[Sciences/BBB] Histamine-induced blood-brain barrier disruption in teething children: a “post hoc ergo” on glucocorticoids.

Recently, I have been aware about some parents concerned about the impact of teething on the blood-brain barrier integrity, such claims was wrapped through one of the most bizarre “ergo post hoc” fallacy following that sequence:
1. Teething induces histamine release
2. Histamine is a vascular hyperpermeable vascular factor
3. Blood-brain barrier in babies is leak
4. Therefore Teething induces a blood-brain barrier breakdown in children.

You have to agree that is one of the most bizarre fallacious association, but it has been repeated and spread enough to have parents concerned about the impact of teething on the blood-brain barrier. To dispel that myth and beat that dead horse once for all, I think it is important to demonstrate why this information is fallacious.

 

1. Teething and histamine release: understanding the mechanism of inflammation.

First, in order to understand the physiological response of teething, you have to understand the mechanism of inflammation. Everyone can provide a clinical presentation of an inflammation: it is red, it is swollen and it is hot.
Inflammation is triggered by lesion or a wound due to internal or external stimuli, in our case teething. Teething involves a mechanical stress (due to teeth growth) and eventually cells and tissue laceration. Such laceration release intracellular contents into the extracellular space that turns on resident immune cells. These cells in turn release what we refer to “pro-inflammatory factors”, a cocktail of different chemicals that triggers the inflammatory bomb on:

We have amino-acids derivatives and peptides (bradykinin, histamine, inflammatory chemokines and cytokines) and arachidonic acid (AA)-derived molecules. The production of AA-derived molecules (also known as prostanoids) are driven by cyclo-oxygenases (COXs). There are two types of COXs: COX1 that is constantly produced at small level and COX2 that is increased during inflammation.  COX1 produce the “good prostanoids” and COX2 the “bad prostanoids”, the latter being the driving force of the inflammation. COXs are the classical targets of the classical NSAIDs found in OTC products including acetaminophen (Tylenol), ibuprofen (Advil) and naproxen (Aleve). All these small molecule target COXs and stop prostanoids production. In the case of teething, inflammation is mostly driven by the release of prostanoids (such as prostaglandin PGE2) and interleukins (IL-1beta) (Blakey, White et al. 1996). Aside of two obscure studies published 40 years ago in obscure medical journals (Cotias, de Medeiros et al. 1968, Soliman, Abdel Wahed et al. 1977) there is no evidence of histamine release following teething. This therefore nullify claim 1.

2. Histamine and the blood-brain barrier

Histamine is not the major mediator of inflammation, but it is indeed the major mediator in allergic reaction. During an allergic reaction, the immune system respond to the allergen by the production of certain types of antibodies called IgE.

IgE are produced by B-cells that positively responded to the allergen, recognizing it as a foreign body. IgE binds to a certain type of immune cells called mast cells. Mast cells are about less than 1% of the total population of immune cells. These cells are super-loaded with histamine, ready to puff it upon signal. Once IgE binds to its appropriate receptor, mast cells puff and release vast amount of histamine. Histamine in turns triggers the anaphylactic response such as “asthma”, “runny nose” and in the worst case an anaphylactic shock. The main treatment for mild allergic reaction is solved by taking anti-histaminic drugs such as Claritin D or Benadryl.
Because the histamine released in teething is much more negligible than the amount of prostanoids produced, the use of anti-histaminic is worthless because you only address a minor component of the inflammation and omit to block the major component. So the histamine relationship with teething is also refuted at this point. But does histamine can cause the BBB disruption and its leakiness? Yes, but only at high doses and only in very specific cases. Studies that have investigated the biological effects of histamine at the BBB are very old (20+ years) and were achieved with high concentrations (10-100 micromol/L) (Gross, Teasdale et al. 1981, Domer, Boertje et al. 1983, Watanabe and Rosenblum 1987, Butt and Jones 1992, Mayhan 1996). If we consider that histamine is produced during teething, we can conservatively assume that such level would not be over plasma levels found during a severe allergic reaction such as an anaphylactic shock. Reported values for an anaphylactic shock are about 6.35 nmol/L (Laroche, Gomis et al. 2014). Even at that high level, that’s put us about 1000X to 16000X less than values reported to have an activity on the BBB. So claim 2 is also refuted.

3. Is the BBB leaky in newborns and babies?

TL; DR the short answer is NO. If you want to understand why and what is the science behind my statement, please check my previous post about it: https://scientistabe.wordpress.com/2016/05/21/neurosciencesbbb-thiomersal-and-the-blood-brain-barrier-where-does-the-science-stand/)

 

4. Conclusions

By now, we should agree that the reason of delaying vaccines in children due to histamine-induced barrier disruption does not stand to science. There is no scientific rationale to support the hypothesis of a massive release of histamine during teething, such release being well below reported values for achieving a BBB disruption and leakage. If you have your baby teething right when he/she is due for immunization, consult with your AAP-accredited pediatrician for what is best for baby.

    5. References

Blakey, G. H., R. P. White, Jr., S. Offenbacher, C. Phillips, E. O. Delano and G. Maynor (1996). “Clinical/biological outcomes of treatment for pericoronitis.” J Oral Maxillofac Surg 54(10): 1150-1160.

Butt, A. M. and H. C. Jones (1992). “Effect of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brain-surface microvessels.” Brain Res 569(1): 100-105.

Cotias, C. T., E. C. de Medeiros, U. V. Lima and C. F. de Santana (1968). “[Determination of histamine release in the blood serum of children during deciduous tooth eruption].” Rev Fac Odontol Pernambuco 1(2): 95-100.

Domer, F. R., S. B. Boertje and S. A. Sweeney (1983). “Blockade of the acetylcholine-and histamine-induced changes in the permeability of the blood-brain barrier of normotensive and spontaneously hypertensive rats by atropine and pyrilamine.” Res Commun Chem Pathol Pharmacol 42(1): 157-160.

Gross, P. M., G. M. Teasdale, W. J. Angerson and A. M. Harper (1981). “H2-Receptors mediate increases in permeability of the blood-brain barrier during arterial histamine infusion.” Brain Res 210(1-2): 396-400.

Laroche, D., P. Gomis, E. Gallimidi, J. M. Malinovsky and P. M. Mertes (2014). “Diagnostic value of histamine and tryptase concentrations in severe anaphylaxis with shock or cardiac arrest during anesthesia.” Anesthesiology 121(2): 272-279.

Mayhan, W. G. (1996). “Role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier.” Brain Res 743(1-2): 70-76.

Soliman, N. A., S. Abdel Wahed, A. M. Abul Hassan, G. el-Asheiry and A. K. Abdallah (1977). “Systemic disturbances accompanying primary teething: a clinical and pharmacological study.” Egypt Dent J 23(1): 1-8.

Watanabe, M. and W. I. Rosenblum (1987). “In vivo studies of pial vascular permeability to sodium fluorescein: absence of alterations by bradykinin, histamine, serotonin, or arachidonic acid.” Stroke 18(6): 1157-1159.