What I have emphasized very early on in my research on GDD is this essential feature: that disease depends on both the presence of the invading entity and the host response. 99.9% of recipients of a GBCA injection seem not to experience long-lasting consequences to receiving the antigen, while 0.01% experience lasting consequences (GDD) with 0.001% of the total of recipients experiencing extremely severe disease. Notice these numbers are similar to the mortality rate of the common Flu and also in the range of COVID-19 (0.5%)
It has been interesting to learn that probably 50% of individuals who have the COVID-19 virus are asymptomatic. Yet despite being asymptomatic can still infect other individuals, and these other individuals may actually then die from the disease. I am not certain what level of asymptomatic individuals occur with other viruses, like the Flu, it may be about the same percentage, and likely varies considerably for different infective organisms. A number of individuals who have transmitted disease are asymptomatic carriers (famously Typhoid Mary) and most often because their immune system ignores the invading enemy (which is good for them, and potentially very bad for everyone else).
So a remarkable similarity between GDD and COVID-19, many people can be perfectly asymptomatic from the foreign antigen, while others can be desperately sick.
What I deduced for GDD is that it had to be primarily the immune system that was the difference: the host response. If the immune system ignores Gd then the individual is fine after GBCA (the 99.99%) The variable severity of the disease reflects the extent of the immune system response, and likely the variety of cells conscripted into the response.
Other critical aspects of foreign antigens (including infections [Covid-19], cancer, and heavy metals [Gd]) are how readily it can be spread from one individual to another (transmissibility, which takes into account the infectious dose[below] and the route of transmission [blood; air borne, mist, particulate; urine; sexual; skin contact; etc) and the related concept of how many particles (for infections: microbes) is necessary to ensure infection, termed ID50, and also called the infectious dose. Generally the fewer particles needed to cause disease the more aggressive and often the more lethal the infection. The infectious dose smaller and transmissibility greater than most Flu strains. What has been clear though with COVID-19, which ofcourse makes perfect scientific sense is the longer the human-to-human contact, and the more confined the space, the more likely for spread (transmissibility to occur) a perfect example is a meat packing plant. Add in more susceptible individuals (nursing homes) then one arrives at a perfect storm for infection spread. So, greater viral load exposure the more likely spread will occur and the more likely the recipient will get severe disease. This ofcourse is also the case with Gd exposure and humans. What was recognized initially with Nephrogenic Systemic Fibrosis: the greater the total body load of Gd, the more likely to get disease and the more likely the disease is severe. This is also true with GDD. The novel observation with GDD, in many respects very similar to a comparison with a virus, is that although the larger the dose (often meaning multiple repeat GBCA injections) generally the more severe disease (and the more difficult to treat as there is more Gd to be removed by chelation), it can also arise from very small dose, if that dose is administered into a small contained space. This is analoguous to a vaccine for a virus. Often the vaccine is injected in a contained space (muscle, subcutaneous fat, intradermal) such that the antigens provide a sufficient local concentration that immune cells congregating around the pocket of vaccine have enough particles to develop a cellular and antibody reaction/response to it. In essentially the exact same immune system process, GBCA injected in a contained space (accidentally, such as an interstitial injection; or deliberately, such as MR arthrography) it is possible to develop GDD from a small dose> often subcutaneous injections may represent 5 ml of GBCA and MR arthrography may be only 1 ml of GBCA. Yet in this setting, a small volume of GBCA can cause GDD. This is not well known, and in not recognizing it, it is even easier for a doctor to dismiss that the patient could not possibly have developed disease to such a tiny amount of GBCA. This type of event defies the strict Bradford Hill criteria (read my blog on GDD and Bradford Hill criteria), but ofcourse fits a more informed Bradford Hill criteria.
