaling lowers BP, lack of ACE2 function would lead to higher BP which might precipitate cerebral hemorrhage.
6. Cerebral infarction (acute cerebrovascular disease causing stroke)
7. Ondine's curse - The central respiratory centres lose their function, which consequently impairs involuntary respiration severely.
8. Acute encephalopathy - headache, altered mental status, convulsions.
9. Myopathy

Interestingly, the CSF in the patients were normal, which implies that COVID-19 does not cross the blood brain barrier and hence cannot cause meningitis or encephalitis. We should keep in mind that the neurological manifestations could be secondary to hypoxia, respiratory or metabolic acidosis and other complications of the COVID-19 infection.

Thank you!

-Vinayak

References:

1. Necrotizing Encephalopathy: CT and MRI Features

https://pubs.rsna.org/doi/10.1148/radiol.2020201187

2. Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy

https://www.cureus.com/articles/29414-neurological-complications-of-coronavirus-disease-covid-19-encephalopathy

3. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study

https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1

COVID-19: Lymphopenia and pneumonia

Hello everyone!

In the context of COVID-19, we will talk about two specific terms: Lymphopenia and Pneumonia.

COVID-19 Pneumonia
We mention "pneumonia" when there is an acute inflammation of the lungs following an infection. Pneumonia is one of the common features in infected patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pneumonia has various clinical and radiological characteristics depending on the stage of the disease. It evolves rapidly, even in asymptomatic patients from local unilateral to diffuse bilateral ground-grass opacities which progress within 1-3 weeks to consolidation or co-exists with. A retrospective study at Wuhan describes radiological findings from 81 patients with COVID-19 pneumonia. The predominant pattern of abnormality observed was bilateral (79%), peripheral (54%), ill-defined (81%) and ground-glass opacification (65%), mainly involving the right lower lobes. [1]

COVID-19: Use of masks

Hi everyone!

We used the WHO guidelines to write the pdf and uploaded it over here

COVID 19: How to limit the spread?

COVID19 spreads primarily through droplets of saliva or discharge from the nose when an infected patient coughs or sneezes (we should so cough or sneeze into a tissue or flexed elbow). The SARS-CoV-2 can also be carried, that's why the handwashing is so important.

We use other means of prevention to limit the spreading, for example, masks and negative pressure rooms. Let us see how it is done.

COVID-19: Containment strategy by South Korea

Hello everyone!

In this post, we will discuss the manner with which South Korea managed to contain the virus rather successfully.

So let me help you catch up:-

COVID-19: SARI treatment facility design

Hi everyone,

One of our guest authors, Tanay Saxena, recently completed a course on Severe Acute Respiratory Infections Treatment Centre. He compiled a very thorough set of notes during the course based on the WHO Severe Acute Respiratory Infections Treatment Centre practical manual that has been developed for the COVID-19 pandemic.

COVID-19: Trained immunity from BCG vaccine

Would BCG vaccination really help in immunizing up against SARS-CoV-2?

Let's dig in. 

BCG is a live-attenuated strain derived from an isolate of Mycobacterium bovis used widely across the world as a vaccine for tuberculosis (TB). But that's not all, BCG vaccination is a potential goldmine against so many diseases.

COVID-19: Hydroxychloroquine mechanism and role in management of SARS-CoV-2 infection

Hello everyone, this post aims to highlight all the important aspects of the recently famous drug hydroxychloroquine in the management of COVID-19.

