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Introduction
 I first attempted to desensitise hay fever patients by placing drops
of pollen extract under the tongue In 1976, and communicated the
results to the European Allergy Congress in Helsinki. This was a
pilot trial, and results were patchy, but encouraging because some
of the most severe cases were much improved.
In 1982
I was consulted just after the pollen season by a young man
with severe hay fever. To confirm the diagnosis I flicked some dry
pollen up his nose using a microspoon, an instrument I had invented
to deliver a measured dose of dry pollen to the nose. The purpose of
this test was to prove objectively that patients were really
sensitive to pollen, or that they had been successfully desensitised
. To my surprise nothing happened, and a repeat test a week later
was also negative.
This observation suggested that he could have
become immune by natural exposure to pollen during the season which
had just passed, and that if he were given pollen extract every day
under the tongue throughout the winter this immunity might be
preserved or even enhanced before the next season. He received
sublingual pollen extract all that winter, and had very little hay
fever next year. Ethical committee permission was obtained for a
double blind placebo controlled trial under the aegis of the Midland
Asthma and Allergy Research Association. The results were published
as a poster at the 13th International Allergy Congress in 1988, and
on three occasions since then at the British Society for Allergy
annual meetings, without attracting any interest.
 Selection of Volunteers
23 volunteers came forward in 1984. Almost all were already well
known because they had taken part in many trials and were accustomed
to keeping good records of symptoms and medication. In spring 1984
they all had skin test titrations using tenfold dilutions of a
pollen extract of the five commonest grasses, ranging from 50,000 to
5 weight/volume ‘Noon’ units, using Morrow Brown Standardised Prick
Test Needles. They also has their nasal sensitivity to grass pollen
assessed as described below.
All 23 volunteers kept satisfactory records of symptom scores and
medication in the pollen season of 1984. They returned in the
autumn, skin test titration and nasal provocation tests were
repeated, and they were issued with coded dropper bottles of SLIT or
placebo and shown how to take it under the tongue. 13 received
active SLIT, and 10 placebo. They were seen again in a month, and
again pre-seasonally and as soon as possible post-seasonally.
The results in 1985 were not statistically significant, although
several cases were very much improved. It was decided to give all 23
volunteers active material every day, even in season, throughout the
following years of 1986 and 1987 in order to find out if they would
improve further with long-term treatment.
33 new volunteers came forward in the spring of 1985. They
were tested as described above, kept records in the season of 1985,
and were issued with coded SLIT or Placebo in September. It was
decided to limit the placebo group to 12 only, and to give 21 active
SLIT. After 1985 all 33 volunteers received active material as a
reward for their cooperation.
Materials and Methods
A mixture of equal quantities of Cocksfoot, Rye, Meadow, Timothy,
and Yorkshire Fog pollens was supplied by Dome laboratories. A 10%
weight/volume extract was made in buffered saline, centrifuged, and
filtered through a Millipore filter with a pore size of 0.22 um, an
equal volume of glycerol added to make a final concentration of 5%,
and dispensed in dropper bottles which delivered 0.05 ml/drop. The
strength was defined in Noon units, so that the 5% weight volume
extract was rated at 50,000 NU/ml, each batch was standardised by
RAST inhibition, and that one drop would deliver 2500 units. These
extracts were used to make all dilutions for skin tests and nasal
tests,. Placebos also contained glycerol, were suitably tinted, and
tasted identical. All bottles were secretly coded by the laboratory.
Administration of SLIT
All volunteers were given one drop of a 1% extract which was
retained under the tongue for 5 minutes and spat out. The very few
who had a slight reaction to this were given a bottle of 1% extract
with instructions to take one extra drop per day according to
reaction, working up to 5 drops. When seen a week later they were
given a drop of the 5% extract, but there were no reactions. Coded
bottles were then issued with instructions to take one drop under
the tongue every day thereafter, retain for five minutes, and spit
out. They were shown how to place the drop behind the teeth under
the tongue, avoiding the lips which would react. They were warned
not to take any drops if there was a dental or gum problem.
Dosage of SLIT
The starting dose was one drop a day from the end of the 1984 season
right through the pollen season of 1985, when one drop continued
through the season. On review in the autumn of 1985 there had been
no reactions to the drops, but the results had been disappointing.
