Ann: DSMB Recommends Continuation of Phase 3 COVID-19 Trial, page-270

ARDS: FIBROSIS STEROIDS

I wasn't surprised at the recommendation to continue the trial. I anticipate overwhelming efficacy in mortality but not necessarily at the specified time. That's partly due to the MOA of MSCs in setting off a healing cascade and also what I learned of ARDS.

Other trials have been stopped early amid much hype and the therapy is now viewed with a degree of cynicism. We have an entirely new (revolutionary) and expensive therapy going up against cheap and familiar ones, such as steroids.

The longer a trial runs the more valuable the data. I also think there could be a need to look for specific things. I never heard the company mention ‘fibrosis’ before, but I noted it three times earlier this year: SI mentioned re. the heart in The Wall Street Transcript; Dr Grossman in the Q3 earnings call transcript re. ARDS sequelae and in a media interview re. ARDS trial.

I did a long-winded post on fibrosis in Post #: 45644466, but imo it's best expressed by @LeftYahoo's succinct Post #: 45658239 where the importance of this is clearly conveyed. I've highlighted what I consider the key part.

"The scar consists of inanimate fibers instead of the living cells that were once there. In other words, no or limited regeneration of cells. And to do the work of metabolism and living, we need cells. So if an organ such as liver, kidney or lung, is progressively replaced by scar tissue due to an ongoing inflammatory illness, the organ will eventually fail. Likewise, if we can heal the organ through a process that doesn't leave scar tissue, and if there's a return of full function, then we can infer regeneration... and that is what we're looking for with stem cells".

I watched the video on YT where Prof Caplan talks about the regeneration of the fingertip if you don't put a stitch through it. What to infer from this? Don't suppress the natural process? Could this be possible with major organs too, but at the same time intercept the message that all is lost?

This has implications for aberrant repair in the form of sclerodermatous skin GvHD and lung GvHD, which are common chronic conditions. Jakafi does a reasonable job with skin GvHD and patients do report relief from this drug, but it hasn't negated the use of expensive in-hospital treatment ECP. Also, lung GvHD is a particularly dreaded complication; patients have frequent bouts of pneumonia, some have to go to hospital to have fluid drained from the lungs and lungs can become stiff, as has been described in ARDS.

Preventing morbidity will not just improve quality of life but also prevent mortality.

MORTALITY IN 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”.8 Severe fibrosis was demonstrated to be a frequent complication in ARDS as early as the 1990s.9 Lung histologic studies of patients with late ARDS suggested ongoig inflammatory injury together with progressive fibrosis".

Damaging inflammation and fibrosis can also affect other organs:

Jain et al (2006) say, “ Finally, most ARDS deaths are due to multiorgan failure. Less than 5% of patients actually die of refractory hypoxemia.48. Since the primary end point of most studies is mortality, patients may be improving from a pulmonary standpoint but may not show mortality benefit because of extrapulmonary organ failure"

Harman et al (2020) say renal failure is a frequent complication of ARDS, particularly in the context of sepsis”.Panitchote el al (2019) studied patients with acute kidney injury. Patients with pre-existing kidney disease were excluded. "A total of 634 ARDS patients were screened The 357 patients were examined for eligibility; however, 113 patients did not develop AKI until day 28 of ARDS (Fig. 1). We included 244 patients with AKI in the study, 60 (24.6%) patients had stage I AKI, 66 (27%) patients had stage II AKI, and 118 (48.4%) patients had stage III AKI. In patients without complete recovery, 14 (9.5%) relapsed without subsequent recovery, and 134 (90.5%) never recovered at any point".

SURVIVING ARDS

We're hearing that some patients who've survived severe Covid-19 have long-term problems. This was also the case before Covid-19.

Rhul et al (2017) published a study on four ARDSNet trials in 44 US hospitals with one-year follow up:"Of 859 consenting survivors, 839 (98%) reported healthcare utilization, Over 12 months, 339 (40%) patients reported at least one post-discharge hospitalization, with median estimated hospital costs of US$18,756. 30% of admission were for pneumonia".

A study by Intermountain Medical Center, John Hopkins University and University of Utah (2017) found survivors of ARDS struggle after discharge.

"If you had ARDS 25 years ago, we thought we saved your life in the intensive care unit, so we'd say, 'All is well, off you go -- you'll be fine,'" said Dr. Brown. "We had no idea as doctors how wrong we were about life after ARDS".

Out of 645 survivors of ARDS, six months after discharge half were not living independently (with relatives or in nursing homes) although prior to suffering ARDS, 91% had been.

Patients and doctors care about quality of life but in terms of the big picture and cost, not just of ICU, reduced QOL is strongly associated with increased health care costs.

STEROIDS IN ARDS

In her review on studies and trials using steroids in ARDS, Catherine L. Hough MD asks, “Should we ever give steroids to ARDS patients?”