Mechanism of action: In a study by Aartjan et al, zinc ions (Zn2+) in high intracellular concentrations have been shown to inhibit viral RNA polymerase. However, zinc being an ion cannot enter the cell through the plasma membrane, so it needs ionophores such as pyrithione (PT) to enter the cell, where, in high concentrations, it can efficiently impair the replication of a variety of RNA viruses. Chloroquine can also act as an ionophore that can increase zinc ions transport into the cell.
According to Harrison’s principles of internal medicine, “Infection of tissue culture cells by viruses such as Semliki Forest virus, vesicular stomatitis virus, and certain strains of influenza virus can be prevented by chloroquine, an agent that blocks the function of lysosomes. Chloroquine is a weak base that diffuses into lysosomes and becomes protonated, raiding the pH and ionic strength of the lysosome. When the pH rises, the lysosomal enzymes fail to function. Viruses that require acid pH to fuse with cell membranes can no longer do so in the presence of chloroquine, and the cells are protected from infection.”

Studies revealed that it also has potential broad-spectrum antiviral activities by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. The anti-viral and anti-inflammatory activities of chloroquine may account for its potent efficacy in treating patients with COVID-19 pneumonia.

Chloroquine can also prevent orf1ab, ORF3a, and ORF10 from attacking the heme to form the porphyrin and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieving the symptoms of respiratory distress. The infectivity of the nCoV pneumonia was not completely prevented by the drugs, because the binding of E2 glycoprotein and porphyrin was not inhibited. You can read more about this on our previous post on: Coronavirus and hemoglobin https://www.medicowesome.com/2020/04/covid-19-coronavirus-and-hemoglobin.html

Current place in the management of COVID-19

1. In India, ICMR has recommended this drug for prophylaxis to healthcare workers dealing with infected patients and asymptomatic contacts of infected people at a dose of 400 mg per week. Besides AIIMS(New Delhi) has recommended this drug for the treatment of moderate to severe cases who are admitted in the hospital at a dose of 400 mg BD for 1 day which is followed by 200 mg BD for 5 days.

2. Chen et al in an unpublished RCT of 30 patients did not find HCQ provided benefit. The study suggests that if it has an impact, it is likely small. 

3. Gautret et al in a non-RCT of 36 patients suggested that HCQ reduced the duration of viral shedding in infected patients. 6 patients in a post-hoc analysis who received HCQ in combination with azithromycin showed further reduction in the viral carriage. However, this was not statistically significant and groups were not well balanced at baseline. 

4.  Chen et al in a double-blind RCT of 62 patients showed that HCQ can significantly shorten the time to clinical recovery and promote the absorption of pneumonia among patients with COVID-19. However, this study has not yet been certified by peer review. 

5. The Marseille study, an unblinded, non-randomized study of 26 infected patients showed a significant reduction in viral load with HCQ. And the number of positive cases was spectacularly reduced by the combination of HCQ with azithromycin. However, this study was full of flaws, there wasn’t adequate matching between the two groups, there were 6 dropouts who weren’t accounted in the study, patients in the control group didn’t have uniform testing, and the patients in the HCQ group had more severe symptoms and were further along in their clinical course. Apparently, this was the study, based on which President Trump promoted the use of HCQ!

6. The patients taking HCQ should be closely monitored for toxicity, in particular, QT prolongation; especially if it is used with azithromycin. Combining lopinavir/ritonavir with HCQ or chloroquine can cause serious arrhythmias and drug interactions due to the increased QT interval. 

Effect of the pandemic on drug supplies for Rheumatology patients

Hydroxychloroquine has been in use since the 1940s for the treatment of rheumatological conditions such as RA, SLE, and Sjögren’s syndrome. The sudden interest in this drug has led to shortages for patients who rely on it for the treatment of their autoimmune conditions. The Lupus Foundation of America has called on drug manufacturers to increase the production of HCQ, in order to ensure that patients with SLE are still able to access it without much difficulty.

Overall, no agent has proven efficacy for COVID-19. A number of approaches are being investigated based on in vitro or extrapolated evidence, including remdesivir, hydroxychloroquine, chloroquine, interleukin-6 pathway inhibitors, and convalescent plasma. When treatment of COVID-19 is being considered, patients should be referred to a clinical trial whenever possible. A registry of international clinical trials can be found at clinicaltrials.gov. 

