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The History of Desensitisation
Two thousand years ago King Mithridates was so afraid of being
poisoned that he took increasing doses of all the poisons available
until he became immune to lethal doses. In other words, as long as
the increase in the dose did not exceed his ability to adapt to the
poison he would suffer no effects, immunity would finally be
achieved, and immunity could be maintained by taking daily doses of
poison. Perhaps he invented the concept of desensitisation, which is
still used today when drugs such as aspirin or penicillin cause
serious reactions.
In 1902 Charles Richet observed that animals injected with a second
dose of an foreign protein died suddenly, even though the first
injection had caused no reaction, and he invented the word
‘anaphylaxis’ to describe this phenomenon. Then in 1906 Clemens Von
Pirquet reported severe reactions in patients to a second injection
of anti-diphtheria antitoxin which had been raised in horses, and
invented the word ‘allergy’ to describe these reactions. In 1908 in
London a Dr Schofield treated a teenager who had dangerous reactions
to egg by giving him pills which, unknown to the patient, contained
gradually increasing amounts of egg, The result was that within six
months he was able to eat eggs every day with no effect.
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Charles
Harrison Blackley (1820-1900)
was a medical doctor in Manchester
who suffered from seasonal hay fever, a complaint so
rare at that time that he could not find anyone else to
experiment on!
He caught pollen from
the air, carried out a daily pollen count for the first
time, and even sent up a pollen trap on a kite to show
that pollen is carried high in the air by the wind.
He also invented the
skin test, and finally proved beyond doubt that pollen
was the cause of his hay fever, by sniffing some pollen up his own nose in
the winter thus producing an attack of hay fever out of
season.
He published a book
describing his researches on Hay Fever in 1873, but his
pioneer work attracted no interest until 1911, when Noon
and Freeman successfully desensitised sufferers with
injections of pollen extract. More details of Freeman’s
methods are given later as a matter of interest, and
because we might learn something from them today. |
Desensitisation techniques were further developed by many
researchers in the USA and in Europe. In the USA ragweed pollen is
such a potent allergen that drugs alone are often insufficient to
control symptoms, so ‘allergy shots’ became, and still is, a popular
method of treatment In the USA. Methods of purifying allergens and
the invention of slow release vaccines made reactions less likely
and required fewer injections. Depots of vaccines emulsified in oil
were developed which required only one or two injections a year, but
were withdrawn because of occasional abscess formation. In the
nineteen sixties I made an emulsifying machine and gave a great many
allergen emulsion injections with excellent results using a wide
range of allergens. Slow release vaccines are even now constantly
undergoing modification in the laboratories of the manufacturers,
targeted at desensitising the patient without
any risk of the injections causing a reaction.
In 1986 the British
Committee for Safety of Medicines, alarmed because some deaths had
followed allergen injections, decreed that these injections could
only be administered when full equipment to cope with any emergency
was at hand, and further that the patient must remain under
supervision in the clinic for two hours after the injection. This
had the effect of stopping this treatment completely, mainly because
of the long waiting period, since modified to one hour. This
over-reaction has deprived British patients of many facilities for
investigation of allergies leading to specific diagnosis and
treatment. It also dealt a serious blow to any development of the
specialty of clinical allergy with consequences which are still with
us today, nearly twenty years later. For example, it is specifically
forbidden to treat asthma, which can be fatal, by desensitisation,
but it is permissible to treat hay fever, which is never fatal.
It is obvious that to give injections through the skin is not a
natural intervention, and that the introduction of foreign material
through a needle into the tissues can never be absolutely free from
the possibility of some sort of reaction against it. The sublingual route (under the tongue)
is not invasive, has
been found in many clinical trials in Europe to be free
from risk, and can be given to children with good results for
allergy to mites as well as pollens.
Trials of
Sub Lingual Immuno
Therapy ( SLIT) for Hay Fever have been carried out recently in the UK,
with excellent results. It has been prescribable on the NHS for
several years, but usually refused on account of cost.