“First, there is no evidence that corticosteroids prevent the development of ARDS among patients at risk. Second, high dose and short course treatment with steroids does not improve the outcomes of patients with ARDS. And third, while there is compelling data that low dose and prolonged treatment with steroids improves pulmonary physiology in patients with ARDS, additional studies are needed to recommend treatment with steroids for ARDS”.

Meduri et al published a 2007 study in 91 patients in early severe ARDS including 66% with sepsis using low dose prolonged methylprednisone. Authors say the ARDS network benefits were lost due to premature discontinuation and that "the review article by Calfee et al (March 2007)1 provides an incomplete picture of the recent literature on prolonged glucocorticoid treatment in ARDS".

Calfee et al reply to this, saying they focused "on the largest and most rigorous trial on this issue: the prospective, randomized controlled trial performed by the ARDS Network, which demonstrated no mortality benefit to corticosteroids"... "The 2007 study by Meduri et al was not published at the time of our review; however, this trial4 has significant limitations as well. For one, the majority of patients randomized to placebo who remained on mechanical ventilation at day 9 of the study were crossed over to open-label methylprednisolone, making outcomes analysis after that point (such as mortality and ventilator-free days) very difficult to interpret".

STEROIDS IN COVID-19 ARDS

David Gorski, who writes the blog respectfulinsolence, calls the announcement about pooled analysis of trials in steroids in severe Covid-19 'science by press release'. He compares it to the hype over Hydroxychloroquine. .

"Personally, I can’t help but note that the question of whether steroids like dexamethasone improve survival in ARDS (regardless of the cause, including COVID-19), 'regardless of the cause', is not a new question".

That made me feel a bit better about a dumb question I asked a scientist friend: Three members of my family caught a virus and had similar symptoms. One case resolved but two didn't. In the beginning I was obsessed with the virus. I was always on the phone asking doctors to try to find it and kill it. It took a while for the penny to drop. The virus had set off an immune reaction and we had to deal with the reaction it had caused. At that stage the virus was now irrelevant. Why then, once patients have reached the phase of severe ARDS, is the virus still relevant?

(According to the guidance by the British Thoracic Society, recommended follow up of patients with a clinico-radiological diagnosis of COVID-19 pneumonia by the British Thoracic Society: "The COVID-19 swab status of patients is not relevant to this guidance".)

I suppose we have to look specifically at Covid-19 ARDS. The virus appears to cause a specific type of ARDS. According to Josh Farkas, whose blog is Pulmcrit, "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".

Macrophage activation syndrome is a subset of HLH. Symptoms of MAS can be dysfunction of the central nervous system and blood flow is affected. Some cases of MAS can result in ARDS and microthrombi have been found in lungs. MAS is not that uncommon and massive doses of steroids have been the mainstay treatment. I noted a couple of papers comparing Covid ARDS to macrophage activation syndrome.

According to the BBC, if the steroid had been given to UK patients at the start of the pandemic, 5,000 people could have been saved. I'd have thought, though, that regardless of the cause, DEX, being known to be a potent immunosuppressant, would have been used in such manifestations of severe Covid-19 ARDS?

DEXAMETHOSONE RECOVERY TRIAL

The WHO did a meta analysis of pooled data on steroids in Covid ARDS. The RECOVERY trial contributed 57% of the weight in the primary meta-analysis of 28-day all-cause mortality. The signal seen in this trial led most ongoing trials of corticosteroids to suspend recruitment.

According to authors of meta-analysis (JAMA September 02 2020): " Overall, dexamethasone resulted in an absolute reduction in mortality of 2.8% (22.9% vs 25.7% for usual care; age-adjusted rate ratio, 0.83 [95% CI, 0.75-0.93]). The benefit was greatest for patients who were receiving invasive mechanical ventilation at the time of randomization with mortality of 29.3% for dexamethasone vs 41.4%"

"This analysis was expedited because of the release of results from the RECOVERY trial, which found that the absolute risk of death was reduced by 12.1% among those assigned to low-dose dexamethasone who were receiving invasive mechanical ventilation at randomization"

The 12.1% difference doesn't sound very good to me, even for a cheap drug, but that's just my own opinion and I'm no scientist.

According to Josh Farkas, whose blog is Pulmcrit, one weakness of the trial was not just the open label design, but lack of granular data about patients (e.g., laboratory values, viral load) but says, "This lack of detail is a necessary sacrifice required to recruit over 6,000 patients".

(I also found protocol that said 'adaptive design'. Does that mean crossover, which is considered inappropriate because bias can be introduced?)

The first commenter on the JAMA article, Prof Brian Lipworth, MD, Scottish Centre for Respiratory Research, Ninewells Hospital, Dundee writes,"However, it is perhaps more clinically meaningful to consider absolute mortality rates". Prof Lipworth also says, " Labelling 6 mg of dexamethasone as low dose is misleading as this is equipotent to 40 mg of prednisolone which is considered to be a medium dose of glucocorticoid when treating patients with airflow obstruction".

