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Anaphylaxis

Category: Illness or disabilities

Type

Involuntary

Introduction and description

Anaphylaxis is a serious life threatening allergic reaction that is rapid in onset and may cause death. It typically causes more than one of the following: an itchy rash, throat or tongue swelling, shortness of breath, vomiting, lightheadedness, and low blood pressure. These symptoms typically come on over minutes to hours.  The mechanism involves the release of mediators from certain types of white blood cells triggered by immunologic mechanisms. 

Worldwide, around 2% of the population is estimated to experience anaphylaxis at some point in their life.   It is much higher in western countries.  The number of people who have had an anaphylaxic attack is around  4–100 per 100,000 persons per year.  About 30% of people suffer more than one attack.   Rates are increasing: with the numbers in the 1980s being approximately 20 per 100,000 per year, while in the 1990s it was 50 per 100,000 per year. The increase is primarily for food-induced anaphylaxis.

Currently, anaphylaxis leads to 500–1,000 deaths per year (2.4 per million) in the United States, 20 deaths per year in the United Kingdom (0.33 per million), and 15 deaths per year in Australia (0.64 per million).

The discoverer of anaphylaxis was Dr Charles Robert Richet, who obtained a Nobel Prize for his work in 1913.  We will use his description, from his Nobel Prize speech, because it is clear that absolutely no understanding of his findings appears to exist, and virtually no progress on stopping this reaction has been made, since he made these discoveries.

 

Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis

It is not without emotion that I address this assembly on the experiments that have brought me, through the most gracious favour of the Caroline Institute, the highest reward that a scientist has the right to hope for. I ask your indulgence in speaking of my own research, as I must do, and in setting out the findings that have given anaphylaxis a leading place in general pathology over the last decade.
First I feel I must explain and indeed justify the use of the word itself, for it may seem somewhat barbarous at first glance. This neologism I invented twelve years ago on the assumption, which I think is still valid, that a new idea calls for a new word in the name of scientific precision of language.
Phylaxis, a word seldom used, stands in the Greek for protection. Anaphylaxis will thus stand for the opposite. Anaphylaxis, from its Greek etymological source, therefore means that state of an organism in which it is rendered hypersensitive, instead of being protected.

More details on how Dr Richet found out about anaphylaxis and the experiments he used is found in the Science section - Anaphylaxis.

When does it occur?

Dr Richet discovered that anaphylaxis occurs when ‘substances’ get into the blood stream through an open wound or more importantly by inoculation – including vaccination.  We now hypothesise that if one has a ‘leaky gut’ then substance can get into the bloodstream via this route too, but at the time that Dr Richet did his research the principle route was deliberate vaccination.  Thus inject a substance into a person and this is the action which may then trigger an anaphylactic reaction LATER, not immediately but later.  The specific circumstances are

(1) the subject has to have had a previous injection, an open wound or had a period of leaky gut in which particles of said substance have entered the blood stream

(2) a three or four week period must elapse before the anaphylactic state results. This is the period of ‘incubation’.  In fact, it is usually the time it takes for the substance[s] to reach the immune system and for it to create an immunological record of that substance as a ‘foe’

Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
……we will consider the example of a subject that has received a poison.  Let us suppose the dosage to be moderate and that after a few days the subject is, or at least appears to be, normal. If, at this point, a further injection is given of the same dosage of the same poison, what will happen?  There are three possibilities.

  • The first and simplest is that there has been no change in the organism and that in receiving the same dosage as one month previously, exactly the same phenomena will result, in exactly the same conditions. Naturally this is what happens most of the time. Specialists and doctors work on this assumption when they repeat the intoxication at one month intervals.
  • The second possibility is that the subject has become less sensitive. In other words, the preceding intoxication has produced a certain condition of tolerance or non-sensitivity. This will mean that a stronger dose is necessary at the second injection to give the same results. This is the case of (relative) immunization or, as it is sometimes called, of mithridatism. The most remarkable case of this tolerance is to be seen when opium or morphine are used. People who take morphine injections need stronger and stronger doses for the morphine to take effect. Some unhappy morphine addicts get to the point of standing a dose of 20 grams, whereas one decigram is dangerous in a normal subject. It has been known for persons to drink one litre of laudanum per day [sic], while one drop of laudanum produces already some effect.

