Transcript Why is aGAL clinically relevant and CCD not?

Why is alpha-gal clinically relevant and cross reacting
carbohydrate determinants not?
Thomas AE Platts-Mills FRS
Oscar Swineford Jr Professor of Medicine
University of Virginia.
We are grateful to the NIH for continued generous support including
AI-20565-31 (TPM) & K-O8 AI-085190 and R-56 AI113095 (SPC).
these studies have also been supported by Phadia Thermo/Fisher in the form of
unrestricted support for IgE and IgG4 assays.
Introduction and History
=Cetuximab induced anaphylaxis and IgE specific for galactose alpha-1,
3-galactose
Chung, et al, N Engl J Med, 2008; 358: 1109-1117
=24 cases of delayed anaphylaxis to red meat in patients with IgE to
alpha-gal
Commins, et al, JACI, 2009; 123: 426-433
=Monitored challenges with red meat demonstrate delay in symptoms
and basophil activation.
Commins, et al, JACI, 2014; 134 (1): 108-115
=Tick bites are a(or the) major cause of IgE responses to alpha-gal
Commins, et al, JACI, 2011, 127: 1286-1293
Delayed Anaphylaxis to Red Meat Masquerading as Idiopathic
Anaphylaxis Tripathi et al JACI in practice, 2014; 2: 259-265.
2004,Dr Van Noonen reported cases of meat allergy following tick bites to the
Sydney allergy society.
1991, Dr Antony Deutch reported cases of red meat allergy to the Georgia Allergy
Society .
2006. Van Hage et al demonstrated that there was an oligosaccharide epitope on
Cat IgA, which was subsequently shown to be alpha-gal..
IgE Antibodies Binding to Cetuximab in Serum from 76 Case Subjects and 462 Controls
Chung CH et al. N Engl J Med 2008;358:1109-1117
Table 4. IgE antibodies to cetuximab (alpha-gal) as predictors
of severe hypersensitivity reactions (SIR) during the first
infusion of Cetuximab in all patients (n = 545)†
SIR
No SIR
†Maier,
#0.35
<0.10 kUA/l
(n=506)
6
500
0.11-0.34 kUA/l
(n=18)
1
17
≥0.35 kUA/l#
(n=21)
14
7
Chung, Morse, Platts-Mills et al., Cancer Medicine; 2014 .
kUA/l is the cut-off used in the original report (Chung, Mirakhur…and
Platts-Mills. Cetuximab-induced anaphylaxis and IgE specific for galactosealpha-1,3-galactose. NEJ Med 2008; 358.1109-1117)
Glycosylation of cetuximab as shown in Chung et al ’08 and
the true structure of the Fc fragment of IgG *
Glycosylation Site Including α-gal
and Sialic Acid
N-88
Fab
N-43
N-299
Glycosylation Site
With Human
Oligosaccharides
Oligosaccharide
Fc
*Lammerts van Bueren, Rispens….. Platts-Mills, and Parren . IgE antibodies to galactose alpha-1,3galactose do not bind to alpha-galactosylated glycans attached to the Fc domain of intact
therapeutic mAbs. Nat Biotechnol 2011.
*Roy Jefferis . Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of
action. Trends Pharmacol Sci, 30: 356-6 2
Case report: problems with the “other white meat”
• Ms. I.C., age 79
– Non-atopic, employed at UVA for >40 years
– Two episodes of hives in May 2012
– June 2012 – ate pork for lunch and 3 hours later began
itching, which progressed to hives, shortness of breath,
and tongue swelling before she collapsed in the hospital
lobby with blood pressure of 60/45
– Received epinephrine, Benadryl, and Solu-Medrol
– Admitted overnight
– Serum tryptase: 36.5 (normal range <11.5 ng/ml)
– IgE to galactose alpha-1,3-galactose 82.5 IU/ml.
