CME INDIA Presentation by Dr N K Singh, Admin, CME INDIA.

See four very interesting scenarios:

Scenario 1

Dr Natraj, COVID Nodal Officer in Govt., Thiruvarur Medical College, Tamil Nadu:

I have seen and treated a lot of cases due to COVID.

Faced many deaths in my College also due to COVID. I have a lot of doubts regarding management.

  1. I find most of the COVID deaths due to ARDS sir. Many present to us in Cytokine storm with Spo2 of < 50% whom we are not able to save. Cytokine storm is due to the hyperimmune response due to a strong immunity by the pts usually presenting in the 2nd week of illness.
  2. Why only certain patients develop it that too middle to elderly pts whose immunity is waning but young patients whose immunity is so good does not develop at all.
  3. Most patients who die are those who present to us in Cytokine Storm in the 1st week of illness itself.
  4. How early steroids can be given and if at all what dose to be given in the 1st & 2nd week of illness.
  5. Clinically any score to predict the onset of ARDS.
  6. The role of Tocilizumab in COVID ARDS.
  7. The role of Ulinastatin and sepsivac in COVID.
  8. Certain patients with >80% lung involvement don’t develop ARDS, but patients with less than <20% lung involvement develop ARDS. Why?

Let us see, what experts say:

Dr Vikram Sarbhai, MBBS, MD, DNB, FCCP, FACP, FISDA, FNCCP Sr. Consultant, Pulmonology, Critical Care and Sleep Medicine National Heart Institute, East of Kailash, New Delhi 110065, President, Indian Sleep Disorders Association:

  1. I am very less convinced about cytokines storm.
  2. I am more convinced about the virus affecting the blood vessels of all generations until the arterioles and veneuls. More the arterial system causing endothelial damage and creating a perfect milieu for RBC damage alongside creating a milieu that activates extrinsic pathway of coagulation while still in vivo leading to a fulminant pro-coagulant state… no different that anti phospholipid antibody syndrome (APLA or APS) due to virus acting through the ACE-2 Receptor on all surfaces endothelium creating endothelialitis – it’s therefore anti-Inflammatory effect of Steroids and Blood Anticoagulants safe lives and have shown definite mortality benefits.
  3. Tocilizumab is effective in few cases where it also helps as an anti-Inflammatory where IL-6 is raised.
  4. All medicines work by moderate severity.
  5. Most medicine loose out in severe cases including Remdesivir.
  6. Virus is itself ineffective after 9-10 days and there is no way one can prevent infection albeit delay getting infection to One-Day get it.
  7. Reasons for medication failure:
    • Impact of virus to initiate and immune process of body to accelerate the inflammatory process of an individual whose blood vessels are already vulnerable cause of – Age / HTN / DM / CAD / CKD etc will lead the vessels to have a fulminant impact causing pan body micro vascular and macro vascular clots – causing ischemic injury to critical organs – Lungs – Heart – Brain – Kidney – Liver – Skin – Eyes.
    • Beyond a certain critical threshold of damage in these per-morbid individuals is medications become ineffective as there can be no substitute to oxygen Delivery blocked by multiple clots all over all organs of body.
  8. Anti-virals are ineffective since – Virus just open the flood gates and once Critical numbers of such gates are opened – killing virus achieves nothing.
  9. All most antiviral reduce viral replication but none get effective in acute cases.
  10. Eventually it’s just anti-inflammatory and anti coagulants help which can restore Blood supply if the organ survives ischemic insult within a critical time.
  11. Most mortalities are sudden in nature or very rampant suggesting vascular insults.
  12. ARDS masquerades multiple millions of micro vascular infants as an alveolar process is and mechanical ventilation therefore is the opposite approach as one can’t treat perfusion defect with ventilation improvements.
  13. Patients reaching late or in severe illness or not taking treatment early are most likely to remain refractory to all treatment unless very aggressive medication approach is adopted.
  14. Possibility of sudden death remains if anticoagulants are not continued well beyond discharge at least 2 weeks post discharge.
  15. Also, other Anti-Viral strategies won’t work – Such as convalescent Plasma.
  16. Killing Virus Mostly won’t make much difference.
  17. Also, Disease worsening is in second week where naturally virus is waning off which means its virus is the Dam breaker; once it breaks the Dam (Vascular endothelial inflammation) simply killing it or reducing its burden doesn’t impact mortality.
  18. Logically therefore investigations looking at cellular damage are raised:
    • Erythrocytes damage / Lysis – raised ferritin.
    • Ischemic hepatocyte damage / Death- raised LDH / SGOT / SGPT.
    • All inflammation markers will raise with even sterile ischemic cellular death happening across all organs – CRP / IL-6.
    • Obviously – Pulmonary thromboembolism or thrombosis and other organs thromboembolism- Raised D-Dimer.