These two cases, of unchanged sensitivity or stability, and of diminished sensitivity or habituation, have been known since long. Now I have shown that there is a third possibility, frequently to be observed in certain conditions which I have specified: this is of heightened sensitivity. The first injection, instead of protecting the organism, renders it more fragile and more susceptible. This is anaphylaxis.

Symptoms

General symptoms

 

Anaphylaxis has been observed in all animals: the horse, the goat, the ox, the rat, the pigeon, the duck and even in frogs.

In very serious cases of anaphylaxis, there may be vomiting, bloody diarrhoea, syncope [heart palpitations or even heart failure], unconsciousness, asphyxia and death.

Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
Anaphylactic symptoms vary to a great extent, although the differences are marked rather according to the nature of the experimental animal than according to the nature of the poison used. It is indeed worthy of note to find that the phenomena are constant, whatever the poison used.. I have made especial study of anaphylaxis in dogs, which permits of greater accuracy in specifying symptoms than in experiments with the guinea-pig. In the dog, four degrees of anaphylaxis may be distinguished, according to intensity.

  • In the lightest form, the main symptom is prurience or itching. The animal, let loose, sneezes and gives various shakes of the head as if there was something inconvenient in his ears. The dog scratches his head and sides with his paws, sometimes frantically. Sometimes he rubs his muzzle against the ground and rolls over.
  • The next stage in anaphylactic intensity is characterized by itching again, but this time more violent. This is followed almost immediately by various symptoms; more rapid breathing, lowered arterial pressure, faster heart-beat, vomiting, blood diarrhoea and rectal tenesmus.
  • At the third degree, depression of the nervous system is such that the itching has gone or almost gone. The animal has no strength to vomit, diarrhoea is marked while the fluid passed from the rectum is often almost wholly blood. The nervous symptoms often develop so suddenly and violently that there is no time for colic and diarrhoea. Ataxia follows at once. The animal reels as if drunk, the pupils are dilated, the eyes haggard and after heart-rending cries, the animal falls to the ground, urinating and defecating underneath himself, unconscious, no longer reacting to the excitations and in complete mind-blindness. Breathing is laboured and agonized. The heart beats are so faint as to be barely perceptible: blood pressure hardly reaches the one or two centimetre mercury level. To sum up, all the symptoms point to the central nervous system being the seat of severe and sudden intoxication. This brutal assault of the poison on the nervous system has been called anaphylactic shock.
  • There is a fourth degree of anaphylaxis, it may be said, which is more serious still: when all the symptoms, instead of passing off, worsen so that within a quarter or a half hour the subject is dead.

In the dog such death at the onset is rare. In most instances, following the anaphylactic shock, the dog revives. After fifteen or thirty minutes, he gets to his feet, staggering a bit, regains feeling and consciousness and is left with only blood diarrhoea still persisting from the anaphylaxis. Often death takes place during the night following the injection; but constantly after a period of apparent recovery.
In the rabbit, according to Arthus, respiration becomes polypneuic. The animal falls on its side, throws its head back, makes running movements with the legs and then suddenly breathing stops. Heart failure is systolic and death ensues within a couple of minutes.
Arthus also observed some interesting local effects of anaphylaxis in the rabbit. The second injection being given in the same ear as the initial injection, ulcers and gangrene appear, although there are almost no general symptoms. This local effect of anaphylaxis is often called the "Arthus phenomenon".
The guinea-pig is extremely sensitive to anaphylaxis. If the anaphylaxis is slight, only symptoms of itching, excitation and heightened breathing appear. Often the animal falls on its side, sometimes in violent convulsions, sometimes on the contrary paralysed and powerless. In both of these cases, death takes place fast and it is almost a matter of seconds between the injection and the final failure of the heart.