See Tripathi et al: .JACI In practice, 2014
Exam. five hours after reaction
and eight hours after eating pork
Further Features of Acute Episodes in Patients with
IgE to Galactose-alpha-1,3-galactose
Urticaria Only
(n=87)
Anaphylaxis
(n=249)
0 – 2 hours#
18%
20%
2 – 6 hours
61%
68%
>6 hours
22%
12%
28%
75%
6:00 – 12:00
4%
19%
12:00 – 18:00
21%
23%
18:00 – 0:00
42%
38%
0:00 – 6:00
21%
33%
Variable
IV. Time to Reaction
V. Received acute/emergency care
VI. Timing of individual episodes of care:
#Some
of this group had reactions involving other antigens, exercise, or alcohol
FACS Detection of CD63, a marker of Basophil Activation
CD63
-PE
Histamine
nuclear membrane
Basophil activation ex vivo following challenges with pork
.
Delayed clinical and ex-vivo response to mammalian meat in patients
with IgE to galactose alpha-1, 3-galactose.
Commins SP, James HR, Pochan S,…, and Platts-Mills. JACI E Pub March 2014
Hypothesis: Alpha-gal may enter the circulation as a
glycophospholipid
α1,3
α1,3
=
=
β1,4
β1,4
P
Alpha-gal
moieties
P
Galactose
N-acetylglucosamine
Chylomicron
HDL
LDL
IDL
VLDL
Absorption of eicosanpentaenoic acid (EPA)* following
ingestion of oils derived from algae or krill
*EPA is an omega-3 fatty acid that is a carboxylic acid with a 20-carbon aliphatic chain and 5 cis
double bonds
A
Meat Status-time
Amino Acids
Peptide
Carbohydrate
Lipid
Nucleotide
Xenobiotic
Total=32 metabolites
B
alpha-glutamyltryptophan
C
dodecanedioate
A
B
Mean Decrease in Model Accuracy (6hr)
Confusion Matrix for Random
Forest Analysis
Predicted group: baseline
MA Class Error
Ctrl
6
2
25%
MA
5
3
62.5%
Predictive accuracy = 56.25%
Predicted group: 6 hour
Actual group
Ctrl
MA Class Error
Ctrl
5
3
37.5%
amino acid
MA
3
5
37.5%
carbohydrate
Predictive accuracy = 62.5%
lipid
nucleotide
xenobiotics
Increasing Importance to Group Separation
Actual group
Ctrl
IgE Antibodies to Oligosaccharides are Well-Recognized as
Part of the Human Immune Response
Antigen Source
Nematodes (Parasite)
Schistosomiasis
Anisakiasis
Ticks (Parasite)
Ambylomma americanum (USA)
Ixodes ricinus (Europe)
Ixodes holocyclus (Australia)
Haemaphysalis longicornis (Japan)
Alpha-gal*
Venoms
MMXF3 (CCD)
Pollen Allergens*
HUXF3 (CCD)
Natural Rubber Latex
*For both pollen allergens and alpha-gal there is very little evidence for immediate
symptoms following natural exposure and many investigators have tried to explain
why.
Conclusions
• Neither CCD nor alpha-gal give rise to immediate
symptoms when consumed orally:
• ie. No rapid onset of oral or abdominal symptoms:
• After eating red meat patients with IgE to alpha-gal
may develop delayed urticaria, abdominal pain or
frank anaphylaxis.
• The only coherent explanation for this phenomenon
is that glyco-lipids can be absorbed and can take part
in lipid particles such as LDL, and that these particles
are responsible for the release of histamine and
tryptase at the time of the symptoms.
Colleagues: 2006-2015
University of Virginia
Scott Commins
Alexander Schuyler
Peter Heymann
Anubha Tripathi
Jake Hosen
Sharma Satinover
Hayley James
Lisa Workman
Josh Kennedy
Elizabeth Erwin/Ohio
Matt Perzanowski/Columbia
Gus Litonjua, Harvard
Diane Gold, Harvard
Africa and Europe
Eva Ronmark, Sweden
Bo Lundback, Sweden
Lucy N’Ganga, Kenya
Joseph Odiambo, Kenya
Adnan Custovic, Manchester
Alpha-Gal Research
Christine Chung, Nashville
Beloo Mirakhur, BMS
Qinwei Zhou; ImClone
Tina Hatley, Bentonville.
Louis Matos.
Tilo Biederman
And the many other colleagues who have enrolled
or referred adult and pediatric
.
cases with the alpha-gal syndrome.
*
Connecting the dots: alpha-gal allergy
leading to delayed anaphylaxis.
