ARDS: What Is It Really About?
This post is a follow up from my post on another thread Post #: 50324821 with more detail and in the light of the CHF results. I discuss and provide evidence for:
Why 30 days may not be the best indicator of mortality in ARDS
Hospital readmission rates and sequelae
The Recovery Trial that contradicted the rigorous ARDS Network trial
Why SOC improving is the least plausible explanation
How the bad luck may potentially work in our favour
An important and confronting truth that MSB appears to know and could potentially prove
Mortality in Survivors of ARDS
According to Cabrera-Benitez et al (2014) “Many patients with ARDS survive the acute phase, but subsequently go on to die, often with evidence of significant pulmonary fibrosis".
Wang et al (2014) report on one-year outcome survival in ARDS:
“More recent data demonstrate a widening difference between ARDS survival at discharge and long-term follow-up. This “survival gap” suggests that while modern ICU interventions have resulted in short-term improvements in ARDS survival, the overall survival after ARDS may not have improved”. Authors report that out of a cohort of 493 patients 22% died in the subsequent year.
Needham et al (2012) evaluated two year survival in patients with acute lung injury who received lung protective ventilation. Investigators found that of 485 patients 311 (64%) died within two years.
Herridge et al found a mortality rate of 11% in survivors of ARDS at one year follow-up. Chiumello et al (2012) say mortality rate is higher in mechanically ventilated patients with ARDS and similarly, in their small study of 26 patients, the mortality rate was 50% at 6 months and increased to 60% at 12 months.
Chiumello et al (2016) say that in follow-up study of ARDS survivors, long-term mortality has been reported to range between 11 and 60%, not dependent on the severity of ARDS but mainly on age and comorbidities. This does seem to be the consensus. Wang et al say the patients who died after discharge were older and had comorbidities.
Readmission to Hospital and Sequelae
Herridge et al (2016) evaluated recovery and outcomes in ARDS patients. Authors found at 2 years after acute hospital discharge, 39% of ARDS survivors required at least one readmission, and overall 20% of these patients were readmitted more than once. Overall. 65% of the readmissions occurred within the first 3 months and nearly half were related to the development of sepsis.
Josh Farkas, whose blog is pulmcrit, says ARDS has a significant overlap with pneumonia and sepsis. Prescott et al examined one-year healthcare utilization of survivors of severe sepsis. Overall 27% of these patients were readmitted within 30 days of hospital discharge and a total of 63% were readmitted at some point during the first year.
Ruhl et al (2015) found a total of 85 (24%) of the 339 patients ever hospitalized during 12-month follow-up, or 10% of the entire 839-patient cohort, had a hospital readmission within 30 days after discharge, with a median (IQR) time to hospitalization of 10 (3-17) days and the most common admission category (20% of readmitted patients) being pneumonia. In this study the mean age of patients was 49.
Herridge et al (2016) report on sequelae in survivors such as muscle wastage, PTSD and mood disturbances. You will read of long Covid and 'brain fog'. The 'brain fog' can be very serious cognitive impairment:
"Cognitive outcome studies conducted to date found that the prevalence of cognitive impairment in ARDS survivors ranges from 70 to 100 % at hospital discharge, 46–80 % at 1 year, 20–47 % at 2 years, and 20 % at 5 years...The cognitive impairments may be severe and are reported to be below the 6th percentile of the normal distribution of cognitive functioning for some ARDS patients".
Unroe et al (2010) evaluated trajectories of care and resource utilization for 126 recipients of prolonged mechanical ventilation, with a median age of 55. At one year, only 11 patients (9% of cohort) were alive and without functional dependency.
We have a relatively expensive therapy that would potentially be reimbursed, so imo it's important to find out what insurers are actually paying for. Josh Farkas says that survival is what matters to patients most. Patients, however, do not want survival at the cost of debilitating and long-lasting effects. Quality of life is directly linked to healthcare utilization. Fundamentally the issue is about surviving badly, and those patients being relatively young.
We have an EAP in MIS-C in children we haven't heard much about. Such a devastating cytokine storm isn't rare at all and I’ve discussed macrophage activation syndrome in previous posts. Despite the use of corticosteroids, there's still significant mortality and morbidity.
I was interested to note that Herridge et al are not the only investigators who link better outcomes in ARDS to the absence of systemic steroids.
The ARDS Recovery Trial in Dex
I’ve been banging on for years that Remestemcel-L/Ryoncil ‘s rightful place is ahead of steroids. When I started researching ARDS, I was surprised to learn that the use of steroids was considered controversial in this condition and mortality benefit had not been clearly established after 25 years. The largest and most rigorous trial, the prospective, randomized controlled trial performed by the ARDS Network, demonstrated no mortality benefit to corticosteroids.