Dr Atri Gangopadhyay, Pulmonologist, Ranchi:

  1. Cytokine storm is yet very unpredictable, as the same markers IL-6 have been seen raised in mild patients beyond 300 yet of no damage, while some patients beyond 50, it can cause severe storm. So, we don’t yet know who is the susceptible phenotype of cytokine storming my personal experience, patients with PTCA/ CABG Do fare worst.
  2. Anyone with multiple comorbidities are on multiple medicine and the poly pharmacology can cause unknown interaction leading to storm.
  3. Early symptomatic fare badly…. Asymptomatic tend to remain asymptomatic till the recovery
  4. Any oxygen requirement, high CRP should be indication for steroids, start SOLUMEDROL 60 – iv once daily for five days, then switch to dexona 12mg five days.
  5. Clinical Scores – Not reliable yet.
  6. Tocilizumab – Give early. No treatment effective, once patients intubate.
  7. The role of Ulinastatin and sepsivac in COVID -No proven evidence at all.
  8. The ARDS due to cytokine storm whereas CT change shows extent of pneumonitis (in viral pneumonitis, recovery is the rule).

Dr. Raghu Ram U, MD, FICM – Asst Prof , Dept of Pulmonology, NIMS Vijayawada , Andhra Pradesh (www.PECSI.Org):

By assimilating data of over 900 in-patients and 96 patients who landed in STORM, whom we treated with morality rate of less than 0.5% (With 71% of our in patients being moderate to severely ill ones) PULSE DOSE Methylprednisolone for Acute Immunosuppressive effect in COVID CYTOKINE STORM SYNDROME (CCSS) & ‘Second’ STORM, is decreasing MORTALITY to a great extent. A clear difference can be seen added with COLCHICINE (Strong IL 6 inhibitor, Anti-inflammatory, Coronary Vascular inflammation controller, Microthrombi preventor). Use of Tocilizumab has been mostly avoided in our hospital by effectively using the above-mentioned drugs.

Dr Akash kumar Singh, Baroda, Gujrat:

Dr. Natraj – your observation that most of COVID deaths are due to ARDS and cytokine storm is absolutely correct but we being a tertiary care set up have been really burdened not with the deaths which are very less but with the oxygen dependency in many patients which refuses to go away in spite of every effort and many patients have to be sent home on oxygen or are incapacitated with poor effort tolerance and compromised lung function. The patients with SpO2 less than 50% are majorly the patients who were not really managed well (majority of them did not get tested, or remained at home without any proper medical care or were in set ups without proper expertise in COVID management).

Another observation that the middle aged to elderly individuals are the ones suffering from cytokine storm may be the case generally but we have many young patients too (not pediatric) who do have a stormy course and develop cytokine storm.

We have approx. 3-4% mortality in our hospital which is mainly due to the fact that we take critical patients (very few hospitals would take such patients in our city) But death in the first week is a rarity at our set up (almost negligible).