Steinke J , Platts-Mills TA & Commins SP
*Reindeer are mammals!
Structure and Mechanism of an active lipid-linked
Oligosaccharide
Flippase.
In vitro LLO flipping assay.
C Perez, Gerber….& Locker. Nature 524: 433, August 2015
Proposed LLO flipping mechanism including five states .
Perez et al, Nature 524: 433, August 2015
Delayed Anaphylaxis, Atopic (n=130)
10000
IgE to Alpha-gal, inhalant, food
and venom allergens in patients
with a history of anaphylaxis
IgE Antibodies (IU/mL)
1000
100
10
Delayed Anaphylaxis,
Atopic (n=130)
0
12
A
lp
ha
-g
al
B
ee
f
1
28
24
54
64
68
76
89
89
78
57
W
as
p
p
H
on
ey
be
e
C
om
m
on
Sh
rim
nu
t
t
Pe
a
W
he
a
d
ra
gw
ee
gr
as
s
in
us
ot
hy
Ti
m
100
10
1
0
6
B
ee
f
36
43
115
115
115
112
113
111
104
87
om
m
W
as
p
H
on
ey
be
e
p
Sh
rim
nu
t
Pe
a
t
W
he
a
d
on
ra
gw
ee
gr
as
s
in
us
ot
hy
Ti
m
on
ys
s
da
nd
er
D
.p
te
r
D
og
's
m
ilk
0.1
C
ow
IgE Antibodies (IU/mL)
1000
A
lp
ha
-g
al
IgE to galactose alpha-1,3
galactose (alpha-gal) induced by
bites of the lone star tick.
D
.p
te
r
D
og
C
ow
's
Delayed Anaphylaxis, Non-atopic (n=115)
10000
Delayed Anaphylaxis,
Non-atopic (n=115) :
IgE neg to mite, grass
and ragweed
on
ys
s
da
nd
er
m
ilk
0.1
Convergent IgE CDR3 Amino Acid Sequences
Table2: Convergent CDR3 Amino Acid Sequences found in Samples A and I
cdr3aa
cdr3_length isotype
AGGISIFGVGSGFGDY
16 IgE
AKGISIFGVGSGFGDY
16 IgE
ARGIANFGVGSGFGDY
16 IgE
ARGILIFGVGSGFGDY
16 IgE
ARGIPIFGVGSGFGDY
16 IgE
ARGISICGVGSGFGDY
16 IgE
ARGISIFEVGSGFGDY
16 IgE
ARGISIFGAGSGFGDY
16 IgE
ARGISIFGIGSGFGDY
16 IgE
ARGISIFGVGGGFGDY
16 IgE
ARGISIFGVGIGFGDY
16 IgE
ARGISIFGVGRGFGDY
16 IgE
ARGISIFGVGSECGDY
16 IgE
ARGISIFGVGSEFGDY
16 IgE
ARGISIFGVGSGCGDY
16 IgE
ARGISIFGVGSGCGYY
16 IgE
ARGISIFGVGSGFGAY
16 IgE
ARGISIFGVGSGFGDC
16 IgE
ARGISIFGVGSGFGDD
16 IgE
ARGISIFGVGSGFGDY
16 IgE
ARGISIFGVGSGFGEY
16 IgE
ARGISIFGVGSGFGGY
16 IgE
ARGISIFGVGSGFGND
16 IgE
ARGISIFGVGSGFGNY
16 IgE
ARGISIFGVGSGLGDY
16 IgE
ARGISIFGVGSGSGDY
16 IgE
ARGISIFGVGSGSGYY
16 IgE
ARGISIFGVGSGVGDY
16 IgE
ARGISIFGVGSRFGDY
16 IgE
ARGISIFGVSSGFGDY
16 IgE
ARGISIFRVGSGFGDY
16 IgE
ARGISIFVVGSGFGDY
16 IgE
ARGISISGVGSGFGDY
16 IgE
ARGISIVGVGSGFGDY
16 IgE
ARGISMFGVGSGCGDY
16 IgE
ARGISMFGVGSGFGDY
16 IgE
ARGISNFGVGSGFGDY
16 IgE
ARGISTFGVGSGFGDY
16 IgE
ARGIWIFGVGSGFGDY
16 IgE
ARGMSIFGVGRGFGDY
16 IgE
found_in_sample
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-I,alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
