Herd Immunity

Let’s talk about antibody testing and herd immunity

Within 1 to 3 weeks after active infection with COVID-19, two types of antibodies start to appear. They are the IgM and IgG antibodies. IgG antibodies generally reflect permanent immunity against a virus. Because we don’t know exactly the accuracy of our current tests, on an individual basis, the value of antibody testing is questioned.

The CDC discourages people from obtaining the antibody test and presuming that they are immune if they test positive for the antibody. Hopefully with further testing will be able to reliably assess the sensitivity and specificity of the antibody test and use it on an individual basis. I’m optimistic that it will be so. This is based on some good news. The good news is that with the SARS virus which presented itself in 2002, patients who did develop IgG antibody had long-term immunity and no evidence of re-infection. And the two viruses acts very similarly to each other. Therefore it is likely that the Covid -19 antibody will provide immunity.
Until we have absolute and better data on the reliability of the antibody testing, the test is being used by centers for disease control for understanding what is described as herd immunity. So while on an individual basis the test may not be very useful, it will be useful in a population.

To understand herd immunity, you have to understand a factor called R(0) which is the transmissibility factor. It asks the question: how many people can one affected patient infect? Data seems to suggest that the number is 2 to 3. In comparison influenza’s R(0) is about 1.5.

To develop herd immunity, the number of people that have to be positive for the antibody is 1-1/R(0).
If R=2 then 1-1/2= 50% So 50% of the population needs to have the antibody for the infection to stabilize.
If R=3 then 1-1/3=67% So 67% of the population needs to have the antibody for herd immunity.

At the present, In New York City which is the most affected city in US, there is 15% positivity for the antibody. Other cities are much lower Therefore we have not received any level of herd immunity.
It Is therefore very important to continue to follow measures of handwashing, wearing a mask and keeping the social distancing. We are all hoping that we will reach herd immunity when the vaccine is out. Or at least when we have treatment options that reduce the patients’ mortality. Until then get out but be safe. And make sure that others are safe from you. This is called social responsibility.

COVID-19 and the Human Immune Response

COVID-19 and the human immune response

In order to understand how Sars-Cov-2 escapes the initial powerful immune defense we must first review the components of the human immune system. My colleagues and I seriously regret sleeping through the ‘boring’ immunology lectures in medical school. It has come back to haunt us. ( To all my colleagues in healthcare, click “thumbs up” if you are guilty as charged). ☺️
Sorry for the digression. The human immune system has two major components namely innate and acquired immunity. Innate immunity refers to the initial barriers mounted by the body which includes physical barriers such as skin, mucus membranes and alike that tries to ward off the germ. Think about how you feel when you catch a cold. Within 1-2 days of getting exposed to another person with a cold, you start feeling a runny nose, runny eyes, sore throat, and maybe a little bit of sinus drainage and maybe a wet cough. Your body is trying to prevent the virus from getting in the respiratory tract. You cant go through enough tissues and you feel a little miserable. After that initial attempt to block the virus by shedding it in your secretions, inevitably some virus gets into the systemic circulation and internalizes in the upper respiratory tract.

At that point, your body recognizes that it must signal your cytotoxic T cells and T helper cells to recognize that there is a foreign object ( called an antigen). The cells release chemokines and cytokines that are messenger proteins that alert those T cells to ‘phagocytize’ the virus, that is like Pac-man eating the bad guys ( remember that game?). T cells which are stored in the thymus gland are nondiscriminatory and eat anything foreign to them .

By the way the chemokine and cytokine proteins give you the fever and mild aches and pains and lack of appetite and your taste for a hearty soup.
In the interim more cytokines and chemokines alert the B cells coming from the bone marrow. B cells are part of the acquired immunity. We have millions of B cells each with a specific type of surface protein. One of these surface proteins will match the virus and attach to it. Once that happens the specific B cell proliferates into millions. Those memory B cells and plasma cells then neutralize the virus but stick around ready for the next time the virus dares enter the body. That is when the host starts getting better. It is important to mention that woman have a stronger innate immunity than men which may be one reason why the mortality is lower in women than men with COVID-19. Children also have very powerful innate immunity. Remember our babies with their runny noses.

Now we come to COVID-19. Sars-Cov-2’s incubation period is about 5 days. That means the host carries the virus for 5 days before exhibiting any symptoms. The virus completely escapes detection by the innate immune response. No runny nose or runny eyes, no sinus drainage, no productive cough. The human host doesn’t shed the virus through secretions. No tissues. This allows for a high viral load to get into the lower respiratory tract.

Then insidiously the viral spike proteins binds the ACE-2 receptor of the cells of the lung and gains entry into cell where it replicates into millions. Then the viral army in its full maniacal might exits the cell and enters the circulation.

