CME INDIA Presentation Dr N K Singh.

“Why does one 40-year-old get really sick and another one not even need to be admitted?” – Ranney, an associate professor of emergency medicine at Brown University.

This graph looks rosy but…

(JNMCH-BHAGALPUR data), and similar from many places in India.

RED ALERT

Dr Hemshankar Sharma, Asso. Prof. Medicine, Bhagalpur (As on 16/12/2020):

• I am perplexed the way COVID-19 patients are showing a change in presentation, as well as predictions on the outcome!!
• I personally suffered, no cough, breathing problems, fever, bowel upset, altered smell or taste!!!! Simply while returning from the hospital on 2nd afternoon, I told my wife, I feel only little heaviness in abdomen, and she insisted for my RAT, came strongly positive, which I got rechecked with CBNAAT, with a Ct value of 14. Today is my 15th day, I have little dry cough, going for a re check in lab.
• In between, I have noticed, unexpected death of a distant relative, 59 years, no co-morbidity, died after marriage ceremony of his son. I advised COVID-19 test, denied by family members, but next day when again I insisted upon other members of family, 6 of them came positive. All in domiciliary treatment. 4 of them male 2 females.
• The ways of presentation have changed, may be strain !! or irresponsible behaviour. Of the patient or family members.
• Males, age groups 40 to 60, are more vulnerable, especially with Diabetes.

First have a look on why Immune systems are hit by friendly fire

• Mystery of SARS0- CoV-2 in individual clinical deterioration is drastically variable. In present wave of COVID-19, it is more perplexing and physicians are shaken to predict silent infection to rapid death. Now common observation is that age group 40 to 60 is getting unpredictable course. I am aware of several deaths which occurred just after 3 to 5 days of infection. It is something which we had not observed till September 2020. More such cases are being reported in November and December. 
• Usual risk factors leading to doomed scenario – Male gender, being elderly and co-morbidities, cannot explain the rocket-speed deterioration in any epidemiological group.

Blame it on your genes

• I am more comfortable in accepting the luck and genetic make-up in present scenario.
• B cell autoimmune infectious phenocopies of three inborn errors of cytokine immunity exist.
• It is known that neutralizing autoantibodies (auto-Abs) against interferon-γ (IFN-γ) (mycobacterial disease), interleukin-6 (IL-6) (staphylococcal disease), and IL-17A and IL-17F (mucocutaneous candidiasis) mimic the clinical phenotypes of germline mutations of the genes
• These genes encode the corresponding cytokines or receptors.
• Human inborn errors of type I IFNs underlie severe viral respiratory diseases.
• Neutralizing auto-Abs against type I IFNs, which have been found in patients with a few underlying non-infectious conditions, have not been unequivocally shown to underlie severe viral infections.

Research is exciting

• Inborn errors of type I IFN immunity could be the real mystery.
• One research has tested this hypothesis
• So, neutralizing auto-Abs against type I IFNs may be the hidden factor leading to critical COVID-19.

What researchers searched for?

Researchers looked for auto-Abs against type I IFNs in 987 patients hospitalized for life-threatening COVID-19 pneumonia

There were 663 asymptomatic or mildly affected individuals infected with SARS-CoV-2, and 1227 healthy controls from whom samples were collected before the COVID-19 pandemic.

Something Unique was Found

• At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against type I IFNs.
• This finding highlights the crucial role of type I IFNs in protective immunity against SARS-CoV-2.
• Worth to note, these auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2—a poor inducer of type I IFNs.
• It clearly suggests that the small amounts of IFNs induced by the virus are important for protection against severe disease.
• So, if you have neutralizing auto-Abs against type I IFS it will set a red -carpet for this virus. The virus will move with all its army and lead to devastating disease.
• Then it will destroy all what comes in his way -also crushes innate and adaptive immune responses.

Clinical Implications

• SARS-CoV-2–infected patients can be screened to identify individuals with auto-Abs who are at risk of developing life-threatening pneumonia.
• Such patients recovering from life-threatening COVID-19 should also be excluded from donating convalescent plasma. Also, not to be recruited for ongoing clinical trials.
• These findings give insight for preventive or therapeutic intervention, including plasmapheresis, monoclonal Abs depleting plasmablasts, and the specific inhibition of type I IFN–reactive B cells.
• Early treatment with IFN-α is unlikely to be beneficial. But treatment with injected or nebulized IFN-β may have beneficial effects. Reason being – auto-Abs against IFN-β appear to be rare in patients with auto-Abs against type I IFNs.