At the start of the pandemic Covid and Remestemcel-L were a perfect match. The cells migrate to the lungs. Competing drugs addressed a single pathway when what was needed was a therapy for multiple pathways. Our cells were safe. These drugs had bad side effects, a bunch of toxic cr@p. The one thing I was sure of was that steroids wouldn’t show up here.
But then they did. The WHO did a rushed pooled analysis of trials in steroids in ARDS for which the Recovery trial in DEX supplied the bulk of data resulting in other trials ceasing recruitment. In the Recovery trial the difference in overall mortality was 2.8% and most mortality benefit was in late ARDS, a difference of 12.1% I’ve read the paper on on the trial and also what my horse’s mouth expert Dr Matthay has written about it. This is my take from what I gleaned but feel free to make any corrections:
The trial was not blinded, had an adaptive design with a crossover
Physicians could choose who to assign to which arm
Lack of information as to why 1707 patients were excluded
Lack of information as to level of oxygen support
Lack of information as to viral loading
Unclear how many patients remained in ICU or hospital beyond 28 day follow-up
28 days may not be the best indicator of mortality
Lack of info as to adverse events (relevant to what Dr Matthay said re. viral loading)
Lack of info as to survival but with organ damage or requiring dialysis
I’ve read that inclusion criteria expanded to include ‘suspected' covid. 15% of patients were waiting for the PCR test result. Perhaps the trial included a number of patients who had ARDS caused by a different virus?
I’m still not entirely sure what Covid ARDS is, with ARDS being a heterogeneous condition. My understanding is that Covid caused a specific ARDS that responded to steroids, DEX in particular? Not just a specific virus but a specific coronavirus; steroids were used in SARS1 with no conclusive evidence in mortality benefit, some reports of actual harm.
Covid ARDS is said to have a vascular manifestation and the central nervous system is affected. According to Josh Farkas,"Dexamethasone has superior penetration of the central nervous system compared to some other steroids. This is a desirable property among patients with hemophagocytic lymphohistiocytosis (HLH), but it’s unclear whether it is coming into play here".
I’ve written about macrophage activation syndrome that severe Covid has been compared with in journals. MAS is a subset of HLH. Symptoms of MAS can be dysfunction of the central nervous system and blood flow can be affected. Steroids are the usual treatment but despite this, there’s significant mortality and morbidity.
I’m interested to see how patients on the Recovery Trial are doing at 6 months follow-up.
We could still get superior results in overall mortality and secondary endpoints. From Dr Matthay's YT presentation in MSCs and ARDS, I was surprised how quickly fluid was cleared from lungs. This is important because it speaks to vascular permeability, which is relevant to any cytokine storm. If we get consistent results and time to achieve it, that is an indication of batch consistency.
Dr Matthay's presentation was so thorough but he didn't mention fibrosis, which made me wonder if it takes time to show up? If the issue is morbidity then fibrosis is the key.
I’ve read that ventilators contribute to the fibroproliferation process, which is why ventilator-free days are important. Perhaps they could be avoided altogether, and this is where corticosteroids showed no benefit in mortality in patients who didn't require supplemental oxygen.
If we have good data for secondary endpoints, we could possibly still get EAU. Most importantly, this could put our therapy ahead of ventilators and therefore ahead of steroids.
IF SI was provided with correct information, that we flew through the first two interim analyses, then In the light of knowing how and when the treatment paradigm changed to the detriment of our cells, the narrowing gap in third interim analysis is not proof the cells don’t work. It’s confirmation of their fundamental MOA. We know when the cells work and when they don't. The how and the when are equally important in clinical practice.
It also corrects a misconception that our therapy is for severe disease and therefore should be at the end of the line. The cheaper options are anything but if you look at the big picture.
How Exactly Did SOC Improve?
I’ve read that SOC improved because doctors worked out how to use steroids and ventilators. This is despite 25 years of discussion of the highest level in journals. Advice to put patients on ventilators early seemed to come from China. I recall dissenting voices at the time. Later in the pandemic, advice and practice changed and patients were treated with multiple anti-inflammatory agents, as SI said.
Those who say MSB now has two RCTs that ‘failed” should note that what the Osiris trial in MSCs in GvHD and later stage of ARDS trial had in common was steroids. What the EAP in ARDS and earlier stage ARDS trial had in common was absence of steroids.
Wyles et al (2015) studied concomitant steroids and MSCs and concluded steroids were harmful to MSCs. Authors say, “Our study suggests that choosing dexamethasone may result in less harmful effects when compared with other injectable steroids”.
Chen et al (2014) examined the interaction between steroids and MSCs during inflammation. They found DEX and other corticosteroids abolished the therapeutic effect of MSCs:
“Therefore, MSC-mediated therapy requires pre-existing inflammation and concomitant application of MSCs with steroids should be avoided in clinical settings”.
