Evidence Related to Physical Activity and Asthma

1
(No Transcript)
2
Anaphylaxis to cetuximab is geographically
restricted .

• States with high prevalence of Hypersensitivity
  reactions to Cetuximab during first infusion
• Tennessee Virginia
• North Carolina Arkansas
• Missouri

Martha Stewart Sold her stock in Imclone on
the day before the FDA delayed marketing of
Cetuxinab.
ONeil et al JCO Aug 07,, Chung et al NEJM
March 13th 08
3
Location of Antigen on Cetuximab that is used
clinically (produced in a mouse cell line,SP2/0).
Qinwei Zhou et al Analytical Biochem 2007
3648-18.
4

• Karl Landsteiner
• Born June 14, 1868
• Died June 26, 1943
• Defined ABO system and
• recognized the presence of other closely related
  B like oligosaccharides on mammalian cells
  which also gave rise to antibody responses in
  humans.

See Macher BA and Galili U. The AlphaGal
epitopea carbohydrate of unique evolutionary and
clinical relevance, Biochim. Biophys. Acta,
178075-88. 08
5
The terminal saccharide structures of the ABO and
related alpha-gal antigens
Milland, J. Sandrin, M. S. ABO blood group and
related antigens, natural antibodies and
transplantations Tissue Antigens 68 (6), 459-466
6
Evolution of carbohydrate epitopes on primates
Blood groups to galactose-alpha-1,3-galactose
(alpha-gal)
Landsteiner K. The Specificity of Serological
Reactions. Revised Edition, 1990. Dover
Publications.
Koike et al. Proc Nat Acad Sci 2006104(2)559-564
.
7
Specificity of the IgE Antibodies That
Cross-React with Cetuximab
Chung CH et al. N Engl J Med 20083581109-1117
8
Questions re the finding that IgEantibodies to
Alpha-Gal are common in one area of the USA

• Why do so many adults 10 in this area have
  these antibodies? Is it environmental or a
  parasite?
• Is pre-existing IgE ab to alpha-gal a risk factor
  for other allergic disease eg anaphylaxis,
  urticaria, or angioedema with foods that are
  glycosylated with alpha-gal?
• Is there an association with asthma? and if not
  why not? i) IgE ab to hapten not effective at
  causing inflamation. ii) No relevant T cell
  antigen airborne..

9
(No Transcript)
10
Patient data, presentation, symptom delay, and
laboratory evaluation
11
Skin Testing Results The Case for Intradermal
Testing
Intradermal
Prick test
Prick test performed using lancette and
intradermal testing with 25 gauge needle in the
same patient on a single clinic visit.
12
Skin testing in patients who have serum IgE
Antibodies to galactose-a-1,3-galactose
?Values represent percent () testing positive to
prick or ID Prick test, using lancette wheal
size 4mm diameter Intradermal wheal size 8mm
in diameter Chicken, Turkey, Dust mite
13
Cross-reactivity of IgE ab specific for a
common mammalian oligosaccharide.
alphaGal may be present at multiple sites
Pork Thyroglobulin
Beef Protein
Cat IgA
alphaGal
Spiro and Spiro JBC 240997 1965
14
Matt Perzanowski in Kenya preparing to run
Matt
15
School children age 10-11 in Kenya (Kabati and
Thika), or Atlanta, Georgia.
Perzanowski Nganga Carter, Odhiambo et al.
J Pediatr 2002140582. Carter, Perzanowski, A
Raymond, et al. JACI 2001 108732.

16
IgE ab to AlphaGal among Children in Kenya
IgE antibodies to AlphaGal IU/ml
Total IgE 1055 IU/ml
See Chung et al NEJMed 08
17
Adult Emergency Room Study Age 18-5064 patients
with acute asthma, 72 Controls
Crater, Peters et al. AJRCCM 1999.
18
Specific IgE ab in 963 18 yr olds in Norbotten
Eva Ronmark, Bo Lundback, Shama Satinova et al
July 2008
Allergen No. Positive D.Pteronyssinu
s 75 Grass
219 Cat
219 Dog
84 Horse
142 A. Alternata
19 Tree
213
Eva Ronmark, Bo Lundbach, Jillian Roper, Shama
Satinover, Anders Bachlund, et al July 2008
19
(No Transcript)
20
Further investigation of the finding that IgEab
to Alpha-Gal are common in one area of the USA

