Therapeutic BCG vaccine protects against long COVID: The BATTLE randomized clinical trial 2024 Jalalizadeh

https://onlinelibrary.wiley.com/doi/10.1111/joim.20033

Abstract
Background
Bacillus Calmette–Guérin (BCG) injected during the COVID-19 convalescence period was safe and enhanced recovery from anosmia and dysgeusia in the acute phase.

Objectives
To report the long-term results of the BATTLE trial, BCG vaccine in adults with mild COVID-19.

Methods
Design: Double-blind, placebo-controlled, randomized (1:1) clinical trial. Intervention: BCG intradermal vaccine and placebo. Patients: A total of 157 BCG and 142 placebo recipients participated in the 6-month follow-up, and 97 BCG and 95 placebo recipients participated in the 12-month follow-up. Measurements: Long COVID symptoms and mechanistic analyses.

Results
BCG reduced hearing problems at 6 months (odds ratio [OR] = 0.26) and sleeping, concentration, memory, and vision problems at 12 months (OR = 0.45, 0.36, 0.38, and 0.36, respectively). Sensitivity analyses confirmed that long COVID-19 symptoms were reduced at the 6- and 12-month follow-ups (p = 0.010 and 0.031, respectively). BCG's crossover interaction paradoxically increased hair loss in women and decreased it in men at 6 months (p = 0.032). BCG immunomodulation is likely mediated through inhibition of Fas ligand expression in the blood and increased induction of IL6, IL10, interferon-induced transmembrane protein 3, and angiotensin-converting enzyme 2 in cultured human macrophages.

Conclusion
Long-term follow-up of the BATTLE trial participants revealed that BCG protects against long COVID development if administered within the COVID-19 convalescence period. The response to BCG was subject-specific, including a paradoxical crossover interaction based on sex. Limitations: Not tested for previous mycobacterial exposure; loss to follow-up, particularly at 12 months.

 

I wonder what the 'placebo' was. BCG gives you a nice red bump to tell you that you had the real stuff. Not many dummies do that. A 'placebo' has to be credible mimic to be any use.

And having a crossover interaction paradoxically causing hair loss all seems a wee bit lie cherry picking.

 

The pre-registration says placebo was just saline.

 

And a distinctive long term spot normally.

hair loss is one of those things that suspicious because that’s an ambiguous term - do they mean like actually having bald patches or people who still have no obvious issue with the amount left on their head being prompted to note the amount they lose in their brush ?

Although to be fair it seems rare anyone would go LESS bald vs before and if you were told to check your head at 6months but not at the start that might be the first time you noticed that but on the back of your head that had been there for a while too?

fir the other things like sleep etc I’ve no idea on the size of the difference and feel that’s the most important thing. If you had 100 people in each and said the treatment meant 1% better sleep or fatigue then any layperson could say that could be as likely to be down to the ambiguity of subjective measure snd if people had a good day so far as anything else or just a few people in one group having something else nothing to do with anything.

the hearing and vision problems I actually find very interesting when you thing large group and if they were objective measures and could be used to pick up fatigue or sensory overload / executive issue implicit in those tests.

I don’t know why we don’t use more of those in general fir me/cfs if done properly ie someone who does psychology scientifically enough they know what factors to control for and if there need to be things like time allowed and light kept constant. And to do it across eg every day for two weeks.

you’d hope they wouldn’t call it hysterical deafness if you can write down or repeat a quickly said sentence more consistently and accurately on rested days than PEM ones. Same with vision stuff.

of course the downside is you have to be well enough to do it at all and not be consigned as drip out

but why do we test just how people feel on fatigue and not eg use tests. I’m sure we don’t with truck drivers or air traffic controllers or when setting their working limits.

so why do we get the claim of no objective measures possible to triangulate what might be eg CBT persuading/conning people to be ‘more positive’ in their answers? I’d like to see a few of these done well to show up how CBT changes the answers but not the fatigue ie distorts and by how much.

 

So the trial was not double blind.
Pretty much a waste of time.

 

According to the pre-registration there was "quadruple masking"

 

Presumably a see-through mask.

 

Yep. From BCG vaccine safety in COVID-19 convalescent adults: BATTLE a randomized controlled trial (2022, Vaccine) —

 

For a properly done trial, what could they have used? Would it be ethical to use something that risks causing a skin ulcer as placebo?

 

This illustrates a general problem we have discussed in the context of cyclophosphamide, as well as therapist delivered treatments - that it can be very tricky finding an ethical 'dummy' for things that can be predicted to produce effects that interfere with blinding.

My own view is that the best way to resolve this is to focus on dose-response studies - something that we routinely do for drugs in other contexts even if we do not use them for proof of concept studies very often. If a treatment works it will have a certain minimum effective dose. You can avoid the blinding problem by allocating groups to doses above and below that. Researchers might complain that it is hard to know what doses to choose. But that simply reveals the vagueness of their theory of action. And if your theory is vague and cannot draw on preclinical data from in vitro or animal studies then it needs to be tightened up by doing the dose response anyway.

If BCG actually works there will be a minimum effective dose and that will almost certainly be different from the minimum dose to produce a local red mark. If cyclophosphamide works there will be a minimum effective dose that will not be the minimum dose to produce nausea, etc. And not only should there be a minimum dose but also an increase in effectiveness for a range of doses above that. Until you have that sort of information you do not now enough about your treatment to justify recommending it.

 

Test BCG vs Covid vaccine, and inject them in the bum? Both cohorts would likely get some local reaction, and it's very hard to get a detailed look at your own derrière.

 

Graphical abstract