Thank you! :) 

-Vinayak

References:

1. CHEN J. ,LIU D. et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci), 2020, 49(1): 0-0.
2. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. [PMID:32205204]
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5.te Velthuis AJ, et al. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS
Pathog. 2010 Nov 4;6(11):e1001176. doi: 10.1371/journal.ppat.1001176. PubMed
PMID: 21079686; PubMed Central PMCID: PMC2973827.

COVID-19: Coronavirus and hemoglobin

Hello Awesomites!

Please refer to the diagrams for better understanding.

Why do we have abnormal hemoglobin-related biochemical indices in COVID-19 patients?
Reports demonstrate that the hemoglobin and neutrophil counts decrease in most patients with SARS-CoV-2 infection, and values of serum ferritin, erythrocyte sedimentation rate, C-reactive protein, albumin, and lactate dehydrogenase increase significantly.

What makes hemoglobin an attractive molecule for the coronavirus?
Porphyrins!

Porphyrins in the human body are mostly iron porphyrins i.e heme. And a lot of heme is not free, but bound to hemoglobin. Viruses require porphyrins to survive. Therefore, the novel coronavirus targets hemoglobin, attacks heme, and hunts porphyrins.

Structure of SARS-CoV-2

Image by Upasana Yadav

The possible mechanism is that orf1ab bound to the alpha chain and attacks the beta chain, causing conformational changes in the alpha and beta chains; ORF3 attacks the beta chain and exposes heme. ORF10 then quickly attaches to the beta chain and directly impacts the iron atoms on the heme of the beta chain. The heme is dissociated into porphyrin, and orf1ab finally captures porphyrin. Orf1ab plays a vital role throughout the attack. Attack of oxidized hemoglobin by viral proteins leads to less and less hemoglobin that can carry oxygen. The invasion of viral proteins on deoxidized hemoglobin will cause less and less hemoglobin that can carry carbon dioxide.

This study found that ORF8 and surface glycoprotein had a function to combine with porphyrin to form a complex, while orf1ab, ORF10, ORF3a coordinately attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. This mechanism of the virus inhibited the normal metabolic pathway of heme, and made people show symptoms of the disease.

What causes the high infectivity of the novel coronavirus?
Medical workers have detected the novel coronavirus from urine, saliva, feces, and blood. The virus can also live in body fluids. In such media, porphyrin is a prevalent substance. At the beginning of life, virus molecules with porphyrins directly move into the original membrane structure by porphyrin permeability. This study showed that the E2 glycoprotein and Envelope protein of the novel coronavirus could bind well to porphyrins. Therefore, the coronavirus may also directly penetrate the human cell membrane through porphyrin. (Means If the virus can bind with porphyrins, it can enter these secretory cells without ACE2 receptors by using the membrane permeability)

What is the importance of knowing the above information?
The drugs based on this mechanism: Chloroquine and Favipiravir.

The primary function of the Envelope protein is to help the virus enter host cells. The primary role of Favipiravir is to prevent the virus from entering host cells and catching free porphyrins. Favipiravir's ability to improve respiratory distress is lower. Favipiravir can only prevent the binding of Envelope protein and porphyrin.

Chloroquine could prevent orf1ab, ORF3a, and ORF10 from attacking the heme to form the porphyrin and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress.

The infectivity of the nCoV pneumonia was not completely prevented by the drugs, because the binding of E2 glycoprotein and porphyrin was not inhibited.

Note for Diabetic patients
Diabetic patients and older people have higher glycated hemoglobin. Glycated hemoglobin was reduced by the attack, which made patients' blood sugar unstable. Since the porphyrin complexes of the virus produced in the human body inhibited the heme anabolic pathway.
Written by Upasana Yadav
(Courtesy:-Thank you Ikan for all the help) 

References:
1. Wenzhong, liu; hualan, Li (2020): COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.11938173.v5
Link to the article: https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173