The History of Desensitisation in England
Injecting hay fever patients with gradually increasing doses of
pollen extract was first used at St Mary’s Hospital by Leonard Noon
and John Freeman in 1911. After Noon died a tremendous amount of
research was carried out by Freeman, who established a special hay
fever clinic where the patients were instructed in how to give
themselves the pollen injections. Presumably this was necessary
because general practitioners were reluctant to give these
injections, and certainly because he wanted to make sure that they
were done properly and safely. No less than thirty pages are devoted
to the intimate details of self injection, complete with diagrams,
in his book on Hay Fever.


The Freeman dosage
schedule
for ‘prophylactic
thorough going desensitisation’ by self-inoculation
Classes were held at the clinic to ensure that the patients were
fully trained and capable of injecting themselves with the correct
dose of pollen extract from the correct bottle out of the ten
supplied which were of increasing strength. They were taught exactly
how to do this, and even how to cope with a reaction, if it should
occur, by giving themselves an adrenaline injection which was also
supplied in the kit. Even children could be trained to carry out
this procedure without trouble. The instruction had to be meticulous
to ensure that they gave themselves the correct dose every day for
fifty-four days and a dosage card is shown below as a matter of
interest. No case of anaphylaxis or death was ever reported from
this regime, which many thousands of patients carried out
successfully.
In my opinion the reason for the absence of serious
problems was that the doses increased each time by small amount (6%), and
the injections were given every day, thus providing a constant
stimulus to the immune system. The results were excellent, probably
because the top dose reached was far higher than any ever reached
since, and the target which had to be achieved was a negative skin
test to grass pollen.
It is astonishing the lengths people would go
to avoid hay fever each summer, but there were no effective drugs
until about 1950, and intensely sensitive cases had to stay inside,
or even emigrate,
during the season This regimen was used from the nineteen thirties
until about 1966, but today would never be permitted. Freeman also
invented a system of “rush Inoculation” for patients who came along
just before the season, the injections being given in hospital every
two or three hours, starting at 5 am and finishing at 11pm, thus
completing the course in a week. The very thought of such a
procedure would give the Committee for Safety a fit, but it was
really effective.

Tracings of skin test reactions to grass pollen decreasing as the
dose injected increased, in response to the daily injections. The
skin test finally became nearly negative after seven extra top
doses!! After this lot courting in a hayfield without a sneeze
should have been possible !
( From “Hay Fever” A key to the Allergic Disorders, John Freeman
1950)
Part of the report on his activities for the year by John Freeman to
the Annual General Meeting of the Asthma Research Council in 1938 is
worth quoting, as it seems to illustrate the character of this great
pioneer.

“Rush Inoculation”
The best alternative to seasonal inoculation is to take the patient
into hospital and give him a “rush” course of treatment. This has
given similarly good results, and the quickness and certainty of the
treatment is very dramatic. We like to remember for instance a
cow-man, who was reported by his noble patron to look like a cow,
think like a cow, and sometimes even talk like a cow : Though he has
no interest in life beyond these beloved animals, yet whenever he
went near them he got fearful attacks of eczema and asthma. He was
rightly ordered not to go near them by his doctor, so he sat in his cottage all day with nothing to do except mourn his
exile from the cow-shed. Five days of a rush course sufficiently
desensitised him, and he has been milking cows without the slightest
trouble ever since, though his doctor has to give him every
fortnight a “maintaining “ dose supplied by us.”

The British Desensitisation Disaster
In 1986 the British Committee for Safety of Medicines, alarmed
because some deaths had followed allergen injections, decreed that
these injections could only be administered when full equipment to
cope with any emergency was at hand, and further that the patient
must remain under supervision in the clinic for two hours after the
injection. This had the effect of stopping this treatment
completely, mainly because of the long waiting period, since
modified to one hour. This over-reaction has deprived British
patients of many facilities for investigation of allergies leading
to specific diagnosis and treatment.
It also dealt a serious blow to
development of the specialty of clinical allergy with
consequences which are still with us today, nearly twenty years
later. Today it is specifically forbidden to treat asthma, which can
be fatal, by desensitisation, but it is permissible to treat hay
fever, which is never fatal. This is illogical because chronic
asthma due to an allergen which cannot be avoided, such as mites,
can be very effectively and safely treated in this way.