Symptoms – human beings

 

If one gives a person an injection – a vaccination, the symptoms characteristic of the second injection, namely swift and total depression of the nervous system, do not in any way resemble the symptoms characterizing the first injection. 

Thus after a vaccination you may think all is OK, that the body has built up immunity to whatever it is you have been vaccinated against and that from then on all will be fine.  Not so.

The anaphylactic reaction comes on exposure to the substance the second time, and it can happen on the tiniest of exposures

Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
…. the effects of anaphylaxis in mankind are very well known. Two doctors from Vienna, Pirquet and Schick, have studied the matter with the greatest care. They have described serum-sickness ("Serum-Krankheit") in children subjected to injections of diphtheria serum and they saw that it was in most cases an anaphylactic phenomenon. It is only in the rarest cases that the first injection is productive of immediate reaction. When it comes to the second injection, an immediate reaction follows for 90% of the cases, that is to say when the period between the first and second injection is from ten to thirty days.

The symptoms to be observed are very close to symptoms observed in animal subjects: urticaria, erythema, pangs of pain, itching and in the worst cases demi-syncope, with nausea, vomiting, hyperthermia, edema over the whole skin area and general urticaria.

Thus by comparison of anaphylactic effects in man and the animals, it will be seen that they are akin. It is as if poison had been produced, which reacts upon the nervous system, especially on the vaso-motor nerves or the trophic nerves of the skin……

Anaphylaxis has caused death in certain instances. …..Some years back I was in Brazil and I heard the story of a doctor who had given himself a preventive injection of anti-plague serum. The next year a new outbreak of plague was feared so he persuaded his students to have a preventive injection of the same serum. He set the example by giving himself another one. This was however an unleashing injection and his body had been affected by the first. The second injection was fatal and within two hours he was dead.

Symptoms - pre attack

 

The symptoms above are usually regarded as specific enough for diagnosis, but Dr Richet also determined that the person or animal always has a raised leukocyte count before the principle symptoms are manifest - in other words this could be a warning that the person is susceptible.  Leukocytes are white blood cells and are the cells used to fight infection.  If the leukocytosis is severe, the person is likely to also appear anaemic and be exceptionally tired.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It is relevant here to indicate the relationship I have been able to establish between leucocytosis and anaphylaxis, a relationship that is hard to grasp without elaborate techniques and prolonged observations. All my experiments have been conducted on dogs, with the help of my friend P. Lassablière who did the calculations.

The number of white corpuscles or leucocytes in the normal dog is 100 per hundredth of a millimeter cubic on average, varying from 70 to 130. In animals, now, that have been anaphylactized, even after a considerable time-lag of say six months, when they appear to be completely normal and in perfect health, the number of leucocytes reaches and often exceeds 200.

An initial injection which makes the body anaphylactic, therefore, induces a marked leucocytosis and this is the only symptom that can be observed.

Symptoms in summary

We are apt to think of anaphylaxis as simply meaning the symptoms associated with severe anaphylaxis – anaphylactic shock, but in reality all the symptoms commonly associated with skin diseases such as eczema and psoriasis; food allergy, and other allergies, as well as asthma are more correctly anaphylaxis, in ascending order of severity they are:

  • Prurience or itching, sneezing, scratching, rashes
  • Joint pain and pain in the location of the rashes and wounds
  • Intense itching, anaemia, extreme tiredness, ulcers and gangrene
  • High leukocyte count
  • More rapid breathing, wheeziness, difficulties in breathing, lowered arterial pressure, faster heart-beat
  • Hyperthermia, oedema over the whole skin area
  • Vomiting, bloody diarrhoea and rectal tenesmus.
  • Ataxia, dilated pupils, the eyes haggard
  • Loss of consciousness. Breathing laboured and agonized. The heart beats are so faint as to be barely perceptible: blood pressure hardly reaches the one or two centimetre mercury level. [anaphylactic shock.]
  • Worsening symptoms then death.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It has long been known that some people are sensitive to cheese or to strawberries or to fish or to shellfish or to eggs or even to milk. Now the symptoms to be seen in such individuals on ingesting such and such foods are analogous to the effects of anaphylaxis: acute stomach pains, vomiting, diarrhoea, colic, erythema, urticaria, severe itching and sometimes cardiac troubles and fever. We know now that these are anaphylactic phenomena; this has become a pathological commonplace.

