This post looks at the subject of why patients react to GBCA either right away or after multiple GBCA administrations; and this is in response to this question submitted to me on Facebook:
Can you help us to understand why some people get sick immediately after one MRI and for some it takes multiple doses before illness begins ?
Could it be that the Gadolinium contrast agent that made us sick was unstable to begin with? I think it would be a good idea to scientifically take a second look at all the contrast agents for stability.
This question really asks to look at again the subject of host immune response, which I have written an earlier blog on.
The classic acute immune reaction is the anaphylactic reaction, where the host experiences a new antigen (example bee sting or peanut) on exposure 1, develops an immune cell battalion to deal with it for the next time, so when the host sees the antigen again, IgE releasing B-cells and mast cells (and others) release substances including histamine, and this reaction can be so intense it can kill the host. I have called this before the second strike immune reaction.
Anaphylactoid (and I dislike the use of 'oid' in anything, it seems so intellectually lazy) is a severe reaction, releasing the same immune system chemicals, a major chemical again is histamine (but there are about 10 chemicals commonly described and in reality more than 100) but at the initial exposure to the antigen. So this I would call a first strike immune reaction. This is the standard severe acute hypersensitivity reaction type described for radiology contrast agents: iodine contrast agents (for CT), gadolinium contrast agents (for MR) .
It turns out that there are atleast 4 variations of anaphylaxis, and the same number for anaphylactoid, including, obviously when there are so many subtypes, overlap.
So severe acute hypersensitivity reaction to gadolinium contrast agents are described as anaphylactoid. But, just because they can arise after the first exposure, does not mean that they only arise after the first exposure. Quite often they arise after some subsequent exposure, so after the 3rd or 4th, etc.
For many reasons, as I have described, GDD can be thought of as an acute hypersensitivity reaction with recruitment of chronic immune cells. It can arise immediately after injection of GBCAs (like an acute hypersensitivity reaction) and can occur after all GBCAs, even the most stable (like an acute hypersensitivity reaction to GBCAs), and can occur after the first exposure or a subsequent exposure.
So how is it that in some people they react the first time that they get injected with a GBCA, while others develop it sometime later. Is it possible that with some first time exposure disease developments it is because the contrast agent is somehow 'spoiled' : stored too long, stored too hot, mismanufactured in the factory? And somehow because of this the Gd has been dissociated from the ligand? Possible, but in developed nations I consider this exceedingly unlikely. I say this mainly for the following reasons: i)the disease originates often in careful modern hospitals (reflecting the number of GBCA injections performed), ii) it occurs with macrocyclic agents which should not be dissociated at the time of disease initiation (frequently it arises immediately after injection, when even Omniscan should be fully intact). So, as I have previously observed, stability of the GBCA does not have much influence on whether GDD will arise from an injection - it occurs even with fully intact agent.
This is not to say that if a particular vial has spoiled, that this won't have any bearing. Obviously is a vial is spoiled or contaminated it will be therefore more immunogenic, and more likely to result in a reaction.
The same phenomenon that reaction can arise after the first or after some future injection is not unique to Gd and GDD, in fact it is the norm with hypersensitivity reactions.
I have considered it essential, as I try to expand the knowledge on GDD to borrow heavily from medical literature on different but similar medical issues, and I believe I have a good sense of when to know when something applies, and when something may not apply, or atleast not fully apply. A study of current literature on acute hypersensitivity reactions is needed to form the most current science-based concept of a process.
There are immune cells that are programmed to interrogate entities that are moving in the blood system, or stationed anywhere in the body. These are antigen-presenting cells - including a relatively large group of cells, but including dendritic cells and Langerhans cells). If they recognize an antigen as a threat, then they set off an alarm for the larger community of immune cells to mount an offensive. There are then a number of safe-guards that develop dampening strategies to reactions as well, to prevent catastrophic reactions to antigens. So, on any given exposure, interrogating immune cells may miss an invading antigen, may misinterpret it, may suppress the reaction, may amplify the reaction, or over-amplify a reaction (eg: in GDD). In such complex, inter-related systems as the immune systems, mistakes happen. As far as I am aware, for 60 or so years of immunology studying this issue they have not come up with an explanation whether this is a variability of reaction that can be explained or anticipated in advance in any particular individual.
Following this point further, cancer is a mistake by the immune system (selective immune system decreased responsiveness), infection the same kind of mistake, and autoimmune disease and GDD the mistake of selective immune system increased responsiveness.
I suspect though, that prediction of when an individual may react to a bee sting with anaphylaxis or to develop GDD to a GBCA may actually be scientifically explainable, but we are not there yet. Except one thing we do know, and I have quoted Paracelsus before to provide historical perspective :"the dose makes the poison" > the more bee stings you get at one time, the more likely anaphylaxis; and the more GBCA you get (also cumulatively) certainly the more likely NSF (in renal failure patients) and probably GDD (in all subjects).
I do however hypothesize that GDD individuals can atleast partially break macrocyclic bonds, and this should be studied in the future. In general though the stability of the GBCA (recognizing even the least stable are in reality actually quite stable) does not play a huge role for GDD.
Stay tuned on the latest advancements: