On The Line of Fire?

What went wrong with Padmashri, Padmabhushan Mr. S. P. Balasubramanyam, the legendary singer from India? He was recovering and suddenly he deteriorated and succumbed to the illness.

COVID can surprise you anytime, even in the recovery period. I got another note from social media, of a young doctor, a father of a six-month child – obviously a young family. He succumbed to complications of COVID. He was waiting to be discharged and go home.

Well, these unusual stories are gradually becoming common, and I thought of sharing it with you since doctors are seeing such scenarios very often. What is going wrong? Can we truly control it? Understanding these 10 points may possibly help prevent COVID-19. (Reading time 5 – 6 minutes; Scientific perspective).

(Note: We are planning to conduct a cross cutting expert global advisory session to clarify all relevant questions. We are planning to conduct this half day session before the start of the SECOND WAVE. Please share your questions to me in person or on this page as we are crowd sourcing questions from all).

Well, these unusual stories are gradually becoming common, and I thought of sharing it since doctors are seeing such scenarios very often (Please scroll to the bottom of the blog to see the detailed note). 

I had another gentleman who went to a Salon. He argued that he should support the local economy, a lame excuse. Well, even if he wants to support the local economy, he can donate bigger amounts and support the local economy, like many others who have supported their dependent workforce.  Time and again, I have been sharing rejoinders on awareness and precautions, and I am summarizing those below – 

1. A Constantly Mutating Virus:

The virus is constantly changing. It has a gene called RDRP (RNA-dependent RNA Polymerase) that encodes for an enzyme that makes a template for the RNA’s to produce in copies in billions. RDRP has a vulnerable to mutations and this results in the constantly changing nature of the virus. It is this enzyme that makes a (defective) template resulting in mutations. Every time, RDRP makes a template, it ends up producing an erroneous copy that results in mutant copies with every generation of the virus reproduction. 

2. Comorbidities and Unknown Risk:

Selective comorbidities and risk factors are known,however many are yet unknown. We all now know that diabetes, hypertension, smoking, cardiac problems, asthma, immune-compromised, and other respiratory illnesses predispose to COVID. However, we are seeing several youngsters without any of these comorbidities who are suffering and sometimes succumbing to COVID. 

3. Incomplete understanding of the Impact:

Also, we see that some have comorbidities and dies of COVID, whereas others with similar comorbidities survive despite having COVID. Knowing your comorbidities, science still cannot say if your disease will be asymptomatic, mild, moderate, or severe. 

4. Clean recovery or Long Haul Disease:

Despite the recovery, Science cannot predict if you will be ‘long hauler’, i.e. those have long term consequences. According to few reports, almost 10% to 1/3 recovered patients land up with Long Haul disease. The legendary singer, mentioned above, started showing signs of recovery, including light speech and physical activities. He deteriorated due to post COVID complication and eventually died of post recovery complications. 

5. Status of Vaccines:

Vaccines are in pipeline and serious efforts are being made to develop and durable vaccines but we don’t have one that we can rely upon. 

6. Repurposed drugs but No Specific Drugs:

We have supportive drugs but no specific drugs to remove the virus. We know it very well that HCQ was the mainstay at the beginning of the pandemic. Later, it fell into disrepute. Steroids were questioned and only after the ‘Recovery Trial’ substantiated the use of steroids with a randomized controlled trial, that changed the management of COVID. Tocilizumab similarly came in and had an ignominious walkout after the COVECTA trial. Just a few days back, the Japanese FDA approved Favipiravir. the later drug, with its RNA-dependent RNA polymerase activity, has anecdotal evidence of effectiveness since it’s a proofreading enzyme that renders the removal of nucleoside analog (drug molecule) and despite continue inducing mutations. Changes to the use of these guidelines may be anticipated as well. 

Different modalities of therapy for treating COVID-19.

7. Reinfections:

Several are indeed recovering but several reports of reinfections are emerging. It is a fact that several people are recovering from COVID, however, it is equally true that many lands up with severe disease, and those recovering are having long-term debility and need rehabilitation? 

