Childhood infections: Early fright and long-term hazard

Children get sick. A lot. Part of the reason children seemingly catch everything around us that’s bad is that their immune systems need to grow up, too. The immune system has to learn how to deal with the dangerous world around us with the difference being that it doesn’t care about cars or bullies getting in its way but instead about tiny pathogens like viruses and bacteria who can wrack havoc in our bodies. When immune systems grow up they invariably make mistakes or get taken by surprise on their way. Once this happens, not only do kids’ reddened little cheeks and large, watery eyes cause parents to do everything in their power to help, but infections in childhood can sometimes pose a real threat with children requiring hospitalisation and medical care. More often than not, this is just an early fright and no need for future bother once the acute infection is defeated. As it turns out, however, infections might pose long-term risks, too. Resulting from a collaboration between University of Cambridge and Karolinska Institutet, we just published a study in the journal JAMA Psychiatry, which shows that childhood infections might increase our risk for later development of severe mental illnesses such as schizophrenia. Strangely enough, the reason for infection posing such risk might be partly related to another risk factor for schizophrenia: low intelligence.

“So stupidity causes schizophrenia?” – it’s not that simple!

To find out what low intelligence has to do with childhood infections and schizophrenia, it’s very important to clarify one point first: When researchers talk about risk factors for a disease, this not necessarily means the risk factor itself is what causes the disease but merely that there is an association present. Consider the following example: Smoking is a risk factor for lung cancer because more smokers than non-smokers develop the disease. Everyone who doesn’t shut his/ her eyes to the evidence out there would probably agree that smoking does actually cause lung cancer. Yet consider this: If you were somehow able to remove the tar that gets from the cigarettes into someone’s lungs (which people have tried unsuccessfully), smoking would no longer cause lung cancer. Similarly, if you magically transported the tar into a pair of lungs, you could induce cancer without there ever being any smoking. So is the tar the real culprit of this story and cigarettes/ smoking are only innocent bystanders? You might think that, in fact, it’s the other way around: Smoking is at the beginning of a causal chain that leads to lung cancer through tar, which constitutes the intermediate link. Thus, smoking represents the causal origin while the tar (that happens to “almost innocently” hang around the cigarettes) just happens to be in the way.

Going back to childhood infections, low intelligence, and schizophrenia, research suggests we might see a similar phenomenon here. Although low intelligence is a risk factor for future development of schizophrenia (as shown by lots of research), like the tar in the smoking example it might only be intermediate in a causal chain. In the intelligence case, scientists explain this phenomenon with the so-called neurodevelopmental hypothesis of schizophrenia. The neurodevelopmental hypothesis is an idea initially put forward by Daniel Weinberger, Robin Murray and Shôn Lewis in 1987 who suspected that low intelligence before the symptom presentation of the disease might already be one of its manifestations. Specifically, schizophrenia might develop throughout childhood and adolescence, thereby already causing damage to the brain without yet generating any of its well known symptoms such as hearing voices. In turn, this disease-related brain damage could become visible in the form of lower IQ or intelligence.

Throughout the past 30 years, there has been much more research and support for this theory, such as evidence of early-life brain changes in future patients. What particularly interested us before starting our study was an investigation by Kenneth Kendler and his colleagues who cleverly took apart the low IQ-schizophrenia findings by including yet another of the disease’s risk factors in the investigation: genetics.

In a large group of more than 1 million Swedish men, they not only looked at everyone bunched together but identified pairs of relatives based on unique genetic relationships:

  1. full siblings (who share 50% of their genes or all if identical twins)
  2. half siblings (who share 25% of their genes)
  3. (first) cousins (who share 12.5% of their genes)

Taking into account the fact that schizophrenia has a large genetic component, one can expect higher risk in those individuals who have a relative suffering from the disease. Moreover, this increase in risk due to genetics will be dependent on the level of relatedness between individuals. For example, the risk will be greater with an affected full sibling compared to an affected half sibling or cousin.

Comparing these relative pairs, Kendler and his colleagues tested whether the risk for schizophrenia posed by low intelligence would also depend on the level of relatedness, that is, whether there would be less risk posed by low intelligence in highly related individuals (full siblings) compared to less related (half siblings/ cousins) or unrelated individuals. If this was the case, it would mean that there are genes causing both schizophrenia and low intelligence. As it turned out, however, low intelligence posed risk for schizophrenia independent from genetic relatedness, which has a very important implication: Something must occur in patients’ early lives- detrimental to brain functioning and intelligence- which may ultimately lead to severe psychotic illness such as schizophrenia. In our new study, we tried to identify what this something could be and this brings us back to childhood infections.

Childhood infections: one common thread

The reason for our interest in childhood infections was previous work showing relationships between childhood infections and psychotic illness as well as between infections and intelligence. Considering the large research base for low intelligence as a risk factor for schizophrenia, these findings suggested to us that low intelligence might only be the above-mentioned intermediate link, for which childhood infections constituted (at least one of) the actual culprits. To test such linkage between these three factors (i.e., infection, intelligence, and schizophrenia), we analysed data from more than half a million Swedish men. Due to the excellent data storage in Sweden, we had information indicating who suffered severe infection as a child (requiring hospitalisation) and who was diagnosed with schizophrenia or other psychotic illnesses as an adult. Additionally, at the start of the obligatory Swedish military service at age 18-20 years, all men were assessed on a variety of tests, among others tests of general intelligence. This is also the reason why we, unfortunately, weren’t able to do any analyses on women: Swedish women were not obliged to follow military service, so there is no information on intelligence levels for them.