Personal experience with Desensitisation - a Historical Note
or a demonstration of the possible?
Before desensitisation became impossible my standard treatment plan
was to identify the causative allergen, and confirm that this was
the correct allergen by carrying out a nasal or bronchial
provocation test. The provocation test was to prove that
desensitising injections were really necessary, and were a
justifiable treatment. Furthermore, another provocation test at the
end of the course of injections would prove if the patient had been
successfully desensitised or not. If still positive further
injections would be given, followed by another provocation test.
This approach, which was made possible by my personal development of
bronchial and nasal provocation tests which could be carried out on
out-patients, put desensitisation therapy on an objective basis with
clear proof of effectiveness.

For hay fever patients the ‘microspoon’ provocation test enabled a
measured dose of dry grass pollen to be flicked up the nose to prove
sensitivity, and again at the end of the usual treatment course to
prove immunity, or the need for more injections until a negative
response was achieved. The microspoon is 1mm wide, 0.5 mm deep and
holds 100 (+/- 10) micrograms of grass pollen, (about 10 grains) which is
approximately the amount inhaled in a day at the peak of the season.
If pollen injections were given until the
nasal test was negative the results were excellent. This new
approach to make sure that the injections had been worth while was
published, but attracted no interest whatever.
This was one of the first patients I desensitised, and also
monitored the result with a peak flow meter before and after
treatment The decrease in daily swing in the peak flow is a common
result of this type of treatment.
Before 1986 there were two forms of desensitisation available, the
delayed release vaccine given weekly,. and aqueous or watery
extracts which were available for a wide range of allergens,
particularly dust mite. Injections of aqueous extracts deliver the
allergen directly into the circulation, so they must be treated with
respect and are best given in hospital.
A revised dosage schedule
was used, the steps in dosage were small, and injections were given
three times a day over a period of ten days. Bronchial provocation
tests were carried out before and after, and if still positive
further injections of the top dose given until the bronchial
provocation test was negative. The patient would be discharged to
receive booster or maintenance injections for some time in order to
maintain the hard-won immunity.
A few examples of the results obtained with these methods are
included here as a matter of interest, and as a demonstration of how
it was possible to practically cure patients of their asthma in this
way.
This patient was a very unstable mite allergic asthmatic who had to
be stabilised in hospital with high dose oral steroids before
desensitisation could be carried out using pure mite extracts.
He
then remained in hospital receiving three injections a day until his
bronchial provocation test was negative, and boosters were arranged
to be carried out by his GP
The contrast with before treatment is
remarkable, this effect was long lasting, and he required very
little treatment.
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This athletic
patient had exercise provoked asthma so severe that his peak
flow would drop to 100 just 12 minutes after exercise.
Desensitisation abolished this response almost completely,
as shown. |
This asthmatic response to a nasal provocation test with dust mite
shows how the nose and bronchi react as one.
Desensitisation
abolished this reaction to some extent, but the delayed reaction two
days later still occurred. |

The life of this chronic asthmatic mother was completely
revolutionised by this therapy.
She was able to swim and do physical exercise for the first time in
20 years, and enjoy playing with her children.
She remained well thereafter in spite of the fact that her
maintenance booster injections could not be continued because they
became taboo for asthma.
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In 1977 Timothy was only twelve, and really was a respiratory
cripple who could not be controlled effectively on Becotide alone,
and often required oral steroids

After a course of dust mite injections in hospital Timothy was still
very difficult to control with Becotide 800 micrograms daily, quite
a large dose at that time, but the peak flow does not fluctuate so
much as before