According to authors of meta-analysis, "The definitions and reporting of serious adverse events were not consistent across the trials and therefore a meta-analysis for this secondary end point was not conducted" ...."We are aware of no reason that the effect of corticosteroids on postdischarge 28-day mortality would differ from that on predischarge mortality, but it will be important to report on longer-term mortality, including postdischarge mortality", in future analyses".

There was no follow up so we don't know how many patients survived but with lung, kidney, heart damage or cognitive impairment. We don't know how many patients were re-hospitalized after discharge. Some patients die after discharge. In the study by Combes et al, 58 out of 197 patients died 1-57 months after discharge.

STEROIDS AND FIBROSIS

The rationale of the research by Meduri et al in steroids and ARDS is to target the fibroproliferation phase, consensus being that this phase starts much earlier than previously thought.

I've been reading in journals that steroids have both potent anti-inflammatory and anti-fibrotic action. I was surprised to learn about anti-fibrotic action because steroids are still widely used in IBD and there remains a high rate of surgery due to aberrant scarring in terms of fistulae, strictures and PSC affecting the liver. In my post on fibrosis I referred to above, I cite researchers who say there's currently no specific anti-fibrotic therapy for IBD. Steroids are first-line therapy in acute GvHD but despite this, complications of aberrant repair in the form of sclerodermatous skin GvHD and lung GvHD are common in chronic GvHD.

With regard to DEX specifically, Lui et al (2008) conducted research in rats. Authors say, "Our data indicate that neonatal DEX administration in rats leads to renal failure in later life, presumably due to an early inflammatory trigger that elicits a persistent pro-fibrotic process that eventually results in progressive renal deterioration".

Manuyakorn et al (2012) found pro-fibrotic effect of Dexamethasone in human airway fibroblasts. "These findings suggest that apart from their immediate anti-inflammatory effects, corticosteroids may have a long term detrimental effect on collagen cross-linking, affecting airway wall mechanics.Should such an action be evident in vivo this could have a detrimental effect on decline in lung function and disease persistence in asthma".

Dik et al (2003) studied 15 premature babies. Authors say,"Treatment with systemic dexamethasone (DEX) is commonly used in infants with or at risk of CLD and improves pulmonary function, facilitates weaning from the ventilator and reduces pulmonary inflammation 8. However, it has been suggested that DEX treatment may not inhibit the development of pulmonary fibrosis in CLD, since it does not decrease fibronectin concentrations in bronchoalveolar lavage (BAL) fluid"

Authors conclude:

"In conclusion, the present study suggests that systemic dexamethasone treatment, as opposed to its anti-inflammatory action, does not reduce pulmonary fibroproliferation in chronic lung disease of prematurity. Therefore, this study does not support the use of dexamethasone for preventing the fibrotic response in infants at risk of chronic lung disease of prematurity".

Steroids have saved a lot of lives and significantly reduced the death rate in conditions such as ulcerative colitis. I’ve always seen them as broad immunosuppressants but maybe they can be more specific than I thought; however, in certain conditions, looking at the big picture, I don’t see how they can compare with cells that don’t have off target effects and secrete factors for repair such as folistatin and growth factors. In the presentation by Dr Matthay, researchers found removal of growth factor KGF largely abrogated MSCs' ability to remove edema fluid from lungs. Given the gut/lung axis, this has implications for MSCs ability to restore gut integrity too, as has been shown with growth factor enemas in UC, and restoring gut integrity is likely the key switching off a cytokine storm.

My conclusion about steroids in Covid ARDS is this is not competition but greater contrast, not just to these drugs, but our rigorous design of trial and absence of any hype.

ALL IMO GLTAH

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991945/

https://www.mayoclincproceedings.org/article/S0025-6196(11)61672-8/pdf

https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-019-1439-2

https://link.springer.com/article/10.1007/s00134-017-4827-8

https://intermountainhealthcare.org/about/who-we-are/trustee-resource-center/newsletter/newsletter-archive/icu-patients-who-survive-ards-may-suffer-from-prolonged-post-intensive-care-syndrome-study-finds/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297198/#:~:text=No%20studies%20support%20the%20use,outcomes%20of%20patients%20with%20ARDS.

https://journal.chestnet.org/article/S0012-3692(15)36685-X/pdf

https://respectfulinsolence.com/2020/06/17/dexamethasone-and-hydrochloroquine-a-tale-of-two-drugs-for-covid-19/

https://www.researchgate.net/profile/Vincent_Bloks/publication/309731322_F768fullpdf00_M/links/582020b508ae12715afafe97.pdf

https://www.jacionline.org/article/S0091-6749(11)02808-9/fulltext

https://erj.ersjournals.com/content/21/5/842