With COVID-19, it seems not so clear in humans if the immune system ignoring the virus explains the asymptomatic nature of the disease, or if it is effective killing/neutralizing of the virus. It may be 1 or the other, or both. I did listen recently to an interesting interview on CNN of one of the expert virus hunters. It seems most of the zoonotic viruses that have afflicted humans in the last century (maybe for many centuries) are derived from bats. Poor bats getting such a bad wrap. Zoonotic means transmission from animals to humans. He explained that many bats contain a multitude of viruses in their gastrointestinal tract: Ebola, many species of Corona. Somehow they are perfectly fine from that, they do not make the bats sick. His explanation was that since bats fly, and this causes a great strain on the system, they do not have the reserve to deal with other strains, so their immune system has evolved and adapted such that it ignores the presence of these viruses that are so lethal in humans. This would suggest that often times ignoring the presence of viruses may render them innocuous. The obvious question is: in humans how often is this the case that the immune system ignoring viruses renders them safe. By further extension, to what extent is it the host reaction that makes viruses proliferative? Some cytokine, antibody or other cell product that stimulates or facilitates the virus to replicate or enter cells and replicate? The other scary thought about viruses, is that a number of viruses live in us for the entirety of our lives, starting from the time we first acquired them. Herpes viruses, Epstein Barr virus (mumps), Varicella virus (chicken pox/shingles) all are living in us> they're ok, we're ok. One has to wonder how many others. Many also reside on nerve roots by the spinal chord > also frightening to think of (Herpes, Varicella). Yet, by and large these do not cause enormous problems for most humans, we live with them fine enough, essentially because our immune system has learned to ignore them, except in moments of stress. Perhaps it is the moments of stress with release of immune cell products that these viruses replicate. Will COVID-19 then simply live in us for all of our lives?
A very interesting aspect of COVID-19 is the loss of the sense of taste and smell. To me, this also harkens to the variety of unusual neurological issues we see with GDD. I have discussed this in greater length in prior emails. With COVID-19 does this relate to the common feature of viruses that live with us that they also have a predilection for developing a relationship with the nervous system. Is it some relation with the nervous system, seen also with some other viruses that is causing this? It may also be a local effect from the propensity of COVID-19 to infect nasopharyngeal membrane tissue, because of the presence of cell surface membrane receptors. In some respect the nerve issue with GDD is easier to understand: Gd substitutes for Ca, and maybe only 1 atom in 1 million is sufficient to disrupt/ cause havoc with the nervous system: severe pins and needles, hearing issues, some of the visual disturbances, gait and balance issues. I have opined that the dysregulation of the immune system may allow access to these Ca channels, which otherwise in normal circumstances are blocked: a toll-like function. Does the immune system possess a toll-like function in controlling these calcium channels even in other cells?
What about stroke in young healthy adults with COVID-19? This is a result of the dysregulation caused in the immune system- that cell products released are also stimulating the clotting system, recently experts (see below) have described complement-mediated microvascular angiopathy with COVID-19. As I have mentioned in many previous blogs, there is probably 1,000 + moving parts in the complex immune system and from that interactions with the complement system, clotting system, nervous system... and essentially everything else. Vascular calcification and smooth muscle vessel wall affliction are not a rare longterm consequences in GDD, this is likely a similar concept of clotting/vascular wall issue that COVID-19 causes with general blood cell dysregulation.
My opinion is that when diseases predilect young to middle aged individuals the primary cause of the disease is the host response: the individual's own immune system. This is the case with GDD, in the vast majority of individuals disease originates in young to middle age adults. Cytokine storm is the strong response that the healthy immune system creates in the presence of an antigen, that the immune system is going all out to attack. My opinion, as I have written previously, is that cytokine storm is responsible for severe GDD. There are variations of severity of cytokine storm, and cytokine storm can readily kill the host - and may be the principle cause of death in young to middle aged sufferers with COVID-19, and other infections (Swine Flu of 1918). Cytokine storm is also the most probably cause of death in patients with severe anaphylactoid reactions to drugs (including GBCA). Interestingly, the cytokine storm of GDD almost never results in death, just severe disease - hence there must be different types and different severities of cytokine storm - like there are variations of weather storms.
Diseases that target the immature immune system (young children) and the senescent immune system (the elderly), the principle effect is of the invading antigen and not the host response. Most flus for example. But even then, there are differences in the targeting between the immature system and the senescent system, which I won't discuss. It is interesting that very recently a variant disease from COVID-19 has been described in children, ultimately with more experience the similar concept of a variant, will be seen with GDD.