We give steroids once the patient has O2 saturation which is dropping or already compromised or the 6 minute walk test is showing 4-5% drop in oxygen levels, or the patient is symptomatic with fever, bodyache with rising CRP, IL-6, Ferritin (inflammatory markers) The dose if orally given is minimum 16 mg prednisolone, or 6 mg dexamethasone. IV we give IV metylprednisolone 40mg od as the least dose and may give 80 mg bd as the higher dose. It all depends on the clinical parameters and the labs.

We don’t use any clinical score but judge the severity by clinical evaluation of our patients and the inflammatory markers. We have given up use of Tocillamab as we did not have good experience. Lot of our patients improved but succumbed to sepsis with the last patient having invasive candidiasis as the culprit. We start the patients deteriorating oxygenwise first on inj remdesivir. If still significant dependence on oxygen or increasing oxygen demand, we give 2 units of convalescent plasma on consecutive days. If still no response, we are happy to use Inj sepsivac 9 doses tds over 3 days. No role of unilastatin and we have used it in one patient with no success.

As I said oxygen dependence is the major issue which keeps on troubling us rather than mortality which is comparatively less. Lot of immunocompromised patients, patients of HIV, DM, IHD, RA have just gone home with no major complications which again is surprising to us.

We have also used Inj methylene blue 100 mg iv over 3 days in 4 patients. We haven’t seen any semblance of improvement in these patients. However, Remdesivir, convalascent plasma (given early on during the course of treatment) and sepsivac are the most effective molecules as per our experience

COVID Cartoon

Scenario 2

Dr Ambrish Bhattacharya, Kolkata:

What to do with COVID suspects who are testing negative on RT-PCR? We are getting many such patients. The HRCT is typical. And everything else also points towards COVID.

  1. Where to keep the patient? Isolation ward, COVID ward or general ward?
  2. We have given Favipiravir in a few but now we are using Doxy + Ivermectin. Problem is if there is a medicolegal dispute.
  3. When and how frequently to send repeat test?

Dr Nishith Kumar, Pulmonologist, Ranchi:

  • We are all facing this problem in our day to day Clinical practice. Winning Patient’s trust is key here. Effective communication is the foundation on which you can establish trust with your patients. Share real life data of RT PCR sensitivity & experience with other similar cases.
  • Doxy/ivermectin can be prescribed in such patients without any problem.
  • Favipiravir is approved for the treatment of seasonal influenza strains unresponsive to current antivirals Japan. But in negative cases I tend to avoid it as it doesn’t offer any Mortality benefit.
  • In selected few cases you may prescribe it after weighing risk/benefit.
  • Remdesivir is a strict NO in negative patients.
  • If the patient has presented late then you can test for antibody. If it comes positive, then it gets a lot easier to convince the patient.

Scenario 3

Dr Akash Kumar Singh, Consultant physician, Baroda, Gujrat:

I was wondering on a specific treatment modality for doctors and healthcare workers who contract COVID19 as the mortality is higher in this subgroup and Remdesivir seems most effective agent as of now amongst anti-viral drugs, should all doctors and paramedics be offered Ramdesivir as the initial antiviral agent to decrease their morbidity and mortality.

Scenario 4

Dr Gurdeep Shergill, MD Med Sirsa, Haryana:

A Patient aged 50 years with no comorbidity suffered 35 days ago and at that time his CTSS was 25/25, Now maintaining Spo2 97%, at oxygen 5 lt per min. Without O2 fall up to 80%.

Is there any role of antifibrotic therapy in this patient with post COVID severe PF?

Dr Atri Gangopadhyay, Pulmonologist, Ranchi:

This person has severe lung involvement even residual. He should be given everything in the armamentarium including antifibrotics looking at the oxygen requirements and desaturation without oxygen.

Dr Nishith Kumar, Pulmonogist, Ranchi:

Pirfenidone is a hypothetical treatment option for Post COVID-19 related fibrosis as of now. No RCT result is available to prove its efficacy. Most of the severe cases that I have seen, the Pneumonia gradually resolved with time (>2 months) & oxygenation improves.

