Blog, para el estudio, la publicación, la investigación, la asesoría y la consulta médica,prevención, diagnóstico, tratamiento de las enfermedades alergicas, el asma, la inmunología y la pediatría global en niños y adultos. En Venezuela e internacionalmente.
Blog for the study, publication, research, assesment and the consultancy of medical prevention, diagnosis, treatment of the allergic diseases: asthma,immunology and pediatrics in children and adults in Venezuela and world-wide.
LAS REACCIONES POR ALIMENTOS PUEDEN SER TOXICAS Y NO TOXICAS. ENTRE LAS REACCIONES NO TOXICAS SE INCLUYE LA REACCION ALERGICA A ALIMENTOS Y LA INTOLERANCIA. LA ALERGIA ALIMENTARIA PUEDE SER MEDIADA POR LA INMUNOGLOBULINA E, O, POR OTROS MECANISMOS INMUNOLÓGICOS O NO, LOS CUALES ESTAN EN ESTUDIO. LOS ALIMENTOS MAS FRECUENTES EN ALERGIA EN NIÑOS Y ADULTOS, SON: LECHE, TRIGO, HUEVO, SOYA, MANI Y NUECES DURAS Y PESCADO Y MARISCOS. LA ANAFILAXIA POR ALIMENTOS ES UNA EMERGENCIA Y REQUIERE EL USO DE ADRENALINA INTRAMUSCULAR O INTRAVENOSA. CONSULTE EL ALERGOLOGO.
Anualmente, 48 millones de personas en
los Estados Unidos se enferman por consumir alimentos contaminados. Los
causantes comunes incluyen bacterias, parásitos y virus. Los síntomas
varían de leves a severos. Incluyen:
Malestar estomacal
Cólicos abdominales
Náusea y vómitos
Diarrea
Fiebre
Deshidratación
Las bacterias dañinas son la causa más común de enfermedades por
alimentos. Los alimentos pueden contener bacterias cuando los compra. La
carne cruda puede contaminarse mientras matan al animal. Las frutas y
las verduras pueden contaminarse mientras crecen o se procesan. También
puede ocurrir en la cocina, si deja los alimentos a temperatura ambiente
más de 2 horas. Manipular los alimentos con cuidado puede prevenir estas enfermedades.
En la mayoría de los casos, el tratamiento es tomar más líquidos.
Para las enfermedades más serias puede ser necesario hospitalizar al
paciente.
NIH: Instituto Nacional de la Diabetes y las Enfermedades Digestivas y Renales
IgE in the diagnosis and treatment of allergic
disease
Thomas A. E. Platts-Mills, MD, PhD,a Alexander J. Schuyler, BS, BA,a Elizabeth A. Erwin, MD,b
Scott P. Commins, MD, PhD,c and Judith A. Woodfolk, MBChB, PhDa Charlottesville, Va, Columbus, Ohio, and Chapel Hill, NC
Traditionally, the concept of allergy implied an abnormal
response to an otherwise benign agent (eg, pollen or food), with an
easily identifiable relationship between exposure and disease.
However, there are syndromes in which the relationship between
exposure to the relevant allergen and the ‘‘allergic’’ disease is not
clear. In these cases the presence of specific IgE antibodies can
play an important role in identifying the relevant allergen and
provide a guide to therapy. Good examples include chronic
asthma and exposure to perennial indoor allergens and asthma
related to fungal infection. Finally, we are increasingly aware of
forms of food allergy in which the relationship between exposure
and the disease is delayed by 3 to 6 hours or longer. Three forms of
food allergy with distinct clinical features are now well
recognized. These are (1) anaphylactic sensitivity to peanut, (2)
eosinophilic esophagitis related to cow’s milk, and (3) delayed
anaphylaxis to red meat. In these syndromes the immunology of
the response is dramatically different. Peanut and galactose
a-1,3-galactose (alpha-gal) are characterized by high- or very
high-titer IgE antibodies for Ara h 2 and alpha-gal, respectively.