Perhaps the over-riding similarity between COVID-19 and GDD is that they are both multisystem disorders, and as is common with multisystem disorders, various tissues/organs may predominate. The lung though plays the dominant role in severe COZVID-19 infection, but other organs can be seriously affected as well. The principle cause of the multisystem disorder for severe COVID (I have just learned by listening to a video by Cynthia Magro, MD, chief of Dermatopathology at Cornell University) is complement-mediated microvascular angiopathy, which results in endothelial damage and thrombosis (there is a lot more detail to this). The lung, brain, heart, skin, and kidneys are dominantly effected with COVID-19, but all organs fundamentally can be effected, as the disease is vessel-based. The intestines can also be effected, either by vascularity or direct COVID-19 infiltration. The multisystem pathology of GDD likely reflects a combination of direct Gd deposition with local immune cell reaction (skin, bones), nerve cell involvement, including a sympathetic neuropathy, which may be due to substitution of Gd- for Ca in Ca channels, and diffuse muscle, including smooth muscle (vessel walls, bowel wall) dysfunction both from Gd-Ca substitution, reaction to Gd deposition, and blood cell dysregulation. A number of organs of frequent involvement overlap between COVID-19 and GDD (skin and brain for example) and differ (lung with COVID-19 and bone with GDD). There is also COVID toe which likely represents microangiopathy, and appears to be quite permanent, and GDD foot where a vast array of different colors may arise, and remarkably also be transient, reflecting a combination of the above features of GDD, but possibly primarily a sympathetic dystrophy.
The key for treatment of a foreign antigen disease that is from a non-replicating antigen and where host response is the principle cause of disease, is twofold: 1. remove (much of) the foreign antigen, and 2. control the immune response. This is the case with GDD.
An interesting aspect of removing the antigen with GDD, also has its companion with COVID-19. Effective removal of the foreign antigen in GDD, achievable with a strong chelator has the property of restimulating the disease: the Flare reaction. This is a reflection of immunological memory, and why Flare is much worse in recent onset GDD, because the immunological memory is both fresh and strong. That is why it is 100% essential (by which I mean 100%) to control the Flare with an extended hypersensitivity drug regimen (FRAME). This is what we do in essentially all patients.
The treatment for a foreign antigen disease that is from a replicating viral antigen, in which both: 1) direct viral replication and its causation of dysregulation of the immune and other systems, and 2) in which host response is also a source of disease, is challenging in a variety of ways: neutralizing the antigen directly is crucial (the companion to Gd- chelation in GDD); but in some individuals enhancing the immune system is of value, whereas in others, suppressing the immune system is crucial. As in other disease states, like septic shock, immune system modulation is life-saving, but timing is crucial: in some phase of disease immune system promotion is critical, and in other phase immune system suppression is critical. This alternation of immune promotion and immune suppression varies through the course of the infection, and when to do which is the difference between life and death. To the best of my knowledge, this understanding is imperfect at present with COVID-19. In broad stokes, in general immune suppression is probably helpful in young and middle aged adults for much of the disease infection period, but correct timing through the course of disease is likely crucial; whereas immune system promotion is important in the young and old. In the normal setting in all of us, our immune system carefully choreographs these phases of responding to attack: intense early strike forces, battling, clean-up at the end of combat. We know of at least 10 cell types and 100 or so of their products involved in this choreography.. and likely there are many more involved- with constant changing balance between promoters and suppressors of activity at all phases. The immune system on its own: recognizes the foreign antigen, promotes attack of the foreign antigen, wages battle, cleans up the battle field, calms the troops down, imprisons enemies it can't/didn't kill; but at each step the opposing force is simultaneously occurring, but at the correct, lower, balancing level. Analoguous to the interplay of musical instruments in a harmonious musical piece, such as Beethoven's 9th Symphony.
As we hear repeatedly in the news, the most important method of dealing with COVID-19 and other viruses is the development of a successful vaccine. The vaccine serves to essentially alert and train the host immune system to recognize and neutralize/disrupt the viruses when they enter the domain of the internal body. It is difficult to grasp the concept of viruses not being a living organism.... when they seem so intent on causing us harm. I also read a report of a virus that could insert a CRISPR gene fragment into a bacteria, the virus found in the islands off the coast of California, that instructs the bacteria not to kill it, but to kill other species of viruses. How is it possible that it does not have a brain, let alone is not living? At any rate, it is not a living organism, just an encapsulated collection of molecules containing polypeptides, proteins, and RNA or DNA.
With GDD we essentially want to selectively decrease the host response to the reaction against Gd (and other heavy metals, probably some other things); while with COVID-19, in some settings we want to increase the immune response to them, and others to decrease. Hydroxychloroquine as used for autoimmune disease, and as I have used it on occasion as part of the low potency autoimmune treatment for GDD (AMASE) works as a generic low potency immune suppressor. We want this immune suppression effect at all stages of treatment with GDD, but only some of the time with COVID-19, and most of the time the immune suppression will probably be a disaster (as present larger scale scientific studies appear to be showing - in addition to the uncommon adverse effect of cardiac arrhythmia).