8. Asymptomatic Spreader:

Are you sure, if you will just get the mild form of COVID or remain asymptomatic? Even if you remain asymptomatic, are you sure, you will not pass it on to your family members and if they get COVID, are you sure, like you, they too will be unscathed?   

9. Herd Immunity:

It is like playing with fire. Some insist that we should expose ourselves to build our innate resistance. Remember, this is not a natural virus, also, it evokes severe inflammatory and immune reactions within the body. It is structured or has been structured to keep changing. Our immune systems are built to remember, called immune memory. The changing nature of the virus renders the previously learned immune phenomenon useless. So even if we expose ourselves, our immunity will not last long. It is similar to Influenza. We see a different strain at least every year. With COVID, we see a different strain every few weeks. 

10. Convalescent Plasma and Antibodies:

Plasma from patients having recovered from COVID-19 has antibodies to SARS CoV2. Plasma, thus drawn from recovered patients helps treat and or contain COVID in infected patients. The earliest experiment was done by Edward Jenner in 1796 when he scratched the fluid from the blisters of a cow suffering from smallpox into the skin of a normal healthy man and induced protection. As we now know, Smal Pox is completely irradicated. Convalescent plasma (CP) uses the same principle, of tapping into existing antibodies for treating existing COVID-19 patients. 

However, there is a catch. CP is nonspecific, ie. it has other unrequired antibodies that may trigger untoward reactions. Also, if the virus itself is changing, those antibodies are ineffective. More so, the antibody levels drop after a certain period. Thus monoclonal antibodies become relevant. Placebo controlled randomized trials are being underway (as of this writing) that will offer solace to the treatment of COVID-19. Antibodies have to be targeting specific proteins called epitopes. In the presence of changing epitopes, it is fluid to understand the reliance on monoclonal antibodies. 

Myriad Complexity –

a) Cytokine and Bradykinin Storm: For the common men, the difference is nimble, it does, however, matter for the doctors though. Cytokine storms – processes in which the immune system overreacts to an infection. Ideally, cytokines disappear once the virus copies reach a threshold. COVID, however, puts the body into an overdrive mode and produces cytokines that ultimately result in damage to the organs. (drives the body to produce the immune system keeps producing them and the organs take the brunt from these excess cytokines). Cytokines are associated with myeloid differentiation and disease severity, concurrently the T cells are reduced as is evident from the reduced numbers of CD4+ and CD8+ T cells in patients with COVID-19. 

b) Kallikrein–kinin system: Irrespective of the pathognomic phenomenon (mechanism of the disease), COVID unleashes vast reaction from your own body to damage itself. Think, of this like a natural defense which is supposed to protect you, has turned up against you, causing a perfect storm to disrupt and incapacitate you.

Remember the fluid build up around the lungs, which is primarily caused by bradykinins. Bradykinins causes the blood vessels leaky and result in edema (swelling) around vital organs such as the lungs (short of breath), muscle (body aches), gastrointestinal tract (diarrhea), kidneys (congestion and rising serum creatinine), and a multitude other clinical features.    

c) Endothelial Nitric Oxide System: Endothelial nitric oxide synthase (eNOS) becomes a potential therapeutic target. Hypercholesterolemia, diabetes mellitus, arterial hypertension, and smoking are associated both to nitric oxide synthesis reduction or degradation increase. This nitric oxide bioavailability reduction is followed by endothelial dysfunction

A Picture is Worth 1000 Words:

A review of the work – A great deal of work has been done in the treatment and or containment of COVID-19 in the last 9 months. LitCOV provides an exclusive insight on the amount of scientific literature exclusively within the field of COVID-19. Based on the data from Milken Institute, select treatment modalities have been captured in the pie chart below (cumulative progress in the treatment of COVID).

Reflections On Human Urge to Move Freely

Our fundamental human urge to move and intermingle has been severely constrained, however, historical evidence shows that no calamities remain constant. If you recollect, no rains, volcanoes, earthquakes, or twisters (andhi) remains forever. One day it wanes and so will this virus, it is nature’s law and this virus too will follow those laws. 