Causes

 By injecting anything into the blood stream an immunological response will be triggered.  If we take the example of a vaccine, then the first injection is, to all intents and purposes a ‘primer’ and the immune system will create antibodies that will fight the substance – whatever it is – if it reappears.  If on the first priming the symptoms were relatively mild or insignificant, the person’s immune system was fully operational and they were not tired or stressed, or otherwise ill, then the immune system may mark the substance as needing fighting but not of any great danger.  If however, the body had a significantly hard time fighting the injection, the immune response will be correspondingly severe.

 

When we are vaccinated, we make the assumption that we are being vaccinated against a virus or bacteria.  But we would be wrong.  Vaccines contain excipients [the holding fluid], adjuvants [the booster to the immune system] and then the pathogen itself.  The vaccine may also contain culture medium.  There is a helpful list on Wikipedia that shows the ingredients of the various vaccines.  If you examine this list you should be able to see it contains the most extraordinary substances – egg white, alcohol, castor oil, lactose, bovine extract, gelatine, citric acid, yeast – foods in other words.

The immune system does not know whether a protein is a food or not, all it knows is that it is an alien protein and it is primed by the first injection - either in a major way or to a lesser degree depending on the time of injection and the reaction provoked - to repel the proteins it has encountered - excipient, adjuvant and culture medium combined.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It is now opportune to examine the substances apt to develop the anaphylactic state. They can be defined very simply, by using a fairly arbitrary system of classification, which groups substances in colloids on the one hand and crystalloids on the other.

Crystalloids are on the whole non-active. I am not aware of any successful attempt to induce anaphylaxis by one crystallizable salt or by any alkaloid. On the other hand all the proteins without exception produce anaphylaxis: one has seen this with all sera, milks, organic extracts whatsoever, all vegetable extracts, microbial proteinotoxins, yeast cells, dead microbial bodies. It would be of more interest now to find a protein which does not produce anaphylaxis than to find one that does.

Dr Richet also made a very good case for limiting the type of proteins to soluble proteins in the cases where anaphylaxis is caused by ingestion of the food at a later date - in other words food allergies - see the detail in the science section

So if we summarise so far.  A person can be primed for anaphylaxis by:

  • Vaccines - containing proteins as excipient, adjuvant or culture medium
  • Injections - of other sorts, for example intravenous fluids, dental injections,  injections during surgery with anaesthetics
  • IBS  - caused by antiobiotics, laxatives and other pharmaceuticals that have destroyed the protective gut flora and are allowing substances to enter the blood stream
  • Wounds - open wounds dressed with ointments and creams containing plant or other proteins.  In effect an open wound should never be covered with anything which has proteins in it.  All these shampoos with food stuff extracts in them could be causing untold problems if the person's skin is broken

The immune system – after a few weeks - is primed to consider the proteins in the blood stream a very dangerous foe.  Some weeks later, the person eats that substance, for example – peanuts [peanut oil was used as an excipient once], eggs, dairy products [some excipients contain the proteins found in dairy products], and the immune system reacts in the way described – and the person goes into anaphylactic shock.

But this is where food allergies, skin diseases such as eczema and asthma also come from, because these symptoms are those of mild anaphylaxis - first and second stage as opposed to third stage.

To date, all experiments mentioned above have been carried out by parenteral injections, that is to say that the substance introduced into the blood was introduced by other means than the digestion, and namely by means of subcutaneous, intravenous, intraspinal and peritoneal injections.

