richard w. weber, m.d. national jewish health denver, colorado usa
DESCRIPTION
SPECIFIC IMMUNOTHERAPY Session 1: History, Mechanisms and Future History of SIT 22 nd World Allergy Congress Cancún , Mexico. Richard W. Weber, M.D. National Jewish Health Denver, Colorado USA. DISCLOSURES. SPEAKERS BUREAUS:ASTRAZENECA, GENENTECH - PowerPoint PPT PresentationTRANSCRIPT
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Richard W. Weber, M.D.National Jewish HealthDenver, Colorado USA
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DISCLOSURESSPEAKERS BUREAUS:ASTRAZENECA,
GENENTECHRESEARCH GRANTS: NOVARTIS,
GLAXOSMITHKLINE, PFIZER, MERCKASSOCIATE EDITOR: ANNALS OF
ALLERGY, ASTHMA & IMMUNOLOGYASSOCIATIONS: AAAAI, ACAAI, CAASNO CONFLICTS OF INTEREST
PERTAINING TO SUBJECT MATTER OF THIS TALK
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William Dunbar, M.D.Zur Ursache und specifischen Heilung des Heufiebers, München, 1903
Mucous membranes and skin of hay fever sufferers sensitive to pollen not seen in normal individuals
Injection of pollen into animals rises neutralizing “antitoxin”
Specific precipitation of pollen extracts by patient’s serum
Pollen extract prepared by freezing and thawing, followed by ten minutes of boiling, then sealing
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Carl Prausnitz (Giles), M.D.
•Hamburg, 1904•1st attempt at pollen vaccination administered to Dunbar by Prausnitz•Resulted in violent systemic reaction
•Prausnitz-Küstner reaction, 1921•1st successful cutaneous transfer of hypersensitivity•Fish sensitivity transferred from Küstner to Prausnitz•Pollen sensitivity not transferable
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Leonard Noon, F.R.C.S.Prophylactic inoculation against hay fever. Lancet June 10, 1911
Believed pollen contained toxin and subcutaneous injection of pollen extract induced production of antitoxin
Phleum pratense (timothy grass) extract most potent
Sensitivity defined by conjunctival challenge
6-10 fold decrease in sensitivity could be induced by increasing doses of 3-6 sub-Q injections
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John Freeman, M.D.Further observations on the
treatment of hay fever by hypodermic inoculations of pollen vaccine. Lancet Sept 16, 1911Twenty subjects with >2 pre-
seasonal injections, with final increased strength from 1.1 to 500 fold higher
15 did well; 3 considered failure, “disappointing” or inconclusive; 1 improved clinically but significant adverse reaction to highest dose; 1 from Canada with autumnal sxs
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John Freeman, M.D.Vaccination against hay fever: Report of
results during the last three years. Lancet April 25, 191484 patients with English hay fever inoculated
with Phleum pratense pollen preseasonally18 in 1911; 25 in 1912; 41 in 191330.1% cured or insignificant sxs; 34.5%
markedly improved; 23.9% minimal improvement; 11.5% no better (two patients worse)
“Patients with marked constitutional disturbances, including asthma, do better”
“Patients with an inherited tendency do better”“Age makes no difference to the benefit derived
from treatment”
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EARLY CHRONOLOGY OF ALLERGEN IMMUNOTHERAPY
1904 Dunbar & Prausnitz – Pollen “toxin” injections1911 Noon – Prophylactic inoculations against
hayfever 1911 Freeman - Further observations1930 Freeman - “Rush” inoculations1932 A Brown – Superiority of perennial over
pre-seasonal administration of immunotherapy1932-1935 GT Brown – Maximum dosage pollen
therapy1933 Colmes & Rackemann – Skin reactivity
changes with immuotherapy
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EARLY CHRONOLOGY OF ALLERGEN IMMUNOTHERAPY1935 Cooke, Barnard, Hebold & Stull -
Serologic evidence of immunity1940 Sherman, Stull & Cooke – Serologic
changes in hay-fever with treatment over years
1943 Loveless - Relationship of thermostable antibody & clinical immunity
1948 Alexander, Johnson & Bukantz – Lack of correlation between thermostable antibody titer and degree of clinical protection
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“Rush” inoculation, with special reference to hay-fever treatment.Freeman J: Lancet 1930;i:744-7.
