Medicowesome urges you to take the SARS-CoV-2 virus seriously and to stay safe during the COVID-19 pandemic.



Saturday, April 4, 2020

How to cite articles

Hi everyone,

I wanted to write a quick post on how to cite references for Medicowesome Student Guest Authors (MSGAites!). Medicowesome is not a peer-reviewed journal, we are just a website where we post mnemonics, study material, and cool facts. Recently, we've been writing about COVID-19. Because there has been so much fake news and miscommunication about the characteristics of this disease, we decided that all posts related to COVID-19 would have journal articles in literature as references.

There are many styles in which you can format references. You can read more about it in this paper by Kambhampati & Maini, 2019. [1] It is preferred that you use a particular formatting style for all the references in your article. Simply adding links is not preferred because websites change their links all the time. The best way to ensure that your reader finds the article you're referencing is by using a proper reference format. A DOI is guaranteed never to change, so you can use it as a permanent link to any electronic article.

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.

Friday, April 3, 2020

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]
3. 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. [PMID:32020029]
4. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Zhaowei Chen, Jijia Hu, et al. medRxiv 2020.03.22.20040758; doi: https://doi.org/10.1101/2020.03.22.20040758
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 the index 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, they cause a wide range of infection and disease.

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

COVID-19 and Pregnancy: Should Mothers Be Concerned?

Pregnancy is a special phase in a woman’s life, more so because of the various changes which her body undergoes during these 9 months. Perhaps that is why, the concern about the threat of the novel coronavirus is valid- after all pregnancy is a state of slight immunocompromise, and also because there are two lives at stake. WHO declared the COVID-19 outbreak a pandemic on March 11, 2020. Most countries have taken stringent measures to control the spread of this disease, but do pregnant women need to take more measures? So, avid obstetricians out there, let’s find out deeply about the connection between these two:

WHO’s official stand is that there is no higher risk in pregnancy of severe illness BUT because there are trials underway and due to the bodily changes in pregnancy, one can not know the extent of COVID-19 in these patients. [1] Due to the evolving crisis, we are seeing newer studies every day with new results. A study conducted in early February on 38 pregnant women showed that it did not lead to maternal deaths, and neither were there any confirmed cases of intrauterine transmissions, with rt-PCR being negative in all the neonatal specimens tested, hence leading to the belief that there is no intrauterine or transplacental transmission. [2] Even the CT scans done on pregnant women with COVID-19 positive samples, did not show major changes and recovered from pneumonia adequately. [3]

Thursday, April 2, 2020

Lysosomal storage diseases mnemonic


COVID-19 : Impact on Cardiovascular system

Coronaviruses can have a dramatic impact on the myocardial functioning and hemodynamics as exemplified by the steep mortality patterns observed in patients with cardiovascular comorbidities.

COVID-19 AND ACUTE CARDIAC INJURY

ACE2 might be the cause of acute myocardial injury caused by SARS-CoV-2 infection. ACE2 is widely expressed not only in the lungs but also in the cardiovascular system and, therefore, ACE2-related signaling pathways might also have a role in heart injury. Other proposed mechanisms of myocardial injury include a cytokine storm triggered by an imbalanced response by type 1 and type 2 T helper cells, and respiratory dysfunction and hypoxemia caused by COVID-19, resulting in damage to myocardial cells. Furthermore, fulminant lung injury associated with the infection can potentially worsen right ventricular functioning and even trigger cardiac arrest.

COVID-19: Case fatality rate in Italy

Hello everyone, this post explains the factors behind the higher case fatality rate in Italy compared to the other COVID-19 infected countries.

As of today, there are 937,941 coronavirus cases in the world with 47,273 deaths; that comes down to a mortality rate of around 5%. On the other hand, China, the former epicenter of the disease has a COVID-19 case fatality rate of approximately 4%; while Italy has a much higher rate of 11.897%.

COVID-19: Vaccines under development

COVID-19 pandemic has led researchers around the world to work on developing a safe and effective vaccine. At present, there are 5 agents which are being extensively tested as potential vaccines. Here is some information about them.
1. mRNA- 1273 

Trial: Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis SARS CoV-2 Infection
   
- novel lipid nanoparticle encapsulated mRNA based vaccine that encodes for spike protein of SARS-CoV-2
- an open-label phase I dose-ranging clinical trial in the United States
- Study Population: 45 healthy people, males and non-pregnant women aged 18-55
    - enrolled in one of three cohorts - 25mcg, 100mcg, 250mcg
    - IM injection of the vaccine on Day 1 and 29 in deltoid
    - Follow up: 1,2,4 weeks post each vaccination, 3,6,12 months post second vaccine