The innate immunity insights

• The innate immune response is the major front line of defense against viral infections.
• It involves hundreds of genes with antiviral properties which expression is induced by type I interferons (IFNs) and are therefore called interferon stimulated genes (ISGs).
• Type I IFNs are produced after viral recognition by pathogen recognition receptors, which trigger a cascade of activation events.
• Human and mouse studies have shown that defective type I IFNs induction may hamper the ability to control viral infections. [3]

Take Home Message

• Our immune system is mysteriously complex.
• it involves many genes. Many such genes encode cytokines knowns as Interferon (IFN). Interferons are like a Fire Alarm and a Sprinkle system all in one.
• Individuals that lack specific IFNs can be more susceptible to infectious diseases.
• The autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation.

Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19)

• Zhang et al. 
  1. They used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity.
  2. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection.
• Bastard et al. 
  1. Identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia.
  2. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals.
  3. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified.

CME INDIA Discussion

 Dr Supriyo Mukherjee, Internist, Samstipur, Bihar:

• A study in nature of more than 2200 intensive care patients has identified specific genes that may hold the answer.
• They make some people more susceptible to severe COVID-19 symptoms.
• Mutations in a gene called TYK2 can trigger an excessive immune response to COVID-19 and damage lungs. A class of anti-inflammatory drug targets this biological mechanism, including a drug called Baricitinib.
• Response of this drug has been shown in a paper published in NEJM.
• Mutations in a gene called OAS can keep the protein it encodes from doing its job, which is to stop viruses from replicating.
• And defects in the IFNAR2 can prevent the body from launching an early immune response, giving the coronavirus time to make a foothold.
• Dr Kenneth Baillie, a consultant in medicine at the Royal Infirmary in Edinburgh, who led the Genomic project reflected that
• “Vaccines should drastically decrease the numbers of COVID-19 cases, but it’s likely doctors will still be treating the disease in intensive care for a number of years around the world, so there is an urgent need to find new treatments.”
• The Genomic study – and several others – has revealed a cluster of genes on chromosome 3 strongly linked to severe symptoms. But the biology to support this is not yet understood. Dr Vanessa Sancho-Shimizu, a geneticist from Imperial College London, said that the genetic discoveries were providing an unprecedented insight into the biology of the disease.
• Dr Baillie said: “We need everyone, but we’re particularly keen to recruit people from minority ethnic groups who are over-represented in the critically ill population.”
• Adapted from Nature briefing 15th Dec 2020.

Dr Subhash Kumar, Patna:

• I feel we are missing some more important links to death. We must investigate higher complications rate with use of certain drug particularly in doctors and paramedics and their relatives.
• I have seen many old ages with all possible comorbidity getting a milder form of COVID19 survived with minimum support. Meaning by there are there some factors we are not able to screen which can be responsible and need further investigations.

 Dr Atri Gangopadhyay, Pulmonologist, Ranchi:

• The important changes in winter are:

1. Blood viscosity-leading to more incidence of fatal thromboembolism in COVID, a disease where already thromboembolism is more rampant.
2. Rapid conversion of viral infection to secondary bacterial infection.

These risk factors make any person with pre-existing risk factor for thromboembolism and existing lung disease at more risk.

Dr P R Parthasarathy, Chest Physician, Chennai:

• I would like to highlight a few points:
  1. It seems that the female gender escapes with mild infection most of the times. (Unless they are obese, Diabetic with poor control, immunocompromised.)
  2. Staying in closed spaces with lack of ventilation (for prolonged period s) –
  3. Not following standard procedure s – Masking, hand washing, social distancing
  4. People who travel – It’s found that people who travel do not follow SMS & the proper sanitation procedure is not followed by the authorities.
  5. In such a situation, the best thing one can do is to follow SMS for ourselves & to change the clothes & have a good bath once they reach home.
  6. Why only some persons are affected in cases of train / bus journey of longer duration? Or has it affected people without any comorbid?