“Leisurely Desensitisation:” (c. 1909) single injections @ weekly intervals off-season
“inoculations were given weekly merely because our out-patients at St. Mary’s were in the habit of coming every week.”
“Intensive Desensitisation:” (c. 1924) single injections every day with increasing doses (10-20% increase)
Used initially for horse dandruff sensitive asthmatics with success
Increasingly adapted to hay-fever patients (c. 1926)
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“Rush” inoculation, with special reference to hay-fever treatment.Freeman J: Lancet 1930;i:744-7.
“Rush Desensitisation:” (c. 1928) multiple injections q1.5-2h throughout 14 hour day; completed in 2-4 days
Patient in “hospital or some such institution” – treatment continued through symptoms of urticaria, headache, throat & nasal congestion, and treatment with adrenalin
Used in dust asthma, fish allergy, horse dander, hay-fever
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“Rush” inoculation, with special reference to hay-fever treatment.Freeman J: Lancet 1930;i:744-7.
A= good nightB= local reactionC= generalized rashD= sneezingE= throat & nasal
congestionF= headache &
drowsyG= restless nightH= generalized rash
& eyelid swellingI= adrenalin?= out of hospital
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“Rush” inoculation, with special reference to hay-fever treatment.Freeman J: Lancet 1930;i:744-7. Advantages of the “rush” method
Saving of time Convenient scheduling – “one may
even wait till the patient is in real distress – always a good time for getting a patient to do what he is told.”
Closer observation of reactions with more expeditious therapy
Doses can be more readily adapted
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“Rush” inoculation, with special reference to hay-fever treatment.Freeman J: Lancet 1930;i:744-7.“In choosing a system of desensitisation, one
need not, of course, adhere rigidly to the leisurely, intensive, or “rush” methods; an intelligent blend may serve one’s turn better.”
“The ‘rush’ method of desensitisation offers many advantages when used either alone or in combination with other systems. To get successful and safe results, however, it is just as necessary as ever to be cautious.”
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CLINICAL EFFICIACY OF ALLERGEN IMMUNOTHERAPY DOUBLE-BLIND PLACEBO-CONTROLLED STUDIES
Rhinitis Asthma*Northern grasses *Northern grasses*Short ragweed *House dust*Ragweed Amb a 1 *Ragweed Amb a 1*Mountain cedar *Mountain cedar*Birch/Alder/Hazel *Birch/Alder/HazelParietaria *D. pteronyssinusCladosporium CladosporiumAlternaria Alternaria
Dog dander*Cat dander
Hymenoptera Allergy*Venom *(1954-1984)
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EARLY CHRONOLOGY OF ALLERGEN IMMUNOTHERAPY
1954 Frankland & Augustin – First DBPC efficacy study with grass hay-fever & asthma
1965 Lowell & Franklin – First DBPC short ragweed hay-fever study
1967 Franklin & Lowell – Dosage comparison in ragweed immunotherapy
1971 Aas – First DBPC house dust asthma study
1976 Pence et al – Mountain cedar rhinitis & asthma study
1978 Warner et al – D. pteronyssinus house dust mite asthma study
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Seasonal IgE Levels
020406080
100
1st yr
2nd yr
3rd yr
4th yr
5th yr
6th yr
7th yr
8th yr
Time (yrs)
IgE
spec
ific
Ant
ibod
ies
no ITIT
Modified from Gleich GJ et al J Allergy Clin Immunol 1982;70:261-71
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“Stock” Respiratory Vaccines Hollister-Stier
Staphylococcus aureus 6 x108/cc; Staphylococcus albus 6 x108/cc; Streptococcus viridans/pyogenes 2 x108/cc; H. influenzae 1.5 x108/cc
DanishS. aureus 9 x107/cc; S. viridans/pyogenes 6
x107/cc; D. pneumoniae 3 x108 /cc; H. influenzae 12.5 x108/cc; K. pneumoniae 2 x107 /cc; Neisseria 8 x107/cc
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Frankland, Hughes, Gorrill, 1955: Autogenous
Johnstone, 1959: Autogenous, Stock, or Staphylococcal toxin
Aas et al, 1963: Stock vaccineBarr et al, 1964: Stock vaccine
BACTERIAL VACCINES – Negative DBPC Efficacy Studies