- Objective
    - To evaluate the safety and reactogenicity of a 2-dose vaccination schedule of mRNA-1273, given 28 days apart, across 3 dosages in healthy adults 
    - To evaluate the immunogenicity as measured by Immunoglobulin G (IgG) enzyme-linked immunosorbent assay ELISA to the SARS-CoV-2 S (spike) protein following a 2-dose vaccination schedule of mRNA-1273 at Day 57

2. BCG Vaccine

BCG vaccine — developed for Tuberculosis. It has favorable in vitro or in vivo effect against RSV, Yellow fever, HSV, HPV. The hypothesis is that it may induce partial protection against the susceptibility to and/or severity of SARS-CoV-2 infection

Trial 1: BCG-CORONA reducing health care workers absenteeism in SARS-CoV-2 pandemic through Bacillus Calmette-Guérin vaccination, a randomized controlled trial (BCG-CORONA)

- RCT in the Netherlands 

- Study population: 1000 Health care workers with direct COVID-infected patient      
  contact
- Study duration: 6 months
- Objective: 
    - To reduce absenteeism among HCW with direct patient contacts during the epidemic phase of COVID19
    - To reduce hospital admission, ICU admission or death in HCW with direct patient contacts during the epidemic phase of COVID19

Trial 2: BRACE - BCG Vaccination to Reduce the Impact of COVID-19 in Australian Healthcare Workers Following Coronavirus Exposure (BRACE) Trial

- Open-label two group phase III RCT in Australia

- Study population: 4170 Healthcare workers
- Study duration: 12 months
- Objective:
    - COVID 19 disease incidence over 6 months, by 12 months
    - severe COVID 19 disease incidence over 6 months, by 12 months


3. Synthetic Minigene Vaccine

Artificial antigen-presenting cell Vaccine - a synthetic minigene that has been engineered based on conserved domains of the viral structural proteins and a polyprotein protease. The vaccine will be produced using a vector system to express viral proteins and immune modulators genes to modify artificial antigen-presenting cells (APC) and to activate T cells


Trial 1: Safety and Immunity of COVID-19 aAPC Vaccine

- Open-label phase I study in China

- Study population: 100 participants aged 6months to 80 years
- Objective: 
    - Injection of COVID-19/aAPC vaccine to volunteers to evaluate the safety
- To evaluate the anti- COVID-19 reactivity of the COVID-19/aAPC vaccine

Trial 2: Phase I/II Multicenter Trial of Lentiviral Minigene Vaccine (LV-SMENP) of COVID-19 Coronavirus

- Open-label Phase I/II study in China

-Study population: 100 participants aged 6months to 80 years
- Objective:
    - Injection and infusion of LV-SMENP DC and antigen-specific cytotoxic T cell vaccines to  
healthy volunteers and COVID-19 infected patients to evaluate the safety
- To evaluate the anti- COVID-19 efficacy of the LV-SMENP DC and antigen-specific  
cytotoxic T cell vaccines

4. ChAdOx1 nCoV-19 Vaccine

Trial: A Phase I/II Study to Determine Efficacy, Safety, and Immunogenicity of the Candidate Coronavirus Disease (COVID-19) Vaccine ChAdOx1 nCoV-19 in UK Healthy Adult Volunteers

- Single-blinded, Randomized Phase I/II study in UK
-Study population: 510 participants aged 18 to 55 years
- Objective: 
    - To assess efficacy of the candidate ChAdOx1 nCoV-19 against COVID-19
    - To assess safety of the candidate ChAdOx1 nCoV


5. Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector)

Trial: A Single-center,Open-label,Dose-escalating Phase I Clinical Trial to Evaluate Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector) in Healthy Adults Aged 18-60 Years Old

- Open label, dose-escalating Phase I study in China
-Study population: 108 participants aged 18 to 60 years
- Objective:
    - To evaluate the safety, reactogenicity and immunogenicity of Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector)

Written by Devi Bavishi
Reference: clincialtrials.gov

COVID-19: App based clinical trials

Let’s see how scientists are using app technology to generate data for research on COVID-19.

Wednesday, April 1, 2020

COVID-19: Lessons from coronavirus outbreak in China and formulating a strategy

Hello awesomites!

The following information is regarding the situation of COVID19 in China and how did China manage to reduce the incidence of new cases.


Image by  Nakeya. Medicowesome 2020

Tuesday, March 31, 2020

COVID-19: Was SARS-CoV-2 genetically engineered for biological warfare?

An article published in Nature Medicine noted that it is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. This article disproves most conspiracy theories about the artificial origin of the SARS-CoV-2 virus.

I am going to try to explain what the article says in simplified terms but you need to have some background in biochemistry to understand what it says. Let's begin!