A ‘delayed infection’ theory of childhood leukaemia | Hacker News Reader

A ‘delayed infection’ theory of childhood leukaemia

icr.ac.uk

148 pointspera73 comments

I found this line very interesting:

> but primarily in children who experienced 'clean' childhoods in the first year of life, without much interaction with other infants or older children.

And:

> Professor Greaves suggests childhood ALL is a paradox of progress in modern societies – with lack of microbial exposure early in life resulting in immune system malfunction.

Reminds me of childhood asthma which some have claimed is also caused by under-exposure to contaminants in the air in early childhood.

Yes, but later they say:

Population studies in people together with animal experiments suggest this second genetic ‘hit’ can be triggered by infection – probably by a range of common viruses and bacteria. In one unique cluster of cases investigated by Professor Greaves and colleagues in Milan, all cases were all infected with a flu virus.

The picture in the article says that the following is needed.

1. A mutation.

2. A clean childhood that does not build your immune system.

3. A follow-up mutation that can be caused by infection.

So the clean childhood and infection as part of the picture are not contradictory to each other.

Makes you wonder how many diseases and bacteria we specifically evolved alongside

I have yet to see compelling evidence that separates the effects of "clean environments" and "environments with lots of cleaning agents used".

Are there any studies which investigate, for example, the difference between mechanical cleaning of an environment with a pressure washer and deionised water, vs chemical cleaning with household cleaners?

I think the article actually sort of addresses this, but only in passing and indirectly by mentioning that what they actually mean is growing up without breastefeeding and with limited exposure to other children. When they say clean, they don't really mean how well scrubbed the floors and counters are.

When these sorts of studies are coming out, they are very rarely talking about the cleanliness of the house, more so the lifestyle and habits of the occupants.

Now there could well be a correlation between households that clean with cleaning agents and those that limit interaction and breastfeeding, but I do think it's very unlikely that that is what is going on.

There was a study recently that (in a mouse model) linked residual soap from baby wipes to food allergy development. https://news.northwestern.edu/stories/2018/april/food-allerg...

There is probable correlation between home distance from highways and rates of childhood asthma (though my mental guess is that may be confounded by mostly poorer people living close to the highway or having a high traffic road built next to them). I just picked one article for reference. Of course both methods could be responsible in some way. https://www.scientificamerican.com/article/traffic-pollution...

Regarding asthma, I know that recently we went hiking (as a family) for the first time, and the state park we visited was had much cleaner air than in the valley... so much so that all my minor allergies vanished when we showed up.

I wonder if "contaminants" should really be read as "clean air with natural particulates" as opposed to the vehicle-generated emissions/tire particulate which seems to comprise most cities?

I wouldn't necessarily assume that the mountain trees are less allergy-inducing. It could just be that higher altitude means stronger and further reaching wind currents to disperse allergens.

Given the connection to asthma you mentioned, here is something that you might also find interesting per this analysis of a few different factors:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877483/

> Results of this meta-analysis indicated an inverse association between atopy/allergies and childhood ALL; the pooled odds of any reported atopy/allergy were 31% lower among cases than among controls and were 21% lower for asthma, 26% lower for eczema, and 45% lower for hay fever.

I've always considered myself unlucky for having hay fever and eczema since childhood, but what if those conditions (whether they be from overly clean environments or the opposite) actually do play a role in preventing childhood leukemia? It makes sense that a child with open sores from dermatitis, or with a persistently runny nose and frequent sneezing, would be better at collecting germs than one without those things.

I'm not familiar enough with asthma to know if that could actually help collect germs, or if it's just that eczema and hay fever are so commonly associated with asthma that it's just a common comorbid condition (the "allergic march" as it's called).

My family lives in one of these "clean freak" cultures of Europe, where there is a high priority placed, mostly by the heads of households, on maintaining the absolute pristine cleanliness of everything and staying out of the dirt. I've always resisted this, because my intuition is that kids who don't or can't get their hands dirty because of neuroses inherited from their parents are sick in other ways - but its interesting to have some scientific reasoning behind this.