By contrast, eosinophilic esophagitis is characterized by low
levels of IgE specific for milk proteins with high- or very high-titer
IgG4 to the.
same proteins. The recent finding is that patients with
alpha-gal syndrome do not have detectable IgG4 to the
oligosaccharide. Thus the serum results not only identify relevant
antigens but also provide a guide to the nature of the immune
response. (J Allergy Clin Immunol 2016;137:1662-70.)
Key words: Asthma, allergen particles, IgE antibodies, eosinophilic
esophagitis, alpha-gal, IgG4
The first awareness of immediate hypersensitivity came from the
separate investigations of seasonal hay fever over the period 1870-
1910 by Blackley, Wymann, Noon, and Von Pirquet.1 At that point,
no evidence of an immune response to pollen could be detected in
serum from these patients.2 However, in 1921, Prausnitz and
K€ustner showed that serum of allergic subjects could transfer sensitivity
locally in the skin.3 This Prausnitz-K€ustner test was used
widely between 1921 and 1960 and played a major role in the discovery
of IgE. Once IgE was established, it was possible to investigate
many different aspects of allergic disease both in terms of
diagnosis and in understanding the relevant treatment. Thus the discovery
of IgE completely changed the investigation of these diseases
because measurements were of a specific molecule
measured in fully defined units (first in international units and
then by absolute quantitation; ie, 2.4 ng/unit). The initial purification
of Prausnitz-K€ustner activity was primarily related to ragweed pollen.4
Interestingly, Ishizaka et al4 did not consider that the establishment
of a new isotype of immunoglobulin, IgE, changed the
argument about the causal role of pollen in hay fever. By contrast,
measurement of IgE has now played a major role in the diagnosis
of many allergic diseases other than hay fever. However, it has to
be admitted that it is difficult to replicate the simple elegance of
the evidence about the role of airborne pollen grains in hay fever.
Early in the 20th century, Coca5 became Editor of the Journal
of Immunology and proposed the concept of atopy or the hereditary
tendency to become allergic to allergens in the environment.
He included asthma, food allergy, and eczema, as well as hay fever,
among the atopic diseases. Furthermore, he clearly implied
that the sensitizing allergens had a causal role in these diseases.
For the main forms of food allergy recognized at that time (eg,
fish, nuts, egg, or milk), the rapid development of symptoms,
including hives or angioedema, after exposure left little doubt
about causality. By contrast, for chronic asthma in patients sensitized
to 1 or more of the perennial allergens, the evidence of a
relationship between allergens and disease is more difficult to
establish. This is particularly true for allergens, such as dust
mite or cockroach, where the allergens only become airborne during
disturbance.6,7 We would like to focus on the evidence for causality
and the role of IgE in relation to 3 conditions:
1. chronic asthma in patients who are sensitized to 1 or more
perennial allergens;
2. allergic symptoms in patients who are colonized with fungi
in their lungs, sinuses, or nails; and
Abbreviations used
ABPA: Allergic bronchopulmonary aspergillosis
Alpha-gal: Galactose a-1,3-galactose
EoE: Eosinophilic esophagitis
From the a
University of Virginia, Asthma and Allergy Disease Center, Charlottesville; b
Nationwide Children’s Hospital, Center for Innovation in Pediatric Practice, Columbus;
and c
the Division of Rheumatology, Allergy, and Immunology, University of
North Carolina, Chapel Hill.
Supported by the National Institute of Allergy and Infectious Diseases (AI-20565 to
T.A.E.P.-M. and AI-113095 to S.P.C.).
Disclosure of potential conflict of interest: T. A. E. Platts-Mills has received a grant from
ThermoFisher/Phadia. E. A. Erwin is employed by Nationwide Children’s Hospital;
has received royalties from UpToDate; and has received travel support from the
American College of Allergy, Asthma, and Immunology. S. P. Commins has received
personal fees from Genentech and UpToDate and has received a grant from the
National Institutes of Health. J. A. Woodfolk has received grants from the National
Institutes of Health/National Institute of Allergy and Infectious Diseases and the
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and
Skin Diseases. A. J. Schuyler declares no relevant conflicts of interest.
Received for publication April 12, 2016; revised April 22, 2016; accepted for publication
April 22, 2016.