alpha-gal-A
Conclusions
• Synthesis of glycoprotein and glycolipids in
mammals:
• Oligosaccharide synthesis occurs in the
endoplasmic reticulum and in the Golgi. These
are the primary sites for the relevant
transferases, including alpha-1,3-galactosyl
transferase
• There is a specific transfer mechanism for the
transfer of oligosaccharides to the “outside” of
the cell: Flippases
• Thus, there is the potential for the presence of
large numbers of mol.ecules such as the blood
group substances on the outside of red blood
cells
Changes Following Red Meat Challenge
Circulation: Basophils
and Serum Markers
N = nucleus
(basophils are
polymorphonuclear
and mast cells are
mononuclear)
Mast Cells in
the Tissues
N
N
N
Allergics
(n=12)
CD63 ↑
Histamine
Tryptase
9/12
5/9
3/12
Controls
(n=12)
CD63 ↑
Histamine
Tryptase
6/12
3/11
0/12
Symptoms
and Urticaria
Symptoms
and Urticaria
8/12
(neg to ++)
0/12
(neg)
A Reactions to Cetuximab
B
Rocky mountain spotted fever
Incidence rates (per 1,000,000 persons)
0
0.1-0.9
1.0-9.9
10.0-14.9
15.0+
C
D
Delayed anaphylaxis to beef
Spread of the lone star tick
Convergent IgE Sequences Vary in Mutations
Ctrl_4h
Color by Group
Ctrl_2h
20
20
*
20
MA_4h
Ctrl
6h
Ctrl_6h
MA_6h
MA bsl
Ctrl_Bsl
MA_Bsl
10
MA
2h
MA_2h
MA_2h
MA_4h
*
5
MA 4h
MA 6h
5
MA_6h
MA_Bsl
*
0
0
-5
-5
-10
MA
bsl
Ctrl_Bsl
MA_Bsl
MA
2h
MA_2h
Ctrl
4h
MA_4h
Ctrl_4h
10
Comp.2 [8.96%]
Principal component 2 (8.96%)
15
Ctrl_4h
MA_4h
Ctrl_6h
MA_6h
20
MA 4h
MA_4h
15
15
MA 6h
MA_6h
Principal component 2 (8.96%)
15
PCA: Meat Allergic
Ctrl_4h
Ctrl_6h
Ctrl bsl
Color byCtrl_Bsl
Group
Ctrl
2h
Ctrl_2h
MA_2h
MA_Bsl
10
10
5
5
0
0
Comp.2 [8.96%]
PCA: All Samples
Ctrl_6h
Color byCtrl_Bsl
Group
Ctrl_2h
MA_2h
-5
-5
-10
-10
-10
-15
-20
-15
-20
-15
-15
-15
-10
0
10
20
30
-10
0 Comp.110
20
30
[17.82%]
Principal component 1 (17.82%)
40
40
-15
-10
-5
0
5
10
-10
-5 Comp.10[17.82%] 5
10
Principal component 1 (17.82%)
15
15
H
h
• Patients presenting with anaphylaxis, or recurrent urticaria who have
IgE specific for alpha-gal have normal lung function no increase in
asthma symptoms and normal FeNO.
• This ectoparasite induced IgE response cross reacts with cat,
can make major contributions to total IgE, and appears to be a
model for IgE responses to parasites that do not create or
increase the risk for asthma.
• The results explain previous enigmatic IgE antibodies to cat in a
Kenyan village and in the ED in Virginia.
