“Problem-solving leaders have one thing in common: a faith that there’s always a better way.” – Gerald M. Weinberg
DEXAMETHASONE VS. METHYLPREDNISOLONE
Produced by: Lennard M. Gettz & Dr. Robert L. Bard
Edited by: FLCCC Technical Team
August, 2020- the current status of the Coronavirus pandemic keeps up a healthy dose of conflicting global news headlines (ranging in levels of scientific validity) as far as potential treatment solutions and vaccines. Countless research groups and clinical trials world-wide bear differing fruits, one closer to the end game than the next.
By June, the W.H.O. launched the headline “Preliminary results about dexamethasone use in treating critically ill COVID-19 patients” [5]. This was echoed immediately by countless European news sources with encouragement like “Dexamethasone to be the proven first life-saving drug”- forming a global cascade of targeted positivity and market demand from a world so desperate for a cure.
Publicly recognized by health agencies like the NIH who stated, “Patients with severe COVID-19 can develop a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction. It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these deleterious effects” [1]
A unique insight into this disease showed that the majority of patients initially present with an inflammatory reaction in the lungs called “organizing pneumonia,” which is the body’s reaction to injury and has been well known to be profoundly responsive to corticosteroid therapy. If the organizing pneumonia response is left untreated or presents as a rapidly progressive sub-type, a condition called Acute Respiratory Distress Syndrome (ARDS) follows.
STRATEGIC TREATMENT CHALLENGE FROM THE FIELD
Meanwhile, teams of American physicians like Dr. Pierre Kory, Pulmonary and Critical Care Specialist (Milwaukee, WI) and his team of front-line Covid care providers (the Front Line Covid-19 Critical Care Alliance) challenged Dexamethasone as the exalted panacea of the pandemic. Dr. Kory’s team dedicated their life’s work to the research and treatment of infectious diseases in critical illness, and recently published a battle-tested and proven Hospital Treatment Protocol called MATH+, a combination of medicines designed to counteract the injurious hyperinflammation, hypercoagulability, and hypoxemia in COVID-19 using synergistic actions. Their group strongly recommends a different corticosteroid called METHYLPREDNISOLONE. Work done by members of the group, in particular, Dr. G. Umberto Meduri, one of the worlds experts on the use of corticosteroids in critical illness, discovered key findings establishing the rationale in support of the preferred use of Methylprednisolone, while also providing a wider scope of evidence supporting corticosteroid therapy for Covid-19 critical cases.
According to Dr. George P. Chrousos (Athens, Greece), leading international expert on glucocorticoids, he detailed conclusive evidence about "homeostasis and the “surprise” of effective glucocorticoid therapy" in a recent medical report with Dr. G. Umberto Meduri (7/2020, Elsevier/Science Direct). His summary included-- "...on the basis of our understanding of the pathophysiological mechanisms of critical disease, one can conclude that the onset of therapy with glucocorticoids and, possibly, other useful or potentially useful agents in severe COVID-19 must take place early, before the homeostatic mechanisms of the organism reach complete, irreversible exhaustion. ... It is questionable whether dexamethasone is more efficacious than other synthetic glucocorticoids when given in equivalent doses. One potential advantage is the almost complete lack of salt-retaining activity of this corticosteroid. As the pleiotropic actions of ascorbic acid, vitamin D, and thiamine include assisting glucocorticoids and mitochondria in the change of the homeostatic immune balance from proinflammatory to anti-inflammatory, it is best for the patients to have sufficient reserves of these rapidly depleted micronutrients. This treatment approach is incorporated into the MATH+ (methylprednisolone, thiamine, ascorbic acid, heparin) protocol (https://covid19criticalcare.com). [6]
BACKGROUND
Between March of 2013, and Dec of 2018, a research group in Spain conducted a multi-ICU randomized trial to treat ARDS to an estimated 250 patients. It resulted in higher ventilator-free days in the DEXAMETHASONE group than in the control group. By day 60, 21% of the patients in the Dexamethasone group and 36% of the patients in the control group had died. [2] This randomized controlled trial showed profound benefits to treating ARDS with Dexamethasone.
A more recent study between Jan-Feb of 2020 at the isolation ward of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China reported much higher survival rates among the 84 patients with severe COVID-19 pneumonia that were treated with early, low-dose Methylprednisolone compared to those who did not receive such treatment. Because this is was an early observational study, it encouraged later and larger randomized controlled trials to confirm the findings and further study the mid- and long-term outcomes after discharge.