Available online April 27, 2016.
Corresponding author: Thomas A. E. Platts-Mills, MD, PhD, University of Virginia
Health Systems, Asthma and Allergic Disease Center, PO Box 801355, Charlottesville,
VA 22908-1355. E-mail: tap2z@virginia.edu.
The CrossMark symbol notifies online readers when updates have been made to the
article such as errata or minor corrections
0091-6749/$36.00
2016 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaci.2016.04.010
1662
3. the different forms of food allergy, including those newly
recognized syndromes in which the relationship between
exposure and response is not ‘‘immediate.’’
CHRONIC ASTHMA IN PATIENTS WITH
SENSITIZATION TO 1 OR MORE PERENNIAL
ALLERGENS
The opinion about the relevance of perennial allergen exposure
to chronic asthma has differed from enthusiastic acceptance to
denial or, worst of all, complete indifference.8,9 In part, this re-
flects the failure of some important avoidance studies and the
relentless pressure for treatment with pharmaceutical products.
A more important cause is that the relationship between exposure
and symptoms is not simple. Indeed, for mite, cockroach,
‘‘domestic’’ mice, and Alternaria species, patients often have
very little sense that they are allergic and do not understand the
role these allergens play in their asthma.10 For cat and dog, it is
not unusual for the allergic patients to report that they have acute
symptoms on entering a house with a relevant animal. However, in
many communities the majority of patients with cat allergy do not
live in a house with a cat, and nonetheless, sensitization is strongly
associated with asthma.11,12 In some studies there is clear evidence
that children raised in a house with a cat are less likely to
be sensitized.12 However, for cat, the levels of this allergen in
schools and homes without a cat increases with the prevalence
of domestic cats in the community.13 Statements of this kind
are possible because the source of these allergens can be identified
(ie, 4-legged animals) and because of the availability of sensitive
assays for relevant allergens in dust or airborne allergens.14 For
cockroaches and mice, visual identification is possible but less
reliable than measurement of specific allergens. For dust mites,
there is no way of evaluating their presence or concentration in
a house without microscopy or the use of an immunoassay.6,15
There are several major variables that have been used to
understand the relationship of allergen exposure to IgE antibodies
and asthma:
1. Many studies have been carried out in areas where dust
mites flourish in all homes (eg, the United Kingdom,
New Zealand, Australia, Costa Rica, and the Southeast
or Northwest of the United States).16-19
2. Studies have been conducted in areas where, because of
cold temperatures and low humidity, dust mites, cockroaches,
and Alternaria species are either absent or at
very low levels in homes.12,20,21
3. There are groups within the United States with dramatically
different attitudes to animals, such that a large section of the
population have much lower exposure and sensitization.19,22
4. Pollens and fungal spores, such as Alternaria species, have
major seasonal and geographic differences in their outdoor
particle counts. Since the 1950s, overall exposure to pollen
allergens, particularly ragweed, has decreased considerably
because of widespread use of home air conditioning,
which started during the 1960s.
DIAGNOSTIC RELEVANCE OF IgE ANTIBODIES TO
ASTHMA
In almost all clinical studies, IgE antibodies or skin tests are
carried out with extracts derived from the relevant allergens, and
these include multiple proteins. The relevance of the results can
be assessed based on the prevalence of positive test results, the
titer of IgE antibody, or the size of wheals or, alternatively, by tests
using specific proteins.13,23 Tests for sensitization to proteins can
use purified or recombinant allergens, but these tests are carried
out almost exclusively with in vitro assays.
There are many situations in which the significance of
sensitization to certain specific proteins is different from
that for the whole extract. A simple example is the tropomyosin
Der p 10, which cross-reacts with both cockroach and shrimp and
might not be a relevant inhalant allergen.23 A more complex situation
has developed with cat extracts. The major inhalant
allergen was purified by Ohman et al24 in 1974 as Cat 1, which
subsequently became Fel d 1. More recently, Fel d 4 has been
recognized as a second major inhalant allergen.25 However, cat
extracts can produce positive skin test or IgE assay results because
of IgE to 2 allergens that are not relevant to inhalant allergy. The
first of these is Fel d 2 (or cat albumin), which cross-reacts with
pork albumin, giving rise to the pork-cat syndrome.26,27 The second
is galactose a-1,3-galactose (alpha-gal), which has emerged
as a major allergen related to red meat and is the main epitope on
cat IgA.28-30 A major cause of confusion comes from the difference
between pelt extracts, which contain cat albumin and
many proteins carrying alpha-gal, and dander extracts, which
may only contain significant quantities of Fel d 1.