This unique collection of information in such a large group of people allowed us to directly test our causal chain hypothesis by running several analyses. First, we again showed (so replicated previous work) that childhood infections were indeed a risk factor for psychotic illness, but we also identified that this risk was particularly due to infections during early years of life (0-4 years) but not later (5-13 years). This highlights the presence of a sensitive period during early childhood, in which the brain is more vulnerable to external threats. Second, we applied the analyses of relative pairs- as was done by Kenneth Kendler and colleagues in their study- to see whether childhood infections and genetics were overlapping risk factors for psychotic illness (meaning specific genes both increased the risk for infections and schizophrenia) which was not the case. Third, we compared different types of childhood infections (those that typically affect the brain versus those that didn’t) and found that risk was not only posed by infections that directly affect the brain, like meningitis, but also by other infections that predominantly act on other parts of the body. Lastly, and most interestingly, we tested what is termed mediation and moderation. This means we tested whether our proposed causal chain did indeed follow the pattern childhood infection→low intelligence→psychotic illness and indeed we found compelling evidence in favour of mediation and moderation. Here, those individuals who suffered severe childhood infection and had low intelligence had particularly high chances of developing the disease. You can also see this in the figure below from the actual paper: The graph shows the predicted percentage of people suffering from nonaffective psychosis (schizophrenia and similar forms of psychotic illness) on the vertical axis, IQ on the horizontal axis, and colouring based on childhood infection (orange) or no childhood infection (blue). The shaded area around the lines is an estimate of uncertainty for our predictions but even taking this into account, you can see a clear trend of increased risk for psychotic illness for people who suffered childhood infection and have a low IQ.

So what to make of these results and why do they matter?

While our findings will not explain the whole complex concept of schizophrenia (as childhood infections don’t constitute the only risk factor), we think the insights gained from our results have important implications for policy-makers, researchers, and clinicians. Due to the additional hazard posed by early childhood infections both for impairing cognitive functioning and increasing the risk for illnessess like schizophrenia in the long-term, more efforts should be directed towards preventing and better treating young children suffering from infections. Important here is also that all severe infections matter and not just those typically thought to affect the brain suggesting increased medical care and attention across the board. This also provides another important insight: There needs to be a route from the body to the brain via which bodily infections can still adversely impact on intelligence (i.e., the brain). One explanation for this link could be provided by our immune system (already discussed in a previous blog on depression): Infections can potentially change our immune systems long-term, which is especially likely when the immune system is just in its infancy itself, so still malleable. We have just published another study that shows how chronic immune system activation (which might arise from severe infection) is associated with lower intelligence, which offers preliminary support for this idea. Lastly, our results might be used to identify high-risk individuals: In addition to family history of psychotic illness, genetic markers, and childhood trauma, information on childhood infection and/ or low intelligence might offer supplementary information to identify people at high risk of developing the disease. In turn, such high-risk individuals could be selected for special interventions that aim to prevent the onset of psychotic symptoms (and eventually illness) in the first place and in this way hopefully decrease the rates of the disease worldwide in the long-term.

 

References

  1. Benros, M. E., Sørensen, H. J., Nielsen, P. R., Nordentoft, M., Mortensen, P. B., & Petersen, L. (2015). The Association between Infections and General Cognitive Ability in Young Men – A Nationwide Study. PLoS One, 10(5), e0124005. https://doi.org/10.1371/journal.pone.0124005
  2. Insel, T. R. (2010). Rethinking schizophrenia. Nature, 468(7321), 187–193. https://doi.org/10.1038/nature09552
  3. Kappelmann, N., Khandaker, G. M., Dal, H., Stochl, J., Kosidou, K., Jones, P. B., Dalman, C., & Karlsson, H. (2018). Systemic inflammation and intelligence in early adulthood and subsequent risk of schizophrenia and other non-affective psychoses: A longitudinal cohort and co-relative study. Psychological Medicine, 1-8. https://doi.org/10.1017/S0033291718000831
  4. Kendler, K. S., Ohlsson, H., Sundquist, J., & Sundquist, K. (2015). IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk. American Journal of Psychiatry, 172(3), 259–265. https://doi.org/10.1176/appi.ajp.2014.14040516
  5. Khandaker, G. M., Barnett, J. H., White, I. R., & Jones, P. B. (2011). A quantitative meta-analysis of population-based studies of premorbid intelligence and schizophrenia. Schizophrenia Research, 132(2–3), 220–227. https://doi.org/10.1016/j.schres.2011.06.017
  6. Khandaker, G. M., Dalman, C., Kappelmann, N., Stochl, J., Dal, H., Kosidou, K., … Karlsson, H. (2018). Association of Childhood Infection With IQ and Adult Nonaffective Psychosis in Swedish Men A Population-Based Longitudinal Cohort and Co-relative Study. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2017.4491
  7. Khandaker, G. M., Zimbron, J., Dalman, C., Lewis, G., & Jones, P. B. (2012). Childhood infection and adult schizophrenia: A meta-analysis of population-based studies. Schizophrenia Research, 139(1–3), 161–168. https://doi.org/10.1016/j.schres.2012.05.023
  8. Murray, R. M., & Lewis, S. W. (1987). Is schizophrenia a neurodevelopmental disorder? British Medical Journal (Clinical Research Ed.), 295(6600), 681–682.
  9. Tsuang, M. (2000). Schizophrenia: genes and environment. Biological Psychiatry, 47(3), 210–220. https://doi.org/10.1016/S0006-3223(99)00289-9
  10. Weinberger, D. R. (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry, 44(7), 660–669.
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Nils Kappelmann

I'm a PhD student at the Max-Planck-Institute of Psychiatry in Munich, Germany, investigating potential biomarkers in the psychotherapeutic treatment of depression.