Other studies continued with varying patient numbers and severity of illness (ie. respiratory distress, elevated respiratory rates and significantly diminished oxygen saturation), all seeking comparative clinical outcomes of COVID-19 pneumonia patients with or without Methylprednisolone treatment. [3] This studies concluded that “early administration of methylprednisolone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS”.
| COVID ARDS / PNEUMONIA: |
| Chinese cohort, ARDS, Wuhan – 84 ARDS patients, 46% mortality with MethylP, 62% if no MethylPrednisolone [7] HR=.38 (62% reduction in death) Other COVID Studies, all using MethylPrednisolone 1) HFHS Trial, Detroit, Fadr R- showed a 45% RR, with early MP compared to 29% with dexamethasone in Recovery Trial 2) French study - steroids reduced rate of intubation from 51% to 8.6% - massive 3) Glucocovid trial - 50% Risk reduction for NIV, INTUBATION/DEATH Iin all, it was less ICU, in young it was less death) 4) Canfolanieri Trial from Italy- mortality was reduced from was 23.3% to 7.2%- a 69% relative reisk reduction (RRR), compare this to Recovery trial which had an RRR of 29% if on MV and 20% if on oxygen. |
| NON-VIRAL ARDS: | ||
| 1 Trial using DEXAMETHASONE (277 patients) -LANCET “DEXA-ARDS’ TRIAL (Villar 2020) – increased MV-free days by 4.8 -duration of MV decreased by 5.3 - Number need to treat to save a life using absolute mortality difference = 8 |
4 Trials using METHYPREDNISONE (322 patients) (Meduri, 1998, 2007, Steinberg 2006, Rezk 2013) – increased MV free days by 8.5 -duration of MV decreased by 10.1 - Number need to treat to save a life using absolute mortality difference = 5.3 |
5 Trials using HYDROCORTISONE (494 patients) (Confalonieri, 05, Annane, ’06, Sabry, ’11, Liu, ’12, REzk, 2013, Tongyoo, 2016 -increased MV free days by 4.0 -Number need to treat to save a life using absolute mortality difference = 9.7 |
CONCLUSION
From the viewpoint of treatment strategy, Dr. Kory and his colleagues offer their assessment based on active historical data of mortality and an evidence based review; “the number needed to treat (NNT) to save one life with a therapy is calculated by dividing the absolute risk reduction associated with the treatment into 100. So let's say 80% of patients die and you get it down to 60%, that's an absolute risk reduction of 20. And that means you only need to treat five patients to save one life. And so we tend to estimate the potency of a life-saving therapy using the NNT. The NNT to save a life in ARDS with Methylprednisolone is about five and the number needed to treat to save a life with Dexamethazone using the existing studies is about eight based on old ARDS studies and in COVID it appears much higher than 8. And so when we're trying to advocate for use of methylprednisone, we’re doing so due to the fact that many more real lives could be saved, given the large difference in the efficacy of the two drugs."
If you can treat five patients and save a life (with one drug), whereas it takes eight patients to save a life with another drug (within your first 10 patients of) using Dexamethazone, you may have missed the opportunity to save a couple of lives - hence we emphasize the need for Methylprednisolone.
Trials are still going on, some are randomized control trials and cohort trials using methylprednisolone, including a famous one that received early attention from Henry Ford health System in Detroit, MI, another recently came out of Italy and another one from France. Those trials using methylprednisolone showed much more dramatic benefits- showing a reduction in mortality by 70%! That's a significant number as far as saving lives.
Another study published in May, 2020, based on work done by a company called Advaita Bioinformatics, Dr. Sorin Draghici led a team that reviewed the comprehensive genetic database which lists the pattern of activation of all the hundreds of genes that are activated in cells cultured with SARS-CoV-2 (the virus that causes COVID-19). Almost all the genes produced inflammatory mediators,protein, cytokines and chemokines.
Advaita then used their database of several thousand medicines in which they had catalogued the patterns of “gene suppression” induced by the medicines, and then they tried to find the “best match” that counteracted the pattern of activation. They did this for different viruses including H1N1 and SARS-CoV-2. At the conclusion of an extensive analysis, they found that the medicine whose suppression pattern most closely matched the activation pattern of SARS-Co-V2 was METHYLPREDNISOLONE. And on this top 10 list of matches, DEXAMETHAZONE WAS 6th. Furthermore, according to their report, the researchers repeatedly stated that they didn't think that Dexamethasone would work very well. Hence, this genomic analysis review strongly supported the use of Methylprednisolone over dexamethasone. [4]
EPILOGUE:
BEDSIDE DETECTION WITH DOPPLER ULTRASOUND IMAGING
by: Dr. Robert L. Bard
In reviewing the genes activated by SARS-CoV-2, almost all were for inflammatory proteins / cytokines / chemokines. A study of the gene “suppression” activity of a large number of medications has suggested the one medicine that best neutralized activity of the virus was methyprednisone. A new screening approach that provides real time evidence of clinical effect is the use of 3D high resolution lung ultrasound on the pleural surface and Doppler flow imaging on the inflammatory vascular dilation and blood velocity.
Lung ultrasound relies on the images produced by artifacts: A-lines from normal pleura, B-lines from abnormal pleural-parenchymal disease and increased Doppler flow in consolidations that are pleural based.