 The Priming substance

 

 Dr Richet also determined another absolutely essential feature about the priming substance.  It did not have to be an identical protein to the one causing the reaction.  The immune system pattern matches to determine friend and foe and it appears the pattern matching is general enough to mean that like proteins can trigger a reaction.  Clearly the reason for this is that the immune system does not want to be fooled by a substance which has slightly mutated or changed in the meantime to protect itself, the immune system uses a general pattern matching strategy 'looks like', not 'identical too'.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis

....the second experiment to be adduced against the specificity of anaphylaxis I conducted with two kinds of toxalbumin, extracted from the Actinia, a substance which I named congestin, as its property is to bring on grave congestion of the circulatory system in the intestines and stomach. Two congestins may be prepared at some pains: yellow congestin, soluble in a fluid containing 50% alcohol, and black congestin, completely insoluble in a fluid containing 25% alcohol. Now I was able to show that black congestin is not unleashing, but is better as the preparatory injection than the yellow congestin. This gives us authority for thinking that the sensitizing (or preparatory) property and the unleashing property can belong to allied protein groups, but not identical ones. Biological chemistry will no doubt unravel these two substances. In practice the two substances, preparatory and unleashing, are almost always lined up together, so that we have a near right to pronounce on strict specificity.

Blood transfusions

We have seen that anaphylatic shock, food allergies, skin diseases such as eczema and asthma all come from.

  • Vaccines - containing proteins as excipient, adjuvant or culture medium
  • Injections - of other sorts, for example intravenous fluids, dental injections,  injections during surgery with anaesthetics
  • IBS  - caused by antiobiotics and other pharmaceuticals that have destroyed the protective gut flora and are allowing substances to enter the blood stream
  • Wounds - open wounds dressed with ointments and creams containing plant proteins.  In effect an open wound should never be covered with anything which has proteins in it.  All these shampoos with food stuff extracts in them could be causing untold problems if the person's skin is broken

 But Richet was also able to prove that if a person's blood contained these antibodies, because the person whose blood was used had been vaccinated, or they had IBS or open wounds, and had developed antibodies to some protein, then a blood transfusion would serve to transfer this sensitivity to the recipient of the transfusion.  In other words, a blood transfusion can result in your developing asthma, food allergies, skin diseases or of getting anaphylactic shock.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
Another experiment of prime importance is this, for it shows the very nature of the anaphylactic process. In April 1907 I showed that the injection of serum from an anaphylactized dog induced an anaphylactic state in untreated dogs, as if this serum contained the toxic substance which activates the unleashing injection.
With actino-congestin, the experiment is clear-cut. Almost harmless doses cause death within a matter of hours in dogs that had not been anaphylactized, but had had injections of serum from anaphylactized animals. This is what is known as passive anaphylaxis.
At about the same time, in May and June 1907, Gay and Southard in America, and Otto in Germany, also showed quite clearly that passive anaphylaxis exists. It has become one of the classic tenets of anaphylaxis.

Combined problems

 

If a person has IBS or has just been given antibiotics which upset the intestinal flora.  If they have taken or are taking pharmaceuticals which also destroy the gut flora, then it is possible one type of protein enters via this route. 

Dr Richet then found that if another type of protein is then either injected, or enters via an open wound, then the two proteins may interact without any involvement in the immune system.  The simple fusing of two alien proteins in the blood stream causes the shock and the anaphylactic reaction:

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
To evaluate this reaction, we must mention a valuable experiment of Claude Bernard carried out long ago. Bitter almonds contain two substances: amygdalin which is harmless and emulsin which is harmless too. Animal subjects survive an injection of either amygdalin or emulsin. But emulsin is a diastase and has the property of breaking up amygdalin, liberating hydrocyanic acid, which is one of the most virulent toxic gases known. Thus if an animal that has been given amygdalin is then injected with emulsin, hydrocyanic acid will be formed in the blood stream and death will take place at once. Yet injected separately, neither the amygdalin nor the emulsin has any effect.