Dr Amy Lightner, who is investigating Remestemcel-L for Crohn's Disease (endoscopic delivery), and colleagues (2019) performed their own study to evaluate this interaction. Authors say:
“Dexamethasone and azathioprine and 6-mercaptopurien affected cell proliferation and migration. Dexamethasone even resulted in cell death at high physiologic concentrations. The same drugs also had the most profound impacts on IL-6, IL-8, and monocyte chemoattractant protein-1 secretion profiles''.
IL-6 and IL-8 were biomarkers that MSB is specifically looking for in ARDS.
Lightner et al say:“In clinical trials with MCSs, a washout period may be recommended for corticosteroids and immunomodulators to minimize any effect of systemic immunosuppression on MSC function and efficacy”.
I know Ryoncil is in EAP for steroid-refractory GvHD, but the children are still tapering off steroids, and I've asked this question here before, whether some of those children might have had an unsatisfactory response to steroids but inflammation has been dampened to an extent, which could affect efficacy in some cases as our cells respond to signals of peak inflammation.
I’m inclined to think how potent our cells are if they can show efficacy in an environment where they’re given a hard time. I always wanted to see what they could do in the absence of steroids and I got a brief window to look, that expression of awe in the eyes of a professional and experienced doctor. But I know that’s not a scientific thing to say.
A Confronting Truth
I provided evidence here that implicates topical steroids in driving chronic conditions such as eczema. Respected dermatologist Dr Marvin Rapaport brought this to public attention. Dr Rapaport isn’t against steroids and has issued a rebuke at Itsan’s cold turkey approach. Some Itsan members, however, have taken themselves through a cytokine storm of sorts, including a close relative of mine, which has resulted in a cure of the severe chronic eczema. The suffering, though, is long and horrendous. The principle is proved but there has to be a better way.
SI has spoken of the benefit of inflammation which has a limit. The key is to harness it but not let it overshoot. He has said that children who survive GvHD to day 100 are “cured''. If the cells support the natural process of the body, they should be able to support it in a cytokine storm and effect a cure.
Although MPCs, our CHF results show best effect when cells respond to peak inflammation shown by CRP. SI calls this a sweet spot. I call it a window.
There were posters here who seemed to have an uncanny insight into the ARDS trial, who were speaking of our cells as salvage therapy, as if that’s how it should be. That prompted me to write the following in Post #: 46049070
“I also question the narrative of the position of Remestemcel-L/Ryoncil at the end of the line after all else has failed. This is because of what I know of Kawasaki Disease, the signals our cells respond to, and how children respond in general...It's looking increasingly important to identify and act in a window of opportunity, as in the case of aGvHD”.
There’s a precedent in Kawasaki disease which MIS-C is said to resemble. Kawasaki Disease can be cured if treated at a certain stage when fingertips have turned red.
That made me think of the rash in systemic JIA that I referred to in the post above. MAS is most commonly seen in systemic JIA. Crayne et al say there’s been a dramatic increase in cases of MAS this century. This fits with the recommendation to use early and aggressive immune suppression in JIA. I’ve said before that I think the fighting fire with fire approach in children is wrong because they’re not mini adults but designed to get better. The chronic disease might be controlled but often grinds away at a low level then can suddenly erupt because the body is trying to cure itself and constantly thwarted in its efforts.
The resulting cytokine storm is imo both a crisis and an opportunity, the window to cure the chronic disease.
In the post above I quoted Peter A Nigrovic, who asks in his review published in 2014 in Arthritis and Rheumatology, if a window of opportunity in systemic JIA exists:
“While some patients continue this so‐called systemic phase for years, a more common course is for fevers and rash to fade away, leaving behind a chronic, destructive, and often therapy‐resistant arthritis. Recent data have raised the possibility that early cytokine blockage might abrogate this latter phase, reflecting a potential “window of opportunity” in the care of these challenging patients".
I appreciate the importance of RCTs but not the narrative that they give a ‘pure’ result because in reality that's often not the case. A drug that does well in clinical practice isn't that common. Temcell has taken off in Japan and has been in the EAP for a decade. Surely MSB derived a lot of data from this. I hope the FDA will approve Ryoncil because a state of disaster exists in paediatric inflammatory conditions.
ALL IMO GLTAH
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226030/
https://www.bmj.com/content/344/bmj.e2124
https://link.springer.com/article/10.1007%2Fs00134-016-4321-8
https://link.springer.com/article/10.1007/s00134-011-2445-4
https://pubmed.ncbi.nlm.nih.gov/28550403/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941154/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598750/
https://pubmed.ncbi.nlm.nih.gov/25187334/
https://www.nature.com/articles/cddis2013537