Survivors are experiencing either new organ system disorders or complications of ventilator dependency and pulmonary fibrosis. CT and ultrasound are useful in the investigation of these disorders and useful in follow up of potentially chronic conditions. While lung CT abnormalities attain greatest severity approximately 10 days after onset of symptoms and tend to reduce after 14 days during the absorption phase with patients achieving normal living ability by about 2 months after onset, CT findings may remain apparent. CT images in the early recovery phase show reduction of GGO and reduced consolidation but pulmonary fibrosis appears as fibrous shadows such as fibrous stripes, subpleural lines and traction bronchiectasis in multiple lung lobes. This finding has been documented previously in SARS patients discharged after treatment. One can follow up fibrosis with non radiation imaging such as chestwall elastography and diaphragmatic ultrasound to compare with clinical respiratory evaluation.
In the months following patients with very minimal CT images, the clinical symptoms in some progress due to a chronic fibrotic response even as the imaging findings improve. This makes the pleural findings an important parameter and suggests initial and serial follow up with non invasive high resolution 3D ultrasound with elastographic scanning. The normal pleural thickness at 18 MHz linear transducer imaging is 0.3mm to 0.5mm and the normal pleural echo may be inhomogeneous due to the expected respiratory motion. Similarly, the expected A-lines have the same features . A pathologically thickened pleura line is optimally imaged with a 3D 17 MHz linear probe or 18 MHz convex probe. The diaphragmatic pleural interface is important since most of the pathology is found in this area which has some B-line activity in recumbent positions or in elderly patients so the pleural thickness is helpful in determining disease aggression. A thin pleural line with good respiratory excursion suggests healthy tissues. Inflammatory or neoplastic hepatic or splenic disorder may cause attenuation of deep pleural echoes.
Doppler imaging of pleural based pneumonic consolidations shows increased blood flow in aggressive disease which decreases as the pneumonia improves or recedes from chestwall pleural contact. This novel approach is undergoing clinical study and has been used to differentiate benign from malignancy that is pleural based.
SUMMARY
Real time imaging of the pleural thickness is a surrogate marker for treatment effect. A pleural A-line that remains the same or reduces in thickness means pharmacologic drug effect is effective. Conversely a thickening line implies disease progression. Similarly, Doppler flow decreasing in a pleural based consolidation is a positive sign of clinical impact.
CONTRIBUTORS
ROBERT L. BARD, MD, PC, DABR, FASLMS
Advanced Imaging & Diagnostic Specialist
Dr. Bard received the 2020 nationally acclaimed Ellis Island Award for his lifetime achievement in advanced cancer diagnostic imaging. He co-founded the 9/11 CancerScan program to bring additional diagnostic support to all first responders from Ground Zero. His main practice in midtown, NYC (Bard Diagnostic Imaging- www.CancerScan.com) uses the latest in digital imaging technology and has been also used to help guide biopsies and in many cases, even replicate much of the same reports of a clinical invasive biopsy. Imaging solutions such as high-powered sonograms, Power Doppler Histogram, sonofluoroscopy, 3D/4D image reconstruction and the Power Doppler Histogram are safe, noninvasive, and do not use ionizing radiation.
PIERRE KORY, M.D., M.P.A.
Dr. Kory is Board Certified in Internal Medicine, Critical Care, and Pulmonary Medicine. He served as the Medical Director of the Trauma and Life Support Center at the University of Wisconsin where he was an Associate Professor and the Chief of the Critical Care Service. He is considered a pioneer and national/international expert in the field of Critical Care Ultrasound and is the senior editor of the widely read textbook “Point-of-Care Ultrasound” (winner of the President’s Choice Award for Medical Textbooks from the British Medical Association in 2015). Most recently, Dr. Kory joined the emergency volunteer team during the early COVID-19 pandemic in NYC at Mount Sinai Beth Israel Medical Center. He is also a founding member of the Front Line COVID-19 Critical Working Group (flccc.net) composed of 5 critical care experts that devised the COVID-19 treatment protocol called MATH+. (www.covid19criticalcare.com/)
REFERENCES
1) Corticosteroids (Last Updated: July 30, 2020) Recommendations for Patients with COVID-19
2) Dexa randomized multi-unit test in Spain/ https://pubmed.ncbi.nlm.nih.gov/32043986/
3) A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186116/
4) Wayne State spinoff Advaita Bioinformatics identifies generic drug shown to be effective against COVID-19 (Wayne State Univ) https://today.wayne.edu/news/2020/05/12/wayne-state-spinoff-advaita-bioinformatics-identifies-generic-drug-shown-to-be-effective-against-covid-19-37290
5) WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients https://www.who.int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients
6) Critical COVID-19 disease, homeostasis, and the “surprise” of effective glucocorticoid therapy - https://www.sciencedirect.com/science/article/pii/S1521661620307002
Epilogue References:
7) Covid-19 Symposium-Italian Experience 2020 European Society of Radiology March 2020
8) Bard R 2021 IMAGE GUIDED TREATMENT OF COVID-19 LUNG DISEASE Springer(in press)
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