It is only then that the dormant soldiers recognize the gravity of the situation and in a frenzy starts producing chemokines and cytokines to alert those T cells and B cells to act. But the response is dramatic and uncoordinated resulting in a cytokine storm resulting in production of large amount of inflammatory and clot producing molecules that devastate the invaded tissues and cause secondary effects. The result is severe inflammation of the lungs into what is termed acute respiratory distress syndrome and production of clots. This is why the host goes from feeling ok to extremely sick in a matter of 1-2 days while harboring the virus quietly for 5 days. We are seeing pulmonary embolism, stroke, heart attacks as a result of this immune system gone wild.

The treatment of COVID-19 has to be tailored towards antiviral agents but also towards agents that suppress the powerful inappropriate cytokine storm.

What is fascinating about this is that COVID-19 has made us realized the powerful intersection of immunology, cardiology, cancer medicine and infectious disease all secondary to cytokines.

 

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Drugs for treatment of COVID-19

Drugs: Remdesivir, Camostat and Recombinant Human TMPRSS2 Protein

In the last post, I described the genetic machinery of human cells and that of COVID-19 . Recall that Sars-Cov-2 is a single stranded ‘positive’ sense virus which means it has an RNA polymerase enzyme that helps it replicate inside the cell. The virus has a spike protein that binds the ACE-2 receptor of human lung cells. Now, one more fact you should know is that there is a protein called TMPRSS2 which facilitates that binding.

So now if you are a scientist trying to block this virus, you have three targets to work on. The first is the viral RNA polymerase. That is where the drug Remdesivir comes into play. The drug Remdesivir is a inhibitor of RNA polymerase. A randomized double blind placebo controlled trial published in New England Journal of Medicine this may described a study of 1000 hospitalized patients half of whom received the drug. Remdesivir was superior to placebo in shortening the time to recovery regardless of age, sex, race, and comorbid conditions such as diabetes or hypertension. Mortality was numerically lower in the Remdesivir group but because the number of patients were small it did not reach statistical significance ( 7% vs 11%).

The human TMPRSS2 which helps the virus enter the cell is also a target for treatment. The drug Camostat is a TMPRSS2 inhibitor and currently being studied. It was successful in animal models. Scientists have also made a recombinant human TMPRSS2 protein that can act as a dummy particle and fool the virus to bind it in lieu of the real protein. Both have been successful in animals trial and currently being studied. You can visit clinicaltrials.gov and search the names of the drugs and see the ongoing trials.
I promised to tell you how the virus escapes detection of our immune system.

The science of viral replication (COVID-19)

The science of Viral Replication (COVID-19)
Please bear with me on this section. Read patiently for a full grasp because it will help you understand the rationale for specific drugs being tested.
To understand viral replication, you must understand human cell division and replication first. Human cells have a nucleus where double stranded DNA material is stored in the form of ladder like sophisticated tangles called chromosomes. For cell division and replication to occur, DNA has to be ‘transcribed’ into double stranded RNA and then ‘translated’ into amino acids which assemble to form proteins. These proteins are the workhorse of our body. They form the structural backbone of the cells; they become receptors; they are engaged in metabolism, and in body defense, and all that makes us go.
Any organism including a virus that wants to invade a human body must be able to exploit the machinery of the human cell assembly line for its own reproduction.
COVID-19 is a single stranded positive sense RNA virus. Most viruses are RNA viruses. So to embed themselves in human cells, they have to be able to enter human cells, then fool the human cell machinery to translate their own RNA to form viral proteins called virions. The virions assemble to become billions of newly formed viruses.
Being single stranded ‘positive’ sense, the SARs- Cov-2 virus has its own RNA polymerase enzyme which reduces it’s dependence on human RNA polymerase to make mRNA. So once inside the human cell, the initial step in replication of the virus is already easier for the Sars-cov-2 virus. But it must pass a few hurdles to enter the cell first. The virus must have the right surface protein and bind to a specific receptor on the human cell. In the case of Sars-Cov-2 the spike protein binds to the ACE-2 receptor of the alveolar cells of the lung.
To do all this, the virus must first be able to also escape detection by the powerful defense system of the body. And unfortunately, it can.
Stay tuned for the next chapter of how it achieves that feat . More to come. Promise it is very interesting.