So its like the whole "clean freaks" culture that is so prevalent in the west (coz: pharmaceuticals gotta sell soap too, yo.) is at the root cause of this - very interesting.

Will be interesting to see a followup to the research in a year or so and see just what is recommended - but again, that old wives tale that so many of us 'un-clean masses' propose - that we get our kids out in the mud with other kids for exercise and fun - seems to have been proven true.

See, my problem isn't that I worry about the children getting ill from dirt etc. If they want to eat mud then be my guest. I just don't want them touching me / my things afterwards...

I think the point is, they kind of need to get a bit ill from dirt, recover again, and .. rinse and repeat .. but, y'know, far be it for me to worry about your kids. Mine won't stay out of the mud.

We lost our daughter to ALL. It's quite hard to read anything like this without thinking what could we have done differently.

That must be far, far beyond "hard". I'm sorry.

We too lost a daughter to cancer, Nueroblastoma. I’ve always wondered if, even though there’s a genetic component, if there wasn’t an infection or other component we could have done something about. So many regrets. It has a 5% survival rate but we still wonder if we could have done something differently.

There is no blame in doing the best that you could have known how to.

If it helps, you are far from alone. My sister lost her son to SIDS - just months before the American Academy of Pediatrics reversed their recommendation from putting babies to sleep on their stomachs to their backs. In one book I read a doctor described how his decision to go to medical school was shaped by holding a dying child he could do nothing for - and he learned the treatment in medical school and had had the materials on hand. I read a heartbreaking interview once with a doctor whose brother died of an infection not long before antibiotics came on the scene which would have made it trivial to treat. I've seen reference to similar accounts from Civil War surgeons who only realized how many their lack of cleanliness killed after Joseph Lister published in 1867.

These examples could easily be multiplied a hundred-fold.

We do the best we can. Learning improves our future. Nothing can change our past.

I am sorry for your loss.

Well said.

My condolences, I cannot imaging the pain. It is very easy to say I know, but try not to torture yourself. The research certainly does not point to this being black and white, more over, who knows what would have happened would you have had newer knowledge and acted differently. It's probably difficult and painful to imagine worse outcomes but who knows how well you handled things compared to what could have been? It's easier to imagine following all recent knowledge but still getting the same outcome. I'm sure you heard this all before.

So sorry for you loss.

As someone has said further down - this is one theory and isn’t a general medical consensus.

Our daughter was diagnosed with ALL 12 months ago. She went to baby groups from 6 weeks and I would never have claimed our house was particularly clean.

What I have always found frustrating is we have never been asked any environmental questions about our daughters early years. There are many theories of cause so I would have expected them to get as much information as possible from us.

Now we have the capacity to capture enormous amounts of data about our everyday lives, I'm amazed that as a society we haven't started doing wide-ranging pattern recognition to attempt to find environmental triggers for common ailments.

Google and Facebook could redeem themselves by putting some resources into looking for statistical patterns in their massive datasets. Finding the smoking gun for Parkinsons or prostate cancer would go a long way to making their data-collection more socially acceptable.

Our daughter was diagnosed with ALL a month ago. Again, as you said this seems to be a theory under discussion and not a general medical consensus. What I've found in my limited exposure to the medical system so far is that their singular focus is on the treatment and they rarely if ever look back for data that could be correlated to a cause. She's our second child and had her first cold at a few weeks old. Our house has never been particularly tidy and my older daughter kept bringing in the cough, cold and fever from pre-school. Interestingly, she had never been a rather sickly child or one that lacked stamina and has weathered most of the cold and fevers brought home by the elder child surprisingly well. Then she got her flu shot a couple of months ago that resulted in a fairly raging reaction (which the doctors dismissed that the flu shot can't do), which led to appendicitis (unusual for a 3 yr old) which led to the eventual diagnosis of ALL.