UNDERSTANDING THE ROLE OF ALLERGENS IN
ASTHMATIC PATIENTS AND THE RELEVANCE OF
IgE ANTIBODIES
We would like to focus on 3 observations about chronic allergic
asthma: (1) the strongest association is with sensitization to
common perennial inhalant allergens, which is true in particular
for high-titer IgE antibodies to allergens that are prevalent in the
patient’s community; (2) the relevant allergens, such as dust mite,
cat, dog, or cockroach, have been shown to become airborne on
particles of 5 to 35 mm in diameter (Fig 1 and Table I); and (3)
many or most acute episodes of wheezing cannot be related to
increased or even high-level exposure to allergens. The implication
of this last observation is that exacerbations are most likely
occurring as a result of viral or other triggers in the context of underlying
inflammation of the lungs and the associated bronchial
hyperreactivity.18,31,32
In a simplistic view the fact that bronchial provocation of an
allergic patient with nebulized allergen extract can induce both a
decrease in FEV1 and eosinophil-rich inflammation of the lungs
could be taken as evidence that allergen exposure is causally
related to asthma. However, the contrast between natural exposure
of the lungs to particles, such as mite feces, and a bronchial
challenge with nebulized allergen could hardly be more extreme
(Fig 2).33,34 Exposure to dust mite allergen is thought to consist of
5 to 100 fecal particles entering the lungs per day. Nebulized
allergen is estimated to be 10 million droplets inhaled over 2 to
5 minutes, where each droplet is approximately 2 mm in diameter.
Mite feces have been estimated to contain 0.2 ng of Der p 1,
whereas the comparable figure for nebulized droplets is less
than 1027 ng (Table I).
We assume that deposition of a particle on the bronchial wall
represents sufficient local allergen not only to activate mast cells
but also to recruit eosinophils, basophils, and lymphocytes. What
is not clear is how long such an inflammatory focus would last.
Our view is that some consequences of local inflammation could
J ALLERGY CLIN IMMUNOL
VOLUME 137, NUMBER 6
PLATTS-MILLS ET AL 1663
persist for months or longer. These include persistence of changes
in the vasculature that encourage local arrival of cells and
persistence of allergen-specific T cells. It seems likely that
allergen-specific T cells, as well as mast cells, could contribute
to the long-term persistence of bronchial hyperreactivity. Taken
together, the results could explain how IgE antibodies are relevant
to the process and that locally accumulating T cells could be a
target for peptide immunotherapy.35
SENSITIZATION TO FUNGI COLONIZING THE SKIN,
NAILS, OR LUNGS AS A RISK FACTOR FOR
ALLERGIC DISEASE
There are literally hundreds of pollinating plants or fungi that
produce spores, which can act as a source of inhalant allergens.
By contrast, there are only a limited number of fungi that induce
the production of specific IgE by growing on patients. Fungi can
be found growing on the skin, on mucosal surfaces, in the sinuses,
or in the lungs. In many cases these fungi have specific properties
that facilitate their growth. Thus dermatophytes have a specific
ability to grow on keratinized surfaces (ie, skin and nails). By
contrast, Aspergillus species are able to grow both at the temperature
of the soil and also at 378C in the lungs or sinuses. Although
the significance of fungal sensitization was recognized in the
1930s, acceptance of their clinical importance fluctuated until
allergic bronchopulmonary aspergillosis (ABPA) was established
by Hinson; Pepys; and Patterson.36,37 With the discovery of IgE, it
became possible to define the diseases better and to show that
many of these patients had IgE antibodies specific for fungal allergens.