Summary of the causes

Anaphylaxis of any sort is an immunological reaction to a protein that has entered the blood stream at an earlier time – usually weeks before.  Where the reaction has been provoked by ingesting food, then the likelihood is the protein is a soluble protein.  The cause is thus a ‘foreign’ protein to be found in one or more of the following:

  • Vaccines - containing proteins as excipient, adjuvant or culture medium
  • Injections - of other sorts, for example intravenous fluids, dental injections,  injections during surgery with anaesthetics, if these contain proteins [subcutaneous, intravenous, intraspinal and peritoneal injections]

Other sources of foreign protein in the blood can be from

  • Damaged intestines/leaky gut - caused by antiobiotics, laxatives and other pharmaceuticals that have destroyed the protective gut flora and are allowing substances to enter the blood stream
  • Wounds - open wounds dressed with ointments and creams containing plant or other proteins.  In effect an open wound should never be covered with anything which has proteins in it.  All these shampoos with food stuff extracts in them could be causing untold problems if the person's skin is broken on the head
  • Blood transfusions – where a foreign protein may be in the blood or the person may have developed an immune reaction to the protein and the antigens are present

The allergy, skin disease, and other symptoms of the anaphylaxis, including any later anaphylactic shock is then provoked either by ingestion of the protein or by one of the causes above being repeated – thus a second vaccination, or the development of a leaky gut that enables the protein to get through, or a sudden open wound exposed to the protein, a blood transfusion or an injection.

The second event might involve a protein slightly different to the first, all that is needed is for the second protein to 'look like', the first and not be 'identical to it'.

Finally anaphylactic shock can be triggered by a non immune response when one type of protein enters via one of the routes above and meets another protein with which it can interact and produce severe poisoning.

Why Anaphylaxis?

The final quote we have from Dr Richet is a superb example of his wisdom.  He asked the question that everyone asks who has had one of these attacks – why on earth does the body attack itself and in some cases kill itself?

 

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It does indeed seem absurd that an organic disposition should make beings more fragile, more susceptible to poisons, for in most cases everything in living beings seems disposed to assure them a greater power of resistance.

But some reflection on the final aim of anaphylaxis will give the answer.

It is in fact important that animal species are of determined chemical entity. If, following the hazard of ingestion or injection, alien proteins were found in the cellular juices as part of our humours, then the chemical make-up of beings would be modified and consequently perverted. Crystalloids dialyse through membranes and are speedily eliminated. In a few days, even in a few hours, they are completely gone. Colloids however, that no dialysis can eliminate, do not disappear once they have penetrated to the blood. They fix on cellules and end up by being integral to them.

Grave danger would thus face the animal species, were they not nicely balanced in their hereditary chemical make-up. If heterogenous substances got fixed into our cellules and definitely intermingled with our humours, that would be the end of the chemical constitution of each animal species, which is the fruit of slow evolution down the generations, and all the progress that has been achieved through selection and heredity would be lost.

It does not matter much that the individual becomes more vulnerable in this regard. There is something more important than the salvation of the person and that is integral preservation of the race.

In other words, to formulate the hypothesis in somewhat abstract terms but clear ones all the same: the life of the individual is less important than the stability of the species.

Anaphylaxis, perhaps a sorry matter for the individual, is necessary to the species, often to the detriment of the individual. The individual may perish, it does not matter. The species must at any time keep its organic integrity intact. Anaphylaxis defends the species against the peril of adulteration.

We are so constituted that we can never receive other proteins into the blood than those that have been modified by digestive juices. Every time alien protein penetrates by effraction, the organism suffers and becomes resistant. This resistance lies in increased sensitivity, a sort of revolt against the second parenteral injection which would be fatal. At the first injection, the organism was taken by surprise and did not resist. At the second injection, the organism mans its defences and answers by the anaphylactic shock.

Seen in these terms, anaphylaxis is an universal defence mechanism against the penetration of heterogenous substances in the blood, whence they can not be eliminated.

Treatment

Treatment of anaphylaxic shock does exist.  The primary treatment of anaphylaxis is an epinephrine injection into a muscle, intravenous fluids, and positioning the person flat.  People who know themselves to be susceptible carry an epinephrine autoinjector and identification regarding the condition.

But might it not be better to eliminate the cause?  Especially since the millions and millions of people suffering from allergies, asthma, food intolerances , debilitating skin disease, ulcers, gangrene, pain and misery deserve something better.

 

 

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