Really sorry for the diagnosis your daughter has had. Our girls were about the same age at diagnosis. If you have any questions or want to chat anytime feel free to contact me. L

My ex-wife is a survivor of childhood ALL and her early childhood was the antithesis of that described by the study. She was the 4th of 4 kids each having been born about 18 months apart. So she was exposed to the germs of 3 young siblings. Her parents were also very socially active, so she was also frequently exposed to the germs of the young children of those in her parents social circles.

Please take this study with a grain of salt and don't beat yourself up based upon it.

I'm so, so sorry for your loss. You can't have known. And even now, the scientists probably don't fully know the situation.

Seems like childhood leukaemia would only be experienced by eldest children if this were so. You'd imagine that almost all children living with an older sibling are exposed to the works to "prime their immune system" from birth. That seems like such a strong signal it would have been commented on, possibly named for it, and yet I've never heard of leukaemia as a oldest child disease.

Obviously this is not my field and I have the cynicism of reading and hearing about cancer breakthroughs since before clickbait had a name.

from a random paper from 1995

https://academic.oup.com/jnci/article/89/13/939/2526258

<< A total of 704 cases of childhood ALL were identified. Among 0-4 year olds, the relative risks (RRs) of ALL for birth order positions 1, 2, 3, and 4+ were 1.00 (reference), 0.85 (95% confidence interval [CI] = 0.68-1.07), 0.91 (95% CI = 0.66-1.25), and 0.57 (95% CI = 0.30-1.06), respectively ( P for trend = .09).>>

<<Children born second or later in the birth order had an increased risk of AML (RR = 1.53; 95% CI = 1.01-2.32) compared with firstborns. >>

Exposure to siblings might not be helpful, since those children, particularly young ones, are probably subject to the same environmental factors/presence (or lack thereof) bacteria and viruses.

You may have misunderstood his rationale. The OP article suggests that kids need to have early infections and less clean environments in the first year, as later dirtiness can trigger a mutation that incurs leukemia. The parent comment says: well, if you have an older sibling, you should be more likely to be exposed to dirty stuff, since they're in/out of the house, picking up dirt, kissing dogs, getting sick from daycare, etc.

The mutation is already present. Per the article, the proposed trigger is an immune system that hasn't been desensitized to common environmental pathogens during early childhood.

There are a couple of cited studies in that paper that show different relationships between birth order and relative risk, but this specific study happens to indeed show an inverse relationship between relative risk and birth order.

That second quote is about AML, which is a different form of leukemia than the one discussed in the paper published today.

My younger brother died from ALL when he was 24, got it at 22. Although he was in his twenties, this was considered the "childhood" form of leukemia. Of course this is anecdotal, but because of my experience as the surviving eldest child, I happen to agree with you.

But it's also entirely possible that he had less exposures than I did early in life, despite being the younger. Just one example off the top of my head, he was brought home after delivery to a different house than I was, a new construction at the time. I could also envision some repeat parents "learning" from their experiences with the first child such that the first child actually has more exposure. I do not particularly want to discuss this with my parents to determine if they could think of a reasoning though, lest I add to their survivor's guilt.

I think there are too many confounding factors to make a strong claim either way. For example, the older a mother is the more risk there is of a child having downs syndrome, and that in turn is associated with higher risk of ALL/AML. So without considering other factors, you may be led to think that the younger siblings might have a higher risk (remember that the paper suggested that a first hit mutation may be required before the infection).

My point is just that to test an epidemiologic hypothesis you have to really think about all the different confounding factors that could bias your results.

A family member was diagnosed with ALL this week. That family member also spent 5 weeks in NICU because they were very premature.

The oncologist noted at time of the ALL diagnosis that NICU babies had a higher incidence rate of ALL later in life.

Perhaps here is the causation for that anomaly - reduced very-early exposure to bad microbes in the sterile NICU environment results in an underdeveloped immune system less able to resist genetic mutations leading to ALL.

Perhaps it's something about very early exposure for infants, as at least in the case of my family member, the parents were _not_ hypoallergenic and the child began daycare at a pretty early age (and thus subject to all kinds of nasty nasty germs)

Many studies suggesting asthma is caused by microbiome (eg: 1), perhaps this is as well? The article reads like it might be. Interesting that they don't mention it directly (I can't find any mention).

