Bad Blood: Brain Bleed Syndrome May Turn Out to Be Infectious

How do you tell if a condition is caused by an infection?

F. Perry Wilson, MD MSCE
6 min readSep 12, 2023

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It seems like an obvious question, right? In the post-Van Leeuwenhoek era we can look at whatever part of the body is diseased under a microscope and see, you know, microbes — the usual suspects.

Except when we can’t. And there are plenty of cases where we can’t — where the microbe is too small to be seen without more advanced imaging techniques, like viruses — or when the pathogen is sparsely populated or hard to culture like mycobacterium.

Finding out that a condition is the result of an infection is not only an exercise for 19th century physicians. After all, it was 2008 when Barry Marshall and Robin Warren won their Nobel prize for proving that stomach ulcers — long thought to be due to “stress” — were actually caused by a tiny microbe called Helicobacter pylori.

And this week, we are looking at a study which, once again, begins to suggest that a condition thought to be more or less random — cerebral amyloid angiopathy — may actually be the result of an infectious disease.

We’re talking about this paper, appearing in JAMA, which is just a great example of old-fashioned shoe leather epidemiology. But let’s get up to speed on cerebral amyloid angiopathy (CAA) first.

CAA is characterized by the deposition of amyloid protein in the brain. While there are some genetic causes, these are quite rare, and most cases are thought to be idiopathic. Recent analyses suggest somewhere between 5% and 7% of cognitively normal older adults have CAA, but the rate is much higher among those with intracerebral hemorrhage — brain bleeds. In fact, CAA is the second most common cause of bleeding in the brain — second only to severe hypertension.

Most of the textbooks continue to describe CAA as a sporadic condition, but there have been some intriguing studies that suggest it may be transmissible. This article in Nature highlights cases that seemed to develop after the administration of cadaveric pituitary hormone.

Other studies have shown potential transmission via dura mater grafts and neurosurgical instruments. But despite those clues, no infectious organism has been identified. Some have suggested that the long latent period and difficulty of finding a responsible microbe points to a prion-like disease not yet known. But these studies are more or less case-series. The new JAMA paper gives us, if not a smoking gun, a pretty decent set of fingerprints.

Here’s the idea. If CAA is caused by some infectious agent, it may be transmitted in the blood. We know that a decent percentage of people who have spontaneous brain bleeds have CAA. If those people donated blood in the past, maybe the people who received that blood would be at risk for brain bleeds too.

Of course to really test that hypothesis, you’d need to know who every blood donor in a country was and every person who received that blood and all their subsequent diagnoses for basically their entire lives. No one has that kind of data, right?

Well, if you’ve been watching this space, you’ll know that a few countries do. Enter Sweden and Denmark, with their national electronic health record that captures ALL this information, and much more, on every single person who lives or has lived in those countries since before 1970. Unbelievable.

So that’s exactly what the researchers, led by Jingchen Zhao at Karolinska University did. They identified roughly 760,000 individuals in Sweden and 330,000 people in Denmark who had received a blood transfusion between 1970 and 2017.

Of course, most of those blood donors — 99% of them actually — never went on to have any bleeding in the brain. It is a rare thing, fortunately.

But some of the donors did, on average within about 5 years of the time they donated blood. The researchers characterized each donor as either never having a brain bleed, having a single bleed, or having multiple bleeds. The latter is most strongly associated with CAA.

Ok — the big question — would recipients who got blood from individuals who later on had brain bleeds, themselves have brain bleeds?

The answer, is yes, though with an asterisk. You can see the results here.

The risk of recipients having a brain bleed was lowest if the blood they received was from people who never had a brain bleed, higher if the individual had a single brain bleed, and highest if they got blood from a donor who would go on to have multiple brain bleeds.

All in all, individuals who received blood from someone who would later have multiple hemorrhages were three times more likely to themselves develop bleeds themselves. It’s fairly compelling evidence of a transmissible agent.

Of course, there are some potential confounders to consider here. Whose blood you get is not totally random. If, for example, people with type O blood are just more likely to have brain bleeds, than you could get results like this — since type O tends to donate to type O and both groups would have higher risk after donation. But the authors adjusted for blood type. They also adjusted for number of transfusions, calendar year, age, sex, and indication for transfusion.

Perhaps most compelling, and most clever, they used ischemic stroke as a negative control. Would people who received blood from someone who, later, had an ischemic stroke themselves be more likely to go on to have an ischemic stroke? No signal at all. It does not appear that there is a transmissible agent associated with ischemic stroke — only the brain bleeds.

OK I know what you’re thinking. What’s the agent? What’s the microbe, or virus, or prion, or toxin? The study gives us no insight there — these nationwide databases are awesome — but they can only do so much. Due to the vagaries of medical coding and the difficulty of making the CAA diagnosis, the authors are using brain bleeds as a proxy here — we don’t even know for sure if these were CAA-associated brain bleeds.

It’s also worth noting that there’s little we can do about this. None of the blood donors in this study had a brain bleed prior to donation — it’s not like we could screen people out of donating in the future. We have no test for whatever this agent is, if it even exists, nor do we have a potential treatment. Fortunately, whatever it is, it is extremely rare.

Still, this paper feels like a shot across the bow. At this point, the probability has shifted strongly away from CAA being a purely random disease, and towards it being an infectious one. It may be time to round up some of the unusual suspects.

A version of this commentary first appeared on Medscape.com.

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F. Perry Wilson, MD MSCE

Medicine, science, statistics. Associate Professor of Medicine and Public Health at Yale. New book “How Medicine Works and When it Doesn’t” available now.