Although the primary focus of studies on fungal sensitization
related to the lungs, it was recognized years ago that
sensitization to both dermatophytes and Candida species can
also be a cause of urticaria and angioedema.38 Diagnostic criteria
have been suggested for some fungal diseases; however, even
with ABPA, a large proportion of patients who are growing either
Aspergillus species or other fungi in their lungs do not fulfill the
criteria for ABPA or allergic bronchopulmonary mycosis. These
patients can be described as having forme fruste allergic bronchopulmonary
mycosis.
There is an important distinction between patients in whom the
fungus is growing at the site of the inflammatory reaction, such as
Aspergillus species or other fungi growing in the lungs or sinuses,
and patients in whom fungi growing on the feet appear to be
the cause of an inflammatory response elsewhere in the
body.39-41 The latter form can be described as an ‘‘ID’’ reaction
(ie, comparable with those skin lesions associated with
FIG 1. Allergens become airborne and are inhaled in the form of particles, which range from 5 to 30 mm in
diameter (Table I). The number of allergen molecules free in the air is essentially zero, and none of the
source materials are inhaled.
J ALLERGY CLIN IMMUNOL
JUNE 2016
1664 PLATTS-MILLS ET AL
pulmonary tuberculosis but did not contain organisms that could
infect a guinea pig). Historically, Candida and Trichophyton species
were well recognized by dermatologists as causes of ID reactions
in the hands or skin.38,42 In Box 1 we present 3 cases that
illustrate these differences.
Over the last 30 years, the field of fungal sensitivity has
changed progressively because of the availability and widespread
use of new oral antifungal drugs. In the early 1980s, the only oral
drugs that were available were griseofulvin and ketoconazole;
both of these drugs had severe side effects. The first new drug to
arrive was fluconazole, and then came itraconazole, terbinafine,
and voriconazole.43-45 This means that there are not only better
drugs that can be used to treat fungal infections associated with
allergic disease but also there might be fewer cases of severe onychomycosis
because of successful treatment in primary care. On
the other hand, the use of antibiotics and steroids encourages
growth of fungi, particularly yeasts. It is well recognized that
many women need to take 2 or 3 doses of fluconazole when
they are treated with antibiotics. It is a different question whether
high-dose inhaled steroids can enhance yeast growth in the lungs.
Our view is that all patients with severe asthma who produce
sputum should be monitored for growth of aspergillus, yeasts,
or other fungi in the lungs (see case I in Box 1).46
With all these fungal diseases, it is an open question whether it
is necessary to obtain cultures before treatment. There is good
evidence that patients with ABPA who are colonized with an
Aspergillus species sensitive to itraconazole respond better to
treatment with that drug.44 The in vitro tests of sensitivity of
cultured fungi to antifungals are improving and have become
more readily available. We would argue that identifying the species
improves the understanding of the condition and can
contribute to the success of treatment. On the other hand, Denning
et al45 demonstrated that itraconazole could improve the outcome
for patients with asthma who have skin sensitization to fungi
without establishing the presence of a colonizing organism.46
ROLE OF IgE ASSAYS IN THE DIAGNOSIS OF
DIFFERENT FORMS OF FOOD ALLERGY: PEANUT
ANAPHYLAXIS, EOSINOPHILIC ESOPHAGITIS
(EoE), AND DELAYED ANAPHYLAXIS TO RED MEAT
(THE ALPHA-GAL SYNDROME)
Over the last 20 years, both the scientific investigation of
allergic disease and the practice of allergy have moved progressively
toward food allergy. In our practice in central Virginia, this
has included major increases in 3 different forms of allergic
TABLE I. Sizes of particles carrying some airborne allergens associated with asthma
Diameter (mm)* Allergen concentration
No. of particles
To deliver 20 ng Entering the lung Allergen per particle or droplet
Pollen grains ;20 ;20 mg/mL ;100 ;5-100/d 0.1-0.3 ng
Mite fecal pellets 15-35 ;20 mg/mL ;100 ;5-100/d 0.1-0.3 ng
Alternaria species spores 14 3 10 Unknown — — —
Rat allergen 7 1 mg/mL ;27,000 ;10,000/h ;0.001 ng
Nebulized allergen 2 1 mg/mL >108 ;108
/2 min ;1027 ng
*Sizes were determined from (1) direct microscopy, (2) distribution on a Cascade impactor, and (3) the theoretic behavior of a Wright nebulizer.