(1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755449/ (google: "asthma caused by microbiome" for more).

We live in the UK. I have a child who was diagnosed with ALL and successfully treated. He is now 18 months post treatment. He did have a very serious infection at the time of diagnoses that was a major threat to his life at the time. However, we don't fit this proposed model. This was our third child. We don't run a "clean" household - we don't use antibiotic soap, we skip meat raised with antibiotics and we did not run to the GP for antibiotics for every sniffle. My wife breast fed all our children from birth past one year of age. We allowed the children to play in the dirt, eat a bit of sand in the sand box and just generally have fun outside. We don't doubt that gut priming is important but this theory does not explain every case. I understand that the researcher does not claim it explains every ALL case. I just share this for those who are wondering what they could have done. I think we ticked all the boxes of gut priming and our child still got ALL. Be at peace.

Thanks for posting - similar situation here although our daughter is our eldest. My partner is now questioning herself even though our environment was just like yours and we don’t fit their model. It’s annoying the way this theory is being reported.

This is why dogs eat their own feces right? It actually makes a significant impact on their immune system and intestinal health.

Suposedly they have already been exposed to bacteria in their own feces. Other dogs' feces however...

Traversing the gut backwards is quite a feat for a bacterium...

Consuming ones own faeces could be an effective way to travel from one end to the other...

Lots of parasites [1] use that method too.

[1]: https://en.wikipedia.org/wiki/Pinworm_(parasite)

No, dogs only eat their own feces when they lack nutrients on their diet.

How can you tell that they lack nutrients? I have a basset hound and despite his supposedly excellent sense of smell he still enjoys "chocolate" snacks on a regular basis. He's an adult dog and getting Kirkland food. His weight is consistent and the vet is happy about what he weighs. I would love to be proven wrong (please!) but I doubt he's "snacking" because he lacks nutrients. I think he might be a little slow mentally and maybe he's _that_ hungry and doesn't have access to anything else to eat.

and why infants eat their nose pickings. nail biting might be related, too.

Their shit is a good source of vitamin B12, which is presumably part of the reason why they eat it.

Why did the B12 pass through their system in the first place? Or is the B12 somehow generated on the way out?

It's produced by bacteria in the intestines, but not absorbed during the first pass through.

Why would it be absorbed any better the second time around?

(This thread is making me feel queasy.)

I'm not sure, but dogs have significantly shorter (looking quickly, 1/4 the length?) digestive tracts than we do. Less surface to absorb things.

probably produced too late in the process...

Rabbits for example re-eat every piece of faeces because the digestion of grasses take so long it takes two passes to get the energy out...

Like others have said, it takes time for B12 to be produced in significant quantities, and by that time it has passed the small intestine where it can be absorbed.

I'm not sure how eating one's own feces would affect the microbiome but Coprophagia is not unusual for many different species. Without a ruminant's multi-chambered digestive system (see: cattle, deer), animals like rabbits actually have to eat once digested food in order to extract the full nutrients from hard to digest grass and plant matter.

Evolution only optimizes for having offspring in the future. Trying to find a rational reason for some evolved behavior is not necessarily a fruitful way to think about it.

Dogs seem to eat feces for many reasons, such as poor digestion, hunger, boredom, stress, curiosity, seeing mom do it when cleaning up after her litter, getting attention, or avoiding punishment by hiding “accidents”.

>Professor Greaves suggests that childhood leukaemia, in common with type I diabetes, other autoimmune diseases and allergies...

I suspect we will eventually realize that an obsession with a sterile household and Anti-Bacterial Everything (TM) has enormous long term health repercussions, particularly for children. After all, a little case of cowpox turned out to be really beneficial for young milk maidens [0].

[0]https://en.wikipedia.org/wiki/Cowpox#Discovery

Isn't the FDA banning certain anti-bacterial soaps? See https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/u... and https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm378393.h...