1981 - After readmission for further desensitisation against dust
mite Timothy became much easier to control and his average peak flow
nearly doubled, but he required only 300 micrograms of Becotide a
day
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This lady was a very unstable asthmatic, as shown, and needed
frequent courses of oral steroids.
The difference after she was thoroughly desensitised to dust is
remarkable, and she was maintained on only 400 micrograms of
Becotide daily.
She was able to play tennis for the first time in years
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This is a very good example of a middle-aged patient who had very
large fluctuations in the peak flow every day.
With weekly
maintenance injections there is a remarkable stabilisation of the
peak flow and the fluctuations were no more than 50 to 100 at the
most.
There was no other change to her treatment.
In 1968 62 asthmatics were intensively desensitised as out-patients
by weekly injections of aqueous extracts of house dust. Of this
group 30 ceased oral steroids, 32 were much better, and 21 failed to
improve. Skin tests for dust became negative in 10, and for mites in
13. The nasal provocation test with house dust became negative in 52
cases, so other unknown allergens were probably part of the problem.
In 1978, when pure mite extracts had become available, 27 asthmatics
were given three injections a day in hospital. 11 of then were able
to stop oral steroids, 17 were much improved, 3 failed, and the case
was complicated by multiple allergies in 8. Nasal provocation test
became negative in 25, and skin test became negative in 10 cases.
In 1979 41 asthmatics were treated in the same way with pure mite
extracts, and 27 were much better, As 14 of the 16 children were
much improved and only 13 out of 25 adults, it was clear that
desensitisation is more helpful in the younger age group. In the
following years 78 asthmatics with proven allergies to yeast, wool,
moulds, dog, and cat were treated with aqueous extracts in hospital
and 57 were much improved.

The Rebreathing Broncho-test
My development of the “Re-breathing Broncho-test”, which will
trigger a mild asthmatic attack to confirm sensitivity to an
allergen, or lack of reaction after desensitisation, enabled these
researches to be carried out. Bronchial provocation tests usually
have to be carried out in hospital because severe delayed reactions
are common, but the rebreathing method avoids this problem and has
only once in many thousands of tests caused a delayed reaction. As a
result this test can be safely carried out as an outpatient.

The aerosol of allergen extract is made into the 2 litre anaesthetic
bag.
The patient breathes in and out from the bag five times. They cannot
inhale more than the dose in the bag, unlike the usual method where
extract is inhaled until a reaction occurs.
Peak flow is checked every five minutes, and the reaction will
subside by 20 minutes.
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An example of a titration of an asthmatic
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A patient performing a rebreathing bronchotest response
to grass
pollen extract
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The future of
Desensitisation Therapy
It seems to me that the future of specific treatment for allergies
may lie under the tongue because this is the area of the alimentary
tract which is the first to encounter all ingested foreign proteins
in food, and to which IgG type antibodies are normally developed.
Perhaps the sublingual area should be regarded as the gateway to the
immune system. The fact that the administration of SLIT every day at
home would be unsupervised will cause grave misgivings to many
doctors, but could be overcome by a positive programme of
instruction and careful follow-up, which could be best carried out
by our growing army of nurse specialists.
Perhaps we should reassess the work of early pioneers such as Dr
Schofield almost a century ago with his egg pills which enabled one
dangerously allergic little boy to tolerate eggs. I will always
remember that Professor John W Gerrard, a Canadian paediatrician and
allergist, successfully tried a very similar method with peanut
allergy, but when this work was presented at a meeting in New York
at which I was present in 1985 his colleagues were horrified at the
potential risks. Nobody seemed interested to try this method, and
much was made of potential dangers, but subsequent attempts in the
USA to treat peanut allergy by the injection method encountered very
serious reactions.
To be condemned to live a life with a dangerous allergy, constantly
at risk of potentially fatal anaphylaxis, and always carrying two
Epipens, must be very stressful for all concerned, especially young
children and their parents. The uncontrollable danger posed by
accidentally eating traces of peanut, or another very potent
allergen, should be contrasted with the more controllable risk of
attempting very gradual desensitisation by the oral or sub-lingual
route, under close supervision in case of a severe reaction. In my
opinion a positive attempt to desensitise a dangerously allergic
child should be less dangerous than the present passive attitude to
these problems
The key to these dangerous allergy problems could be to stimulate
adaptation to these allergens by starting with an almost
‘homeopathic’ dose sub-lingually and increasing it very gradually to
avoid any danger of reaction. The level of sensitivity would be
established with great care before commencing treatment, or the
dosage started at a very low level indeed. Any temptation to hurry
this process would risk increasing the dose faster than the patient
was becoming desensitised, or adapted, to the allergen, so disaster
could happen.
However, in the present medical climate of defensive medicine and
increasing regulation it would be a brave or foolhardy investigator
who would embark on such an enterprise, and most unlikely that any
ethical committee, who would almost certainly be know very little
about allergy, could be persuaded to allow such a trial to take
place. It seems most unlikely that any research into desensitisation
against dangerous food allergies will be carried out in the
foreseeable future.
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