My editor over at Medscape said I tended to have obscure titles for my blog entries. I will not argue, since I sometimes I wonder what the hell I was getting at when I reread the entries for my Gobbet o Pus. The meaning of the title will come clear later in the blog when I beat a metaphor to death. I sometimes wonder if my propensity for obscure word play is due to some residual DNA from my grandmother. She was a high-functioning undifferentiated schizophrenic who had a variety of odd quirks about specific word usages, such as the word ‘job’ leading to her recurring correction in her thick Boston accent: a job is what a dog does on the carpet. Wisdom from the depths of insanity.
There are four approaches to the treatment of infectious diseases. The first is antimicrobials, which almost always targets a specific enzyme in a critical biochemical pathway of the pathogen. There can be other mechanisms of action but the antimicrobial target is usually very specific. When you have to resort to treating an infection with a detergent, you are really hurting for an intervention.
The sooner you give antimicrobials, the better the response. For viri, it is best if the treatment is given less than 72 hours after the onset of symptoms. This is part of why the response of COVID to remdesivir appears so anemic: most of my patients did not get to the ER until day 8 or so of illness.
Another form of treatment is supplementing the immune system, most often in the form of antibodies. That is expensive and inconvenient, but, depending on the infection, can be quite effective. Probably a better therapeutic option for toxic shock syndrome and tetanus than COVID.
Then there is interfering with the host’s response to the infection. Much of the damage from infections can be due to a vigorous response of the immune system to the infection and the collateral damage to the host cells as the immune system attacks the pathogen, a very much ‘It became necessary to destroy the town to save it‘ situation. So the thought is if you can blunt the immune system, you can decrease the damage from infection.
Steroids have been the most popular approach, and the efficacy has been variable. Patients often get better faster from a variety of infections with the addition of steroids, but at the cost of adverse drug reactions: increase in blood sugars, infection and delirium. For many, but not all, infections, the risk-benefit is a wash.
Then there are those drugs that move in mysterious ways. Drugs that mechanistically do not appear to directly, specifically, or predominantly target either pathogens or the immune system.
A semi-classic example is statins. There were many hints that statins decreased mortality in sepsis. By what mechanism? Many alleged, likely what I call the cold fusion effect. The effect isn’t really there, but clever people who talk loudly in restaurants somehow find mechanisms of action:
HMG CoA inhibitors (statins) decrease the production of isoprenoid lipid and inhibit the activation of GTPase protein via their effects on prenylation. Statins have been shown to act on several crucial steps in sepsis: the generation of proinflammatory cytokines (IL-6, IL-8, and TNFα), modulation of leukocyte and monocyte functions, and reduction of oxidative stress as well as improvement in endothelial function and platelet activity. In one trial, simvastatin reduced the systemic response to endotoxin administration and decreased expression of Toll-like receptors that hold a key early role in sepsis. In addition, an antimicrobial effect of statins on methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus has been reported.
The clinical result: Who knows? As one typical meta-analysis concluded
Fifteen studies had mortality data of which 10 showed lower mortality among statin users, 4 showed no difference in mortality, and 1 showed increased mortality among statin users. Nine studies examined the risk of developing sepsis and/or infection of which 5 studies showed decreased risk among statin users, whereas 4 studies showed no difference. The overall conclusion of these reviews was that statins may have a beneficial effect in the treatment and prevention of various infections, but due to heterogeneity and observational design of the included studies, further randomized studies are needed to address this effect.
My take on the entirely of the literature? Much ado about nothing. So often the benefit is found in subgroup analysis, not primary end points. So likely garbage.
This brings us to fluvoxamine and the treatment of COVID-45. I first learned about the topic over at HIV and ID Observations, a great infectious disease blog. I always refer colleagues to his classic “How to Figure Out the Length of Antibiotic Therapy“. It had an entry titled Could This Be Our First Effective, Inexpensive, Widely Available Outpatient Treatment for COVID-19? Fluvoxamine is an old antidepressant. Why would it work for COVID-45?
… it has a legitimate mechanism of action — actually, multiple mechanisms, as it has anti-inflammatory, anti-platelet, and potentially antiviral activity independent of its psychoactive properties. If you want to get into the weeds, read this nice summary. But of course many drugs have in vitro mechanisms of action that don’t pan out.
No. That’s the cold fusion explanation. Coming up for a reason a medication (or cold fusion) could work when, in fact, it doesn’t. Sort of a real medicines corollary to Harriet’s Tooth Fairy Science. When a drug has multiple mechanisms for treating infections that are independent of going after the pathogen, it likely has no mechanism of action.
As Dr. Sax noted:
Most of the secondary endpoints also favored fluvoxamine, though the differences were not always statistically significant
Which to my mind is always suggests the findings are nothing.
Dr. Sax is always skeptical, which is why his blog has been a delight to read.
Look, we’ve all been burned by promising studies of these repurposed drugs, and it’s quite reasonable to reserve final judgment until we see the complete data, and even other studies.
And such a study is now out: “Effect of Fluvoxamine vs. Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19“.
Fluvoxamine didn’t do squat. Or in a more professional assessment:
The median time to recovery was 12 days in the fluvoxamine group compared with 13 days in the placebo group, and there was no significant benefit for the primary outcome of time to sustained recovery. For the secondary composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28, the fluvoxamine group had an event rate of 3.9% compared with the event rate of 3.8% in the placebo group.
When the use of fluvoxamine came up in our group meeting a while back, I suggested it was the usual BS we have seen time and again. No real, single, mechanism of action. No specific antimicrobial effects. Small flawed studies. It was ivermectin, hydroxychloroquine, statins, etc., yet again.
And now the metaphor you have all been waiting for.
So you may not be aware that male cows have pancreatic insufficiency. One of the effects of pancreatic insufficiency is fat malabsorption. Fat floats to the top in water. Like cream, only less appealing. So the stool of steers with pancreatic insufficiency floats in water, in addition to being particularly foul smelling. In clinical research, small, retrospective uncontrolled studies of medications with no good mechanism of action yield findings that are the result of bovine pancreatic insufficiency. Then researchers with anosmia examine the buoyant result and think they found something.
Nope.
And you may find yourself looking at retrospective studies
And you may find yourself with no placebo control
And you may find yourself with a large number of mechanisms of action
And you may find yourself in a beautiful hospital, with a beautiful study
And you may ask yourself
Well…How did I get here?Letting the days go by
Let the studies hold me down
Letting the days go by
Studies flowing underground
Into the blue again
After the money’s gone
Once in a lifetime
Water flowing undergroundAnd you may ask yourself
How do I work this?
And you may ask yourself
Where is that large placebo controlled trial?
And you may tell yourself
This is not my beautiful clinical trial
And you may tell yourself
This is not my beautiful clinical resultLetting the days go by
Let the water hold me down
Letting the days go by
Water flowing underground
Into the blue again
After the money’s gone
Once in a lifetime
Water flowing undergroundYou may ask yourself, “What is that beautiful study?”
You may ask yourself, “Where does that treatment go to?”
And you may ask yourself, “Am I right, am I wrong?”
And you may say to yourself, “My God, what have I done?”Same as it ever was…
Same as it ever was…
Same as it ever was…
Same as it ever was…
Same as it ever was…
Same as it ever was…
Same as it ever was…
Same as it ever was…