Dr Bhanu Pratap Singh, Physician, Siwan, Bihar:

Is histopathologically COVID lung is similar to UIP(IPF), because in most HRCT reports, we are getting GGO but no comments on honeycombing which, so far, I know, is more specific for UIP. And if it is not there, why are we running behind pirfenidone or nintedanib. Because to me it looks like two different pathology in these two diseases.

Dr Atri Gangopadhyay, Ranchi:

There have been multiple spectra reported from the histopathology of such lungs:

  • Patchy fibrosis
  • Organising alveolar damage
  • Cytopathic changes with vacuolar swelling
  • Fibrinal thrombosis
  • Large vessel thrombosis
  • Interstitial fibrosis
  • Abscess formation

Dr Nishith Kumar, Pulmonogist, Ranchi:

Quite a few of my patient who suffered from severe disease still requires supplemental oxygen therapy even after 2 weeks post discharge. But of course, they are getting better & better day by day & their supplemental oxygen requirement is gradually going down. If you check their serial HRCT Thorax a lot of residual ground glass opacities can still be appreciated even after 3-4 weeks of symptom onset & after turning RT PCR negative. Basically, in severe disease radiological resolution is slow & May even take up to 2 months. Of course, some amount of fibrosis/scarring expected whenever there is insult to lung tissue.

It is still not known whether post COVID fibrosis will be progressive or not. If progressive like IPF then antifibrotics like Nintedanib /Pirfenidone may have a place…if not progressive & static (as in post infective sequelae eg Tuberculosis) anti fibrotic won’t be of much help. we can only wait and see how it behaves in future. Pulmonary Thrombo Embolism is another issue.

CME INDIA Learning Points:

  • Cytokine storm is a well-established clinical condition that is characterized by significant proinflammatory cytokine release leading to a dysregulated and hyperactive immune response causing organ dysfunction.
  • There are certain debated crucial questions—when to  initiate the immunomodulatory drugs? How to balance the benefit-risk profile? What patient profile is suitable for such therapies? There is no uniform consensus with regard to the use of a specific class of drugs.
  • Among the immunomodulating therapies, ulinastatin has a broad-spectrum protease inhibitory properties leading to inhibition of cytokines including IL-6. The drug is used commonly in China, Korea, Japan, including India for the management of sepsis and pancreatitis. The anti-inflammatory effects may be considered equivalent to those of steroids without significant suppression of the immune system. No clear consensus on its utility exists.
  • Specific IL-6 inhibitors such as tocilizumab can be useful in severe life-threatening CRS caused by chimeric antigen receptor T-cell (CART) immunotherapy. However, the use of tocilizumab cause even more profound immunosuppression than steroids, increasing the risk of sepsis, bacterial pneumonia, gastrointestinal perforation, and hepatotoxicity.
  • An inflammatory cytokine signature predicts COVID-19 severity and survival. High serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival.
  • IL-6 has been found one of the most robust prognostic markers of survival, eclipsing or outperforming CRP, D-dimer and ferritin after adjusting for the demographic features and comorbidities. It remained independently associated with severity and predictive of outcome when including information about ventilation and end organ damage.
  • COVID-19 infection can lead to the development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome MODS within a few days of disease onset.
  • The capacity to accurately predict and intervene in the cytokine storm during COVID-19 pneumonia, as well as the ability to design effective specific strategies to block excessive inflammation, is critical for patient survival.

CME INDIA Tail Piece:

Recently the 4C mortality score has been published in BMJ.

The 4C Mortality Score uses 8 variables — age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein — to compute a score that ranges from 0 to 21 points.

  1. 0 – 3 Low risk of mortality
  2. 4 to 8 intermediate risk
  3. 9 to 14 high risk
  4. ≥15 highest mortality risk.
Cytokine storm and COVID

Source: Risk stratification of patients admitted to hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score

BMJ 2020; 370 doi: (Published 09 September 2020) BMJ 2020;370:m3339

Indian Score which may affect people post-COVID-19 recovery & is often a missed entity…

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