AJRCCM June 2012
Features Associated with Delayed Urticaria and Anaphylaxis in
Patients with IgE to Galactose-alpha-1,3-galactose
Urticaria Only
(n=87)
Anaphylaxis#
(n=249)
0 – 20 years
20%
16%
21 – 40 years
20%
25%
41 – 50 years
22%
24%
>50 years
39%
35%
46%
52%
Mild
44%
0%
Moderate
45%
75%
Severe
12%
25%
Variable
I. Age of Onset
II. Atopy
III. Severity of Reaction
#Anaphylaxis
was based primarily on patient reports, many cases were
improved by the time they reached the emergency facility
August 29th, 2014 (Charlottesville, VA)
– 43 year old man with metastatic colon cancer developed
anaphylaxis within 2 minutes of starting his first infusion of
Cetuximab*
– Prolonged circulatory collapse-resuscitation
– Transferred to ICU at local hospital
– Generalized organ failure including ARDS and hepato-renal
syndrome
September 3rd, 2014
– Support withdrawn
Serum IgE to alpha-gal
Total IgE
3.1 IU/mL
149 IU/mL
*Information
from Kevin Lawrence, MD
Mount Washington Resort at Bretton Woods, NH
Site of the 1st International Monetary Fund conference, July 1944
Bretton Woods was recognized in the early 1900s as a hay fever resort by the
United States Hay Fever Association (founded in 1873), and also in the 1930s
through the 1950s, along with other areas in the White Mountains, as a retreat
for ragweed hay fever sufferers
Anaphylaxis to cetuximab is regional.
States with high prevalence of
Hypersensitivity reactions to Cetuximab
during first infusion:*
•Tennessee
Virginia
•North Carolina Arkansas
•Missouri
Martha Stewart :
Sold stock in
ImClone on the
day before the
FDA delayed
marketing of
Cetuximab.
Bert O’Neil’
UNC
Oncology
Bentonville
*O’Neil et al JClin Oncology Aug ’07,, Chung et al NEJM March 13th ‘08
In 2006, we knew about four things including two
forms of anaphylaxis that didn’t make sense.
• A patient with carcinoma of the colon died of anaphylaxis within 20
minutes of starting his first infusion of cetuximab*.
• A 43-year-old hunter who reported three episodes of
anaphylaxis, each starting four hours after eating beef.
• A village in Kenya where 70% of the children had IgE
antibodies to cat without exposure or symptoms.
and: You cant grow Azaleas in Central Virginia.
*.
Bert O’Neil, UNC
Delayed anaphylaxis to red meat and the nature of the IgE
responses to galactose-alpha 1, 3-galactose (Alpha-gal)
=Severe immediate reactions to cetuximab in patients with IgE to
alpha-gal (>0.35 IU/ml)
Chung, et al, N Engl J Med, 2008; 358: 1109-1117
=24 cases of delayed anaphylaxis to red meat in patients with IgE
to alpha-gal
Commins, et al, JACI, 2009; 123: 426-433
=Monitored challenges with red meat demonstrate delay in
symptoms and basophil activation.
Commins, et al, JACI, 2014; 134 (1): 108-115
=Tick bites are a(or the) major cause of IgE responses to alpha-gal
Commins, et al, JACI, 2011, 127: 1286-1293
=
IgG and IgE antibody responses to the oligosaccharide galactose alpha1, 3-galactose: potential for distinct/unrelated control mechanisms
IgM & IgG2 to alpha-gal
from gut organisms:
Mesenteric Lymph Nodes
IgE & IgG1 response to tick bites:
Draining lymph
node
Local inflammation with
query local switch due to
multiple seed tick bites
IgG2 is common in antibody
responses to sugars and may
be T-independent
IgE responses are generally
considered to be T-dependent, but
the specificity of T cells related to
tick bites is not known
Current Opinion in Immunology 2013
Rispens et al Plos one 2013
Bites of Amblyomma americanum can be
Extremely Pruritic .
Bites of adult or larval ticks have been
associated with rapid rises in IgE ab and
total IgE.
Rash at 48 hours
Koike et al. Proc
Nat Acad Sci
2006;104(2):559564.
Karl Landsteiner
Defined the 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.
But also established the concept of a hapten.
Macher BA and Galili U. The AlphaGal epitope:a carbohydrate of unique
evolutionary and clinical relevance, Biochim. Biophys. Acta, 1780:75-88. ’08
Platts-Mills TA and Isizaka K. Activation of the alternative pathway of
human complement by rabbit red cells, J.Immunol 1974.
Commins et al. Galactose-α-1,3-galactose-specific IgE is associated
with anaphylaxis but not asthma. AJRCCM. 2012;185:723.