The other 2 major methods to manage viruses in general are 1) antiviral drugs, that somehow will interrupt its 'life cycle' of entering cells and creating the environment to replicate; and 2) injected antibodies, that are already engineered to recognize and neutralize the virus to stop its propagation (the most targeted are monoclonal antibodies with the greatest efficiency at neutralizing the virus). These are direct effects against the virus, with the companion process of chelation for GDD. Tailored to the processes occurring with COVID-19, as the principle multisystem abnormality in severe COVID-19 (again as I learned from Dr Magro) is a complement-mediated microvascular angiography with thrombosis, so anticoagulants are important, as would medications that antagonism complement activation. IL-6 inhibition may be important (this last may also be important for GDD).
GDD is definitely a genetic disease. Experts believe COVID-19 also is genetic, at least in some. If only 50% of patients get sick from the virus and only 0.5% of those who get sick die from the virus, it makes sense that it has to have a genetic component if some of those who die are young or middle aged and perfectly well - that group has to be genetic. Older individuals or those sick from pre-existent disease (obesity, diabetes, metabolic syndrome are all risk factors), probably that group represents nongenetic disease - the deleterious effects of a virus replicating in an already compromised individual. Patients with severe GDD, before they came down with the disease were often perfectly healthy, or even super-healthy, with that superhealth being a reflection of a powerful immune system - but unfortunately that powerful immune system has made them amenable to develop the self-destructive process of GDD. There may or may not be a trigger event: such as recent high potency antibiotics, excessive exercise, and likely trauma.
One of the concerns with the development of an effective vaccine, is that certain formations of a vaccine actually make the infection worse: termed Antibody-Dependent Enhancement (ADE). The principle attacking force of the immune system against viruses include B-cells which are the cells that produce antibodies, and these generally are part of the advanced force (as I have written in a prior blog). The antibody that we want created with a vaccine are generally of the IgG group that we also want designed to neutralize / eradicate the virus, including such functions as presenting the virus from attaching to the cell membrane of host cells, or penetrating the membrane, and probably many other stages of virus activity.
The feared error of antibody vaccine manufacture is that the antibodies developed that recognize the virus, may unfortunately help rather than prevent the virus do any of these functions it needs to survive and replicate. My opinion it is a separate malfunction when antibodies induce cytokine storm, which should mean react too intensely to the presence of the virus... So as with many drugs we want a Goldilocks result: not too weak, not too strong, just right. As with everything that can happened as a result for GDD, there probably is a huge range of possibilities of why vaccines will fail for COVID-19 and other viruses: helping the virus (ADE), too weak (Mama bear - no gender bias intended, negligible effect on controlling any aspect of the virus life cycle), too strong (Papa bear, cytokine storm). Lastly if IgE antibodies are generated by the vaccine, IgE antibodies result in acute allergic reactions, which also can cause a cytokine storm pattern.
An ADE event for a virus that results in a cytokine storm likely often is a result of the vaccine causing too great a reaction of the immune system, such that it destroys not only the virus, but effectively everything else. As mentioned above cytokine storms can have varying severity. In this respect it is comparable to the effective chelation effect-related Flare reaction with DTPA: the effective remobilization of Gd in the vascular system causes the immune system to react, causing Flare. The answer to control Flare occurring during chelation with GDD, is not to use a weaker chelator, because then the problem of redistribution occurs, which is never good; but to either decrease the amount of remobilization with lesser amount of chelator (not my preferred strategy because this means less Gd is removed) or to mitigate the immune reaction with low potency immune suppression: extended hypersensitivity drug regimen (FRAME). If one was 100% certain that a viral vaccine failure was due to too exuberant but appropriate reaction to the virus, a similar strategy of FRAME drugs should work for that as well. Note I use 100% certainty, vaccine failure because the ADE has facilitated the virus entering host cells, then FRAME drugs would make this much worse.
What is also a fascinating aspect of the immune system is that a number of cell lines are very specific to certain types of organisms - so there are specific types of T-cells that respond to just one type of organism, and probably even subtype of organism (T-cells for virus, T-cells for bacteria, T-cells for fungi), B-cells as well, and probably a number of the other cell lines of the immune system are very specific to different organisms, antigens, etc.
This Goldilocks also applies to chelators: too weak (EDTA, DMSA, DMPS, desferroxamine, etc), too strong (unknown, I have postulated the ligands for macrocyclic agents may be too binding to Ca, or perhaps the cage structure inhibits this in vivo, to pick up Gd in tissues- yet to be shown), or just right (DTPA, ?BOPTA (?better), ?HOPO). My hypothesis is the linear structure of DTPA and BOPTA may facilitate picking up Gd in its various speciations in tissues. A linear ligand may act like a ladle picking up chicken chunks (Gd) in a chicken noodle soup, where a macrocyclic ligand may be a box with small holes trying to pick up the chicken in the soup. Although it is possible a macrocyclic ligand could act like a metal tennis ball picking up basket, where the Gd can squeeze between the bars and stay in the basket. This should not be a challenging experiment to perform to sort this out.