Because some triallists had increased the dose on their own
initiative without any problems, it was decided to increase the dose
according to tolerance for the 23 volunteers who had joined the
trial in 1984, and for the 33 who joined in 1985. The result was
that by the spring of 1986 most patients were taking 6-8 drops per
day, and some even 10 drops. Paradoxically these patients were found
to have become more sensitive as shown by the nasal provocation
tests, but reducing the dose to one drop a day resulted in greatly
increased nasal tolerance within a month. Sometimes the nasal tests
were negative at a level of 4000 units, a strength which would
produce a large skin test reaction. The optimum dosage was not
defined, but remained at one drop a day all year including pollen
season.
Monitoring at each Visit
No serious side-effects were encountered except occasional itching
or swelling of the lips if the dropper touched the lip, or the drop
was deposited in front of the teeth. SLIT had to be stopped if there
were gum problems or dental surgery. At the first reassessment it
was found that some volunteers had misunderstood the dosage
instructions and were taking much more, even a whole dropper full in
one or two instances, without any side-effects. The instructions
were then changed to swallow instead of spit, as most people were
already doing. On the whole the side-effects were so slight that
very few guessed if they were having placebo or not.
Titration of Skin Sensitivity
Skin testing was carried out at each visit using tenfold dilutions
of the 50,000 unite extract using Morrow Brown standardised prick
test needles. There was great variation in response, some volunteers
actually becoming skin test negative, but this fluctuated a great
deal on later testing. The general trend was towards an obvious
decrease in skin sensitivity
Nasal Provocation Tests
Nasal provocation tests were carried out at each visit with
increasingly strong extracts the end-point being unilateral sneezing
and congestion. Their nasal sensitivity to pollen was estimated by
delivering 50 microlitres from a micro-pipette into alternate
nostrils until a reaction occurred. The nasal tests were of 62, 125,
250, 500, and 1000 unit strength. Blood was also taken for
immunological tests hoping to find changes in IgG1 and IgG4 as a
result of SLIT
RESULTS OF SLIT
POLLEN COUNTS IN GREEN
PLACEBO OR OBSERVATION IN BLACK
ACTIVE SLIT IN RED
23 volunteers kept satisfactory Symptoms and Treatment charts in
1984 to provide a baseline for comparison with future years. When
assessed after the season of 1985, 10 had received Placebo and 13
Active SLIT.
It was decied that those who had received Active SLIT should
continue to have open Active SLIT for the following years, and those
who had had placebo would now have Active SLIT, as a reward for
their excellent cooperation.
The Total Symptoms and Drug scores for the group for each separate
day provided the data for this chart, alongside the daily pollen
count which provided a very variable challenge for subjects who also
varied greatly in their degree of sensitivity.
This graph compares the total daily symptoms and drug scores for the
Placebo and Active group in 1985 with the daily pollen count for
1985.
Another group of volunteers had been recruited in 1985 and kept
Symptoms and Treatment charts to provide a baseline for future
comparison. 21 of them kept satisfactory records, and their data has
been added to the data from the 10 who were receiving Placebo.
It is clear that the 13 who were receiving Active SLIT were
considerably less responsive to the fluctuating pollen counts than
the 31 who were receiving no specific treatment.
Only one subject
took no suppressive drugs in 1984, but in 1985 6 of the 13 who
received Active SLIT no longer needed drugs, while none of the 10 on
placebo could do without them.
A fresh batch of volunteers were seen in the spring of 1985 and
issued with Symptoms and Treatment charts for June & July, in order
to establish a base-line for 1985.
They were reviewed soon after the
pollen season of 1985, and the 33 who had kept satisfactory records
were issued with coded SLIT in preparation for the Pollen season of
1986.
When reviewed after the season of 1986 they were all given op[en
Active SLIT for following years as a reward for their help in
assessing SLIT.
The progressive improvement in scores in cases those who had had
Active SLIT for two successive years is notable, but the most
remarkable outcome was that 21 out of 30 no longer required any
medication in 1987.
In 1987 all volunteers received open Active SLIT. Seven had dropped
out for various reasons, such as moving to another part of the
country, changing jobs, or did not feel it was worth the bother, but
none dropped out because they could not tolerate the drops on
account of side-effects.
48 volunteers continued into 1987. The symptoms per pollen grain
dropped to 1.84 in 20 cases from Group II.
In 10 and 9 cases from
Group I who had continued in the trial since 1984 the symptoms /
grain was 2.21 and 2.34 respectively, and the average for the 48
cases was 2.13.