The World Health Organization’s initial response to COVID-19

The World Health Organization’s response , I wonder what was going on in their minds?
On January 22 and 23 The meeting of the Emergency Committee convened by the WHO Director-General under the International Health Regulations (IHR) (2005). The topic was corona virus in the People Republic of China with exportations reported in Republic of Korea, Japan, Thailand and Singapore.
The committee report is available online but there is no mention of what the exportations to these countries mean. The public report mentioned 577 cases with a death rate of 4% in China in Wuhan and outside of Wuhan and in the Hubei province but again no mention of disease statistics about the concerned countries in attendance. The Chinese government reported closure of public transportation systems as a measure of strong containment.
In a bizarre statement, the committee reported that it could not decide if this constituted a Public Health Emergency of International Concern (PHEIC) given its ‘restrictive and binary nature’. There is no clear explanation to the term ‘restrictive and binary’ as to the justification to their decision. The committee praised the Chinese for their containment efforts and decided to hold off and reconvene a week later.
Finally, a week later, on January 30, The World Health Organization declared a Public Health Emergency of International Concern (PHEIC) . By then the number of cases in China were reported at 10,000 with 200 deaths. In one month the number had nearly exceeded all the SARS and MERS cases of the world since 2002 and 2012 respectively.
A week after the PHEIC declaration by WHO , the young doctor Li Wenliang who had hopelessly sounded the alarm on the disease in December loses his life to COVID-19 becoming the first health care provider casualty of thousands more to come.
Keep reading and sharing. Come back for more tomorrow. Learn the science.

More about the historical course of COVID-19

More about historical course of COVID-19
By December 31, 2019, the cases of pneumonia from this mysterious virus had grown to 27. And by January 11, 2020, the number was revised to 41. All along it was speculated that the origin of the virus was the seafood market in spite of no clear cut evidence.
There was no consideration of a human to human transmission until January 24 when a publication coming out of the University of Hong-Kong Shenzhen Hospital 500 miles away from Wuhan reported the presentation of 6 members of a family who had travelled to Wuhan two-three weeks prior to their admission. The family had not visited the seafood market of Wuhan and had not consumed any food that could have come from the market. But they had visited a sick relative in Wuhan hospital. During their visit, their 7-year-old child wore a mask while visiting. Upon return all of them except the little girl became sick. They had fever, cough and shortness of breath. And that’s when the doctors and public health authorities became alarmed.
A subsequent study of patients diagnosed between January 1 to the 22nd revealed 200 patients who had never visited the Wuhan market developed the disease and thus human to human transmission confirmed.
What happens next with the decision of the World Health Organization is a little puzzling.
Keep sharing and stay tuned because you want to know

Human Coronaviruses

Human Coronaviruses were first identified in the 1960s and because of a crown like spike protein on their surface, they acquired the Latin name corona meaning crown. Based on shape of proteins on the surface, these viruses are sub grouped into alpha, beta, gamma and delta coronavirus.
The first two groups alpha and beta come from bats. There are seven known human coronaviruses which are SARS-Cov-2, SARS-Cov, and MERS, which can cause potentially fatal disease. Sars-cov-2 is the virus that causes COVID-19 disease. But HKU1, NL63, OC43, and 229E only cause mild symptoms similar to the common cold.
SARS and MERS came from bats but they have intermediate hosts which are civets and camels respectively. The subsequent spread to humans occurred after contact with the intermediate hosts. Civet cats are more related to mongoose than cats. They are nocturnal animals with short legs and long bodies with habitats in Asia and Africa.
A search for the intermediate host of the SARS-Cov-2 which causes COVID-19 disease has led investigators to the intermediate hosts the pangolin and possibly a specific type of snake. But again, there is no true exact match between the human coronavirus RNA and the RNA genomic sequence of the pangolin or the snake.
The snake intermediate host has led to some speculations about the way we should treat this disease. Keep that thought in mind because I will be revisiting this later when we talk about a treatment that has been deemed controversial.
( i.e nicotine patches).
Stay in tune for tomorrow. Keep sharing. There is off course more to this story. You know it.