Norrbotten, Sweden
1000
199/219
9/127
r =0.92; p<0.001
100
10
Association
with asthma
p<0.001
1
Fel d 1 (IU/ml)
Fel d 1 (IU/ml)
1000
Kabati, Kenya
0.1
100
10
1
0.1
0.1
1
10
100
0.1
1000
1
100
1000
Cat Epithelium (IU/ml)
Cat Epithelium (IU/ml)
1000
IgE to Alpha-Gal (IU/ml)
1000
1/233
Alpha Gal (IU/ml)
10
100
10
1
0.1
97/127
100
r =0.77; p<0.001
10
No relationship
to asthma
1
0.1
0.1
1
10
100
Cat Epithelium (IU/ml)
1000
0.1
1
10
100
Cat Epithelium (IU/ml)
1000
The Allergy Epidemics: 1870-2010: Conclusions.
Relevant Changes
Epidemic
~ 1880-1950
a) Clean water, Shoes, and Helminth eradication.
b) Increase in dairy herds and in the pollen of
grass and ragweed
Hay Fever
(Catarrhus aestivus)
~ 1955-2000
Onset of Indoor Life Style:
• Decreased physical activity
• Changes indoors: increased sensitization
to mite, cat, etc.
Pediatric Asthma
~1995
a)
b)
c)
d)
Peanut Allergy in
children
~2007
Increase in tick bites secondary to the rising
population of deer.
Changes in Peanut products
Delayed exposure
Changes in the skin (eczema)
Vaccination policy
Late night anaphylaxis
(due to red meat)
The Allergy Epidemics: 1870-2010. JACI July 2015
Multiple bites from the first hatching of
Amblyomma ticks and IgE ab to alpha-gal.
Photograph: August 23, 2007.
Test
10/26/06
5/21/07
10/9/07
11/6/07
Cetuximab
(alphaGal)
0.49
16.9
48.3
130
Total IgE
127
199
350
532
•Female ticks can lay up to 1,000
eggs and the first hatching of a
tick is called a ‘seed tick’;
approximate size: 1.0-1.5 mm.
•Multiple bites by seed ticks are
not uncommon in the Southeast.
Aalberse and Platts-Mills JACI 2004
Lymph Node or Bone Marrow
Bone Marrow
The enigma of IgE B-cell memory in human subjects:
J.Davies, T.Platts-Mills and R.Aalberse, JACI 2013
Deep sequencing data from Scott Boyd , Stanford , on B cells
from Virginia.
Alpha-gal cases
have now been
reported from:
-Australia
-Sweden
-France
-Germany
-Spain
-Japan
-China
-Zimbabwe
-South Africa
-England
Stockholm,
Sweden:
Marianne van
Hage
Borstel,
Germany:
Uta Jappe
Biedermann
IgE ab to alpha-gal
have been
Reported from
Kenya & Ecuador.
Nancy, France:
Moneret-Vautrin,
And Morisset
Berlin,
Germany:
Jorg KleineTebbe
Sequential class switching is required for the
generation of high affinity IgE antibodies.
Huizhong Xiong , ..Maria de Lafaille, and Juan Lafaille.
Journal of Experimental Medicine: Jan 16th 2012
i. IgE B cells are rare in germinal centers (GC).
ii. IgE plasma cells can be derived by direct switch from
IgM or via IgG B cells which have undergone maturation
in germinal centers .
iii. They suggest that only IgE antibodies made via the
germinal center route are relevant to allergic disease and
even that low affinity antibodies are protective.
NB Deficiency of Bcl6 impairs GC but allows normal IgE
in patients with DOCK8 mutations and immunodeficiency.
See Zhang et al NEJMed 2009
August 29th, 2014 (Charlottesville, VA)
– 43 year old man with metastatic colon cancer developed
anaphylaxis within 2 minutes of starting his first infusion of
Cetuximab*
– Prolonged circulatory collapse-resuscitation
– Transferred to ICU at local hospital
– Generalized organ failure including ARDS and hepato-renal
syndrome
September 3rd, 2014
– Support withdrawn
Serum IgE to alpha-gal
Total IgE
3.1 IU/mL
149 IU/mL
*Information
from Kevin Lawrence, MD
A
Meat Status-basal differences
Amino Acids
Peptide
Carbohydrate
Lipid
Xenobiotic
Co-factor/vitamin
Total=20 metabolites
B
aspartyl
phenylalanine
leucylglycine
C
taurocholate
10-undecenoate