I think points 2, 3 & 4 are common causes of infection now

Dr Rajkamal Chaudhary, Asso. Prof. Med., JLNMCH:

• Death in COVID-19 patients in the recent months in JLNMCH BHAGALPUR have been slow but mysterious, usually of old age having Diabetes and the recent trend might be enthusiastic Dexamethasone use for stopping the inflammatory process of Cytokine Storm from the initial period of admission of the patient.
• This has also resulted to Bacterial and Fungal infection in COVID recovered cases in recent days and mostly death.
• One of the major Complications is Sudden Myocarditis and within no time the patient passes away these days, the Second is CKD with variable serum creatinine ranging from 18 to 30 seen in my Patients who either have no complaints or they have severe complain of Acidosis and with loss of SPo2 40 to 60 but once put on Dialysis for 3 to 4 hours recover very well.
• A good vaccine is in demand of the time which should be Effective, Efficacious and Free of Complications.

I don’t think the first half of 2021 is going to be free of COVID-19 deaths seeing the rainbow in sky when has to finish after the rains.

Dr Akash Kumar Singh, Vadodara:

• Yes, it is becoming difficult to predict which pt will worsen and which will not.
• But what we have observed is that elderly pt deteriorate more and gradually. Maybe they are developing secondary infections, which was difficult to treat or they are the poor responders.
• Maybe some genes are making them more vulnerable as compared to similar other pts.
• Treating with the medications, which is not evidence-based or not indicated in these patients or are newer drugs with no proper data available, also may be causing harm unknowingly (like tocilizumab, sepsivac, convascelent plasma in unindicated patients, newer drugs like unilastatin, alpha thymosin, Glutathione etc all may lead to unwanted side effects. . Coming the the sudden deterioration and deaths in the 40-60 year age group, we have not seen any such death which has occurred suddenly just after 3-5 days of infection. None at all despite having rolled out 2000 plus COVID patients on the indoor or outdoor basis. But here too we have seen some very athletic and fit people getting into severe COVID inflammation and pulmonary involvement and coming out with great difficulty. Our belief is that apart from the standard risk factors of getting severe COVID complications, there is definitely a role of genetic factors that alter the prognosis

(Data from Dr Akash Kumar Singh, Dr Ankur Bhavsar)

Dr Shaibal Guha,Patna

Difference in general covid symptoms in the 2nd wave:

1. Rapid progression/ deterioration in people with comorbities
2. Fever absent or mild
3. Cold/ sputum is rare- mostly its dry cough only
4. Bodyache remains a prominent feature

Rapid deterioration within 3-5 days is definitely more now. High risk are:

Male sex
Elderly to middle aged
Diabetics ( much more related than other comorbities)
High Viral load ( doctors/ hosp staff)

CME INDIA Learning Points

• Clinical outcomes of COVID-19 illness range broadly from asymptotic and mild to a life-threatening situation. This casts uncertainties for defining host determinants underlying the disease severity
• Genome-wide association studies (GWAS) and high throughput sequencing curation revealed genetic errors and gene loci associated with about 20% of life-threatening COVID-19 cases
• Significantly, most of these critical genetic loci are enriched in two immune signaling pathways, i.e., interferon-mediated antiviral signaling and chemokine-mediated/inflammatory signaling.
• Together, key genes unraveled by genetic profiling may provide targets for precisely early risk diagnosis and prophylactic design to relieve severe COVID-19.

Sources:

• [1] Autoantibodies against type I IFNs in patients with life-threatening COVID-19Paul Bastard et al. Science 23 Oct 2020: Vol. 370, Issue 6515, eabd4585
  DOI: 10.1126/science. abd4585
• [2] The genetics underlying severe COVID-19 Laura M. Zahn.Science 23 Oct 2020:
  Vol. 370, Issue 6515, pp. 418-420.DOI: 10.1126/science.370.6515.418-n
• [3] Bourdon, Marie et al. “Host genetic susceptibility to viral infections: the role of type I interferon induction.” Genes and immunity, 1–15. 20 Nov. 2020, doi:10.1038/s41435-020-00116-2

Discover CME INDIA

• Explore CME INDIA Repository
• Examine CME INDIA Case Study
• Read History Today in Medicine
• Register for Future CMEs

Get CME INDIA Highlights

Curated articles in your inbox.

SUBSCRIBE!

You have Successfully Subscribed!