• Why are these IgE antibodies common in VA, NC,
  TN, MI, AK but not in Boston, NYC, Seattle or
  Norbotten? Very unlikely to be a response to an
  inhalant or food allergen.
• Worms ,,round worms but not Ascaris and not
  Anisakis. Could be either a tapeworm or
  schistosome but could be a non-pathogen eg duck
  schistosome
• Ticks, chiggers, seed ticks, etc.
  Dermacentor,or Amblyoma,
  ?? Ixodes.
• Hypothesis These responses are primarily caused
  by ticks that are common on the South East.

21
Adult ticks can lay up to one thousand eggs.
22
Multiple bites from the first hatching of
Dermacentor ticks and IgE ab to alphaGal.

• Female ticks can lay up to 1,000 eggs and the
  first hatching of the Dermacentor or Amblyoma
  tick is called a seed tick approximate size
  1.0-1.5 mm.
• Multiple bites by seed ticks are not uncommon in
  the Southeast.

Photograph August 23, 2007.
23
Colleagues 2006-2008

• Scott Commins UVA.
• Jake Hosen UVA.
• Sharma Satinover UVA.
• Christine Chung.
• Michael MorseDuke.
• Beloo Mirakhur BMS.
• Qinwei Zhou Imclone.
• Dan Hicklin Imclone.
• Diane Gold, Boston.
• Tina Hatley Arkansas.

• Matt Perzanowski NYC.
• Joseph Odiambo Kenya.
• Lucy NGanga Kenya.
• Staffan Ahlstedt Phadia.
• Melody Carter NIH.
• Philip Cooper Equador.
• Julian Crane NZ.
• Judith Woodfolk UVA.
• Larry Borish UVA.
• Jonathon Mozena UVA.

We are grateful for support from NIH grants
AI-20565. U19-070364 DE-017982 and by
Britol-Myers Squibb (BMS), ImClone Systems and
Phadia..
24
(No Transcript)
25
CAP-RAST of Specific IgE Abs in Patients with
anti-Gal IgE
r 0.81
r 0.98
Specific IgE Abs (IU/mL)
Limit of detection
?x4
?x1
?x1
?x3
?x12
?x11
?x12
?x1
?x7
?x1
?x9
26
(No Transcript)
27
Absorption Assays using Alpha-Gal or Beef
Thyroglobulin
28
Absorption Assays using Alpha-Gal or Beef
Thyroglobulin
Error bars indicate 95 CI
29
Rhinovirus Challenge in a 22 year old student
with mild persistent asthma.

• 22 yr on occasional treatment only FEV1 84.
• Total IgE 1168 IU/ml (mite 86 cat 105 20 of
  total), Eosinophils 560, Exhaled NO 190/202ppb.
• May 2008 challenged with Rhinovirus 39.
  Developed moderate cold symptoms
• Day 2 pH of expired condensate fell to 5.4.
• Day 4 discharged slight cough.
• Day 6 Short of breath, wheezing, FEV1 59, Eos
  1,007, eNO 197, started oral prednisone.
• Responded well over next five days.

Peter Heymann, Amy Stallings, Debbie Murphy, John
Hunt, Ron Turner et al personal communication,
July 08.
30
(No Transcript)
31
(No Transcript)
32
Children Hospitalized for Wheezing Positive Tests
for Virus (Children gt Age 3 Years)
Total IgE 377 IU/ml among Wheezing children
versus 37 IU/ml in controls.
plt0.001
Heymann et al J All Clin Imm 2004
33
Measurement of IgE ab to Purified Allergens
Using Streptavidin Solid Phase
Cetuximab Biotin
Streptavidin CAP plus 5ug Biotinylated Cetuximab
Routine assay technique in parallel with
Pharmacia standard curve gives results for
anti-Cetuximab IgE (C-IgE) in IU/ml (IU 2.4 ng).
Erwin et al JACI 05
34
Proposed mechanism for delayed anaphylaxis to
beef in patients with IgE antibodies to alphaGal.
35
Proposed mechanism for delayed anaphylaxis to
beef in patients with IgE antibodies to alphaGal.
36
(No Transcript)
37
South Africa May 2008