Finally, money. There are enormous amounts of money being spent on managing COVID-19, perhaps beyond 1 trillion dollars. If you look into the Christmas stocking of GDD there is only a piece of coal. The reasons for COVID-19 are clear and appropriate. Left on its own, COVID-19 with no management, no isolation, no treatments, no vaccine, probably would have the potential to kill 1 billion people. Consider the death rate of the major plagues that afflicted Europe in the middle ages up to the 17th century - 1/3 of the population killed, small pox, Flu of 1918, as references. In comparison, severe GDD probably afflicts 10,000 people, and mild-moderate GDD 100,000 people. Also GDD is very rarely lethal.... But the other, perhaps even more major problem with GDD is that it is an iatrogenic disease resulting from administering GBCA in MR studies. Essentially all radiologists and the great majority of specialists love MRI for its accuracy in detecting many diseases (and I have personally written a lot of papers on this) and ofcourse there is the money thing too. In the modern era, and I don't want to spoil the fun of this article by dwelling on this, medicolegal considerations are a huge issue. Many stakeholders are dead-set against this entity - which is a shameful tragedy, but it is what it is. Interestingly though, medicolegal and political issues are also present for COVID-19. My opinion is that at best the deaths attributed to COVID-19 are underestimated by 20%, and probably in some countries, some states, underestimated by 100% or much more. The incidence rate of COVID-19 is also unknown, because of the general poor testing for presence of the disease (also with a strong legal and political tinge to this), reported incidence rate is at best 50% of the true total, and likely much lower than that, maybe 100% or more lower in many countries. We don't know the incidence of GDD, except for my experience-derived estimates (described above); the reported estimates are likely less reliable with COVID-19. In the end we may have a better understanding of the death count and incidence for the 1918 Flu, and I fear the Yersinia pestis plague of 1347, than for COVID-19, despite all the computers and everything else we have today.
No money, angry stakeholders, results in no researchers for GDD. Other than the back-and-forth with insults at China and the poor bats, there really is no stakeholders opposed to finding out more about COVID-19 especially cure/treatment. Poor bats. As a segue: all those wet markets, Penguolin scales, rhino horns, bear gallbladder, shark fins, have to stop... if this pandemic has taught us anything: eliminate all of these things. A strong centralized government like China obviously easily could do that if it was motivated... and for those North Americans disenchanted with western medicine and enthusiastic about eastern medicine think Rhino horn and tiger penis (the lesson: critical informed thinking about all of medicine, there are strengths and weaknesses to all systems and ultimately science-based inquiry is very important, and well-informed knowledge-based sense where science is not available). Interestingly random absurd recommendations for treatment with COVID-19 remind me of the variety of inappropriate recommendations posted on-line for GDD... so this is also the same for the two entities. So with no national opposed stakeholders, lots of money, considerable public knowledge, the result is conservatively there are 10,000 researchers and scientists pursuing COVID-19. In contrast, GDD, the despised orphan waste product of the medico-industrial complex, there is only a piece of coal, and knowledge squelched (I know this from the recent spate of journal article rejections I have sustained): I can think of myself, and some who were already or have become friends, whose number I can count on one hand, are pursuing research on this topic.
A final post-script, there is one active research study looking at consecutive patients receiving GBCA, with a number anticipated in the 2,000 - 3,000 range - if the intention is to prove/disprove a disease such as GDD, with an incidence of 1 in 10,000 to 1 in 100,000 for severe disease, the likelihood of seeing just one patient with mild GDD would be 1 in 5, and severe disease 1 in 50 in a study of 2000 consecutive patients. To study this disease one has to perform a study of the patients with GDD in one arm, and in the second arm those who received GBCA and are fine (GSC). This by the way would also be true to evaluate severe anaphylactoid reaction to GBCA, basically the same likelihood. If one refuses to acknowledge GDD then one can substitute in the concept: how likely are we to find severe anaphylactoid reaction. A study with 2,000 consecutive subjects: a 1 in 50 for severe anaphylactoid reaction to 1 in 150 chance of seeing fatal anaphylactoid reaction.
Richard Semelka MD Consulting
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