Hopefully this is still in the works. I like Dial's anti-bacterial foaming soap, but only because it has the best foaming action. All the alternatives at the local stores suck in comparison. I'm too lazy to make my own. It'd be nice if they sold it with the triclosan, but perhaps they'll just put some other non-regulated antibacterial...

... looking at the Amazon images it looks like they did simply switch to a new active antibacterial ingredient. sigh :(

UPDATE: New actual active ingredient: Benzalkonium Chloride. See https://www.dialsoap.com/Products/Hand-Soap/Spring-Water-Foa...

I do want to emphasise this - this is not some "kids need to play in the dirt more" rant - but I fear it is going to be just that in every newspaper by tomorrow.

There is a real pathway identified here - and real monitoring possibilities. It's just the cynic in me thinks it will be taken the wrong way again.

there never was a golden age of "just enough" dirt. what you had was children who were the survivors of bacterial warfare who then happened to have superb immune systems able to take on all comers

(not very)fun fact: Salvador Dali believed he was the reincarnated soul of his older brother who had died in 1903 at two years old - from Gastro Enteritis. That's not what children are supposed to die of, and if that's the price to pay to avoid childhood leukaemia it is too high.

And why shouldn't kids play in the dirt, eh?

> if that's the price to pay to avoid childhood leukaemia it is too high

Curing leukemia requires multiple rounds of chemotherapy, which are drugs that attempt to kill as much as possible without killing anything important. They aren't particularly safe (which is why cancer patients lose their hair). Once you've cured it, you haven't actually cured it[1]. 10% die from ALL, even treated.

Gastroenteritis is an infection. Sometimes it's bacterial and a round of antibiotics (or possibly probiotics) will do the trick. Once it's cured, it's cured for good. We aren't in 1903. 0.085% die from gastroenteritis usually because they go untreated.

[1]: https://xkcd.com/931/

I think Inworded that very badly - of course with modern medicine we can treat Gastroenteritis while still combating leukaemia.

I was too focused on avoiding the "golden past" theory that seems to trot out too often.

Wonder how this immune system 'priming' benefit is weighed against risks of, e.g. anti-vaxers contacting infants who are too young to receive immunizations, or the risks that many illnesses pose for high fevers.

Are there trade-offs or is there a clear answer?

>"anti-vaxers contacting infants who are too young to receive immunizations"

If the infant is too young to receive immunization that means they are protected by maternal antibodies, so there's nothing to worry about. The real problem you are thinking of is that the age of many vaccinations need to be moved up since maternal antibodies from vaccinated mothers wane quicker.

And IIRC the maternal antibodies also make it harder for immunizations to "take", since the antibodies latch onto the viral particles from the vaccine. I think I remember something about the MMR vaccine being given at 1 year because it's less effective when given earlier, for that reason.

Yep, that is exactly the reason vaccination is delayed. They originally tried giving them at younger ages but stopped because it wasn't working (I've never seen any report of a health danger).

A good book about this: https://www.amazon.com/Missing-Microbes-Overuse-Antibiotics-...

I think this matches up well with how centenarians typically grew up around farm animals. Early exposure to disease builds a stronger immune system to tackle issues later in life.

Agriculture was a much higher percentage of the labor force in the past. And farmers might have had more children than people in cities.

Isn't it common for babies to eat dirt if you don't stop them? Just don't stop them.

Well, you still don't want them getting anthrax or botulism or whatever. And many people live in cities, where the soil may have substantial lead levels.

As a parent, I tried to thread a path between cleanliness and exposure. Didn't worry too much about the kid sucking on furniture at home, but did keep her from licking the subway car, for example. :-P To a certain extent it's just about not going to all the extra trouble of sanitizing everything.

so one thing is no infections in the early life when the immune system develops.

It makes some sense.

so could the genetic mutation be tested-for and monitored/treated based on that?

The title is somewhat misleading. I don't think there is such a consensus among the medical community as to the leading cause of childhood leukemia. He has a theory.

We've changed the title to use representative language from the article.

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