Richard W. Weber, M.D.National Jewish HealthDenver, Colorado USA

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

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

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

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

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

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”

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

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

“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)

“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

“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

“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

“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.”

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)

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

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

“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

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