By far the most striking and important feature of the results in
1987 was that 16 of the 20 cases from Group II and 13 out of 18 in
Group I, no longer required medication by 1987.
Immunological Studies
Pollen specific IgG1and IgG4 were measured in all sera by ELISA
using monoclonal antibodies. Very high titres of IgG1, and to a
lesser extent IgG4, were found in 7 cases before starting SLIT,
increasing further as SLIT was continued. This was probably because
5 of them had had pollen injections in the past, but did not explain
high titres in 5 others who had never had injections. Immunological
results bore no relationship to clinical results, and the only
evidence of the appearance of blocking antibodies was obtained by
the “patient/self” test.
The Patient/Self Test
Because conventional immunological investigations were unhelpful it
was decided to use the “patient/self” test to demonstrate blocking
antibodies. This test was invented by the Kate Maunsell over fifty
years ago, and only used once since. It is performed by mixing equal
amounts of two fold dilutions of pollen extract with serum obtained
before or with serum obtained after SLIT. This mixture is then
injected intradermally into the same patient, so there is no risk of
infection. If there are sufficient ‘blocking’ antibodies in the
serum to combine with all the pollen present in the dilution of
extract being used, there will be no pollen left over to cause a
skin reaction. As the strength of the pollen extract mixed with the
serum increases there will be a point where there will be
insufficient antibody to neutralise all the pollen, and a reaction
will occur. The nature of the antibody which combines with the
pollen allergen is unknown.
Top row of skin tests with serum/allergen mixture is before
treatment with SLIT
and the bottom row after treatment shows that
the first positibe reaction does not take place until four filutions
higher than above
This example of a P/S test is from a telephone linesman who spent
much time up poles exposed to all the pollen in the countryside.
He
derived great benefit from SLIT which has persisted from 1985 to
2004. The top row of tests using 1984 serum before treatment with
SLIT shows a negative control on left, and +ves from the lowest
concentration of 0.05 Pharmacia units up to 12.5, 8 dilution steps.
The next row used serum obtained after SLIT in 1985, after SLIT
1986, and after SLIT 1987, showing inhibition up to 12.5 units.
The
bottom row used heated 1987 serum, showing that the blocking factor
was destroyed by heating
The P/S test was carried out on volunteers
who had had several years SLIT and all showed similar responses.
Long term results
The results of an analysis of the results with particular attention
to the duration of treatment have produced remarkable graphic
evidence, as shown above, confirming that is SLIT is persisted with
for as long as possible the benefits become more and more apparent,
particularly on the need for medication. Continuation of SLIT until
1990 has shown similar results, but the numbers lost to follow-up
were high.
Anecdotally, occasional accidental meetings with individuals who had
taken part in these trials have shown that the benefits of the
treatment are long-lasting. Some have not had any Hay Fever for as
long as 20 years or more, suggesting that SLIT can actually cure hay
fever. These encouraging results might stimulate further interest in
SLIT, not only for Hay Fever, but also SLIT using other potent
allergens, and even foods.
Summary and Conclusions
This unpublished work is presented as a poster for the third time in
the hope of arousing some interest in the UK in a risk-free method
of immunotherapy which can be very effective. Since 1986,
suppressive drugs are the only treatment available for hay fever.
Although good news for the drug industry, the increasing numbers of
British hay fever sufferers are deprived as compared with the rest
of the world.
The great interest in SLIT in Europe, and the many successful trials
there since 1988 using different allergens, support the encouraging
findings of this trial, and of the potential importance of the
sublingual route for 'desensitisation' to allergens. To inject
allergens must be an unnatural thing to do, so disastrous reactions
could be expected.
The sublingual area is not only well-known for absorbing medication,
but is the first area to encounter foreign proteins when the infant
is given foods for the first time. This area must be a major portal
to stimulate to the immune system to adapt to foreign proteins. It
follows that this may be the natural route to induce immunological
tolerance to allergens.
The most important findings in this study are that persistent daily
sublingual immuno-stimulation for several years leads to progressive
improvement, and that the need for pharmacotherapy is progressively
reduced year by year. The patient/self test provides clear evidence
that tolerance is being acquired, and perhaps a clue to how the
acquisition of immune tolerance is acquired by the sub-lingual
route.
Scepticism and reluctance to accept a self administered therapy
should not inhibit further investigation of a method of treatment
which may have the potential to readjust the mal-adaptation to the
environment, or to food, which is the basic cause of allergic
disease
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