Remember, humanity has a significant resilience built-in and as the history of human evolution shows, it has never been subdued nor will it ever let any event subdue its spirit and independence. However, events have always taken a huge toll and we never know if we are on the line of fire. 

Death of COVID Treating Doctor:

A 38 yrs old male doctor gen practitioner was admitted to our hosp with COVID on the 6th day of illness with 60% lung involvement, SpO2 borderline with mild dyspnoea. He became critical in the next 2 -3 days with a typical cytokine storm. We shifted him to ICU and on NIV. He was quite tachypneic, tocilizumab 2 doses were given and his NIV requirements decreased ..and eventually, after 5 days of ICU stay, he was weaned off from NIV and stable on nasal prongs 4-5 L o2. Later, he was shifted to the ward with oxygen. On the previous day of his discharge, he developed abdominal distension and severe abdominal pain, and constipation. A Ryles tube was passed and was kept NBM, X-ray abdomen showed dilated bowel loops but no air-fluid levels. GI doc advised enema, a CT abdomen was advised, radiologist suspected some bowel ischemia, so the patient was shifted to Ruby Hospital, Pune. After struggling with the consequences of ischemic bowel complications, the patient succumbed due to Sepsis and multi-organ failure.

It is now a routine, to see notes such as the one below, on social media. 

Do you want to be on the line of Fire?

COVID-19 cytokine storm: The anger of inflammation; Cytokine. 2020 Sep; 133: 155151. Published online 2020 May 30. doi: 10.1016/j.cyto.2020.155151 PMCID: PMC7260598; PMID: 32544563

https://www.bio.org/policy/human-health/vaccines-biodefense/coronavirus/pipeline-tracker

https://covid-19tracker.milkeninstitute.org/#vaccines_intro

11 thoughts on “On The Line of Fire?”

    1. Mariya, it is the culimnation of the proinflammatory and hyper immune mediated response that inflicts an injury over the vulnerable organs. The cumulative risk is driven by the overall comorbidities, threshold of injury (that varies with according to the individual), the time and qualitative and quantitative nature of the intervention.

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  1. Dr Shashank,
    Thanks for sharing such wonderful write up.
    You have explained everything so nicely.
    As usual you did a great job.
    No query in mind right now but will ask you whenever needed.
    Feeling proud of you.
    All the best.
    Anant.

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  2. Dear all
    I have rest this illuminating article with interest.
    As of now I under treatment n quarantine for ” mild ” , asymptomatic infection.my assistant Male nurse was symptomatic n two indoor patients. So I got myself tested and I was positive. RTPCR Ct value 25
    Being 68, and a patient of AVR and Cabg itook aggressive treatment.
    Right from beginning I felt I was asymptomatic. But in retrospect I realized that a pain abdomen. And a loose motion.
    CRP, FERRITIN DDIMER ALL JUST UPPER LIMIT.
    Ivermectin, favipir, doxy , steroids n other supporting drugs.
    Today is 10 day am fine. But one interesting observation, in initial stages my resting SPO2 WAS 96,97 SO ALSO POST EXERCISE.
    But in last two days I realise it is 99 and 99 per,post exercise , 20 minutes biking and surya namaskar 3 sets.
    So is it that I DID HAVE A MILD INVOLVEMENT OF THE LUNGS.
    Should I go for a hrct . (Not done as baseline)
    We also find increasing prescription s of perfenidine in follow up.
    So I feel still we are groping in the dark and the HyBRID VIRUS playing games.

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    1. It is obvious that the second surge is arriving. Several countries in Europe are seeing a second wave. We cannot hunker down but at the least, if we are prepared, that helps. So awareness and precautions certainly become important. However, the progress in the management of COVID-19 provides assurance that this is unlikely to persists longer (prolonged).

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  3. It is obvious that the second surge is arriving. We cannot hunker down but at the least, if we are prepared, that helps. So awareness and precautions certainly become important. Some law should be brought in regarding wearing masks,maintaining physical distancing (whenever you are out in society )not social distancing.

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