The origins of COVID-19

To understand covid-19 you have to start from the beginning. so here is a description of some original data. Please note that I am only going to describe the science with no political connotations or agenda. It is simply intended to inform and educate at a deeper level than the general media. so please do not make any political comments on this platform.
On December 26, 2019, a 41 year old man presented to the hospital in Central Wuhan, China with complaint of fever, shortness of breath, unproductive cough and chest tightness for 6 days. His chest x-ray and CT scan were both remarkable for presence of what was described as ground glass abnormality and showed severe bilateral pneumonia. His oxygen levels were also low. The patient had been generally healthy with no other major medical problems and was tested for all potential suspicious agents such as influenza and chlamydia and mycoplasma. The patient worked at a local indoor seafood market which sold fish and shellfish, and other live animals such as hedgehogs, snakes, birds, and badgers and some animal carcasses but interestingly no bats.
We don’t know the outcome of this man but what we do know is that his symptoms and rapid deterioration was concerning and lead his physicians to suspect a virus perhaps not previously identified. Samples of his sputum were analyzed and a new viral form emerged. The virus was isolated and its genome was sequenced. It was a new virus never seen before in the human body. Where was it coming from? The genome and clinical presentation was similar but not identical to a previously identified virus in 2002 called the SARS virus. The origin of SARS had been traced to a type of bat. It caused illness in 8000 people with close to 800 deaths before it disappeared in 2003.
Another similar virus called the MERS virus had originated in the middle east. It too caused severe respiratory symptoms and was highly lethal killing a third of it’s victims but it was eventually reasonably contained. And so the quest began to identify the source of this virus in the hope that it could be contained if the transmission was from ingestion of the contaminated meat of the animal. Finally, a breakthrough revealed that the virus was very similar to a bat coronavirus called SL-CoVZC45 but the genome sequence had enough dissimilarities that the origin could not be confirmed with certainty. Furthermore, the type of bat which housed this coronavirus had been identified in Zhoushan, Eastern China, a region 600 miles from Wuhan.
More to come tommorrow. stay tuned. feel free to share.

Hydroxychloroquine Review

In 2005, a study sponsored by CDC in U.S. showed that Chloroquine could neutralize SARS virus in cells that were infected with that virus in the laboratory ( that is called an in-vitro study).

In January of 2020, a group of Chinese investigators looking to replicate those results in SARS-Cov-2 published an article looking at Chloroquine to see if it could kill this new virus in vitro. The results were positive .

Chloroquine has two widely different properties. It is an antimicrobial agent shown to have potency against viruses and parasites. But it also has immunomodulatory effect. That means that it can affect the immune system. Recall that in my previous post I explained that COVID-19’s virulence is compounded by its uncanny ability to cause the human body to create a self destructive cytokine storm. Chloroquine has been used extensively in patients with autoimmune diseases such as lupus and rheumatoid arthritis to reduce the cytokine surge.

Let’s focus on the historical use of the antimicrobial properties of chloroquine first. Chloroquine has been shown to be effective in the laboratory in fighting many viruses including the zika virus, ebola, and avian influenza virus H5N1. But in live animals or humans the results have not been promising.

The Chinese started using chloroquine quite early on and in February, The Chinese Health officials recommended the use of chloroquine in all COVID-19 hospitalized patients based on their experience of 100 patients with reported improved outcomes. There is no actual publication with data to back this up so apparently we just have to take their word for it.

In March, a group of French researchers from the University of Marseille reported on 20 patients who got hydroxychloroquine ( a similar but safer version of chloroquine). Those patients improved faster than patients in another hospital who didn’t get the drug (not exactly the most sophisticated study). Furthermore, in May, these same French scientists enthusiastically reported on their discovery of an important way that the drug could bind the virus and neutralize it in laboratory.

Many small ‘positive’ studies followed, And then, The Institute of Medical Research in Chandigardh, India reported that after looking at 16 international studies they could only conclude that patients on hydroxychloroquine had less progression of pneumonia on xray but otherwise nothing encouraging.

Finally a randomized double blind placebo controlled trial at Veterans Administration showed that there was no benefit in giving this drug to severely ill COVID-19 patients. In fact, there was some harm.

I want to bring out a couple of conclusions:
1. At this point the studies on hydroxychloroquine have all been small, poorly designed and not impressive.
2. We do not know if hydroxychloroquine is beneficial in patients as a prophylaxis to ‘prevent’ COVID-19 , the way it is used for malaria prophylaxis. We need a well designed study. It may very well be. But don’t know.
3. We need multi-national well designed trials with large number of patients for statistically more reliable results at different phases (pre-infection, early, middle and late presentation) of this disease.

As always, please refrain from political commentary. But more to come on vitamin D and Zinc and COVID-19. Keep liking and sharing please.

Congratulations Dr. Tebyanian and Dr. Moalemi!

Both Dr. Tebyanian and Dr. Moalemi have been listed as top doctors by Northern VA Magazine for 2019. A huge congratulations to both of our doctors for this accomplishment!

Congratulations Dr. Moalemi!

Our own Dr. Moalemi has been named as a Washingtonian Top Doctor for 2019!

Northern Virginia Magazine names Dr. Moalemi among BEST DOCTORS 2018!

Our own Dr. Azita Moalemi has been listed as one of the best doctors in the Northern Virginia area for 2018!

Every year Northern Virginia Magazine compiles a list of Top Doctors based on peer reviews and panel votes. Dr. Moalemi will appear in their upcoming February issue.

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