Concentration of allergen in mite feces was calculated from quantity and diameter. Concentration of rat allergen was measured in whole rat urine.
Concentration of mite antigen P1 or ragweed antigen E, which are commonly used for bronchial provocation.
FIG 2. Contrast between natural exposure to airborne allergen (A) and bronchial provocation with nebulized
extract (B). Natural exposure is to relatively large particles, which contain a wide range of allergens and
adjuvants.
J ALLERGY CLIN IMMUNOL
VOLUME 137, NUMBER 6
PLATTS-MILLS ET AL 1665
reactions to food. The thing that is truly interesting about this is
that these 3 forms of ‘‘allergy’’ appear to be distinct both in their
clinical presentation and in their underlying immune response
(Table II).28,29,47,48 Peanut allergy is taken as the model for immediate
and often anaphylactic reactions to food in children. This
condition has been well recognized for many years but has
increased rapidly during the period 1990-2010.49 Initially, it
was possible to argue that there was increased awareness of the
disease, but the prevalence of high-titer IgE antibody in random
cohorts of children has increased.50
The second form of food allergy is EoE, which was hardly
recognized at all before 1990 and has become progressively more
common over the last 20 years so that today most academic
centers in the United States have an EoE clinic. The disease is
characterized by chronic inflammation of the esophagus, which
gets better with a diet including avoidance of cow’s milk.51-53
Although many of the children have detectable IgE antibodies
to cow’s milk, wheat, egg, or soy proteins, the titers are consistently
low (Fig 3).47 Recent studies have shown that almost all
children with EoE have high- or very high-titer IgG4 antibodies
to cow’s milk proteins.54,55 Clinically, patients with EoE continue
eating cow’s milk proteins because they are not aware of being
allergic. Thus EoE does not have the features of an IgEmediated
disease and also does not improve during treatment
with omalizumab. If EoE is a T cell–mediated disease, we should
be able to focus on T cells that can recruit eosinophils, give rise to
low levels of IgE, and strongly enhance IgG4. In addition, these
findings have major implications for the correct treatment.
The third group of patients present with anaphylaxis or
urticaria to red meat, which is most common in adults.29,56,57
Indeed, the typical case is a man older than 50 years with episodes
of hives, angioedema, or anaphylaxis that start several hours after
a meal including red meat. On skin testing, they have negative or
weakly positive skin prick test responses to a commercial beef
extract but strongly positive IgE assay results for the oligosaccharide
alpha-gal.28,29,57,58 Similar syndromes have now been
described in many countries, including Australia, Sweden,
France, Germany, and Japan.57,59-61 In each of these countries,
the reported reactions to meat have been delayed for several hours
after eating, IgE antibody is directed at the same oligosaccharide,
and there is reasonable or good evidence that tick bites are the primary
cause of the sensitization.59,61,62 In our practice the presence
of alpha-gal–specific IgE that represents more than 1% of total
IgE, a convincing report of bites from ticks (or chiggers), and a
history of urticaria or anaphylaxis starting 2 to 6 hours after
consuming red meat provide a high level of diagnostic certainty.
Evidence about these 3 forms of food allergy has provided a
stronger basis for evaluating reactions to food in general, and
several other syndromes have become much clearer. A simple
example is the pork-cat syndrome, which was first recognized in
Box 1. Three cases with severe allergic disease, documented fungal infection, sensitization, and response to antifungal treatment
d Case I: 43-year-old woman; repeated severe attacks of asthma; Candida species colonization of sinuses and lungs and full
response to fluconazole; IgE to Candida albicans was 13.3 IU/mL.
d Case II: 62-year-old man; judge with almost continuous facial angioedema, taking 50 mg of prednisone per day; severe fungal
infection of feet for ‘‘many years’’; skin test Trichophyton 11 IgE antibody of 5.0 IU/mL; Trichophyton species grown from nail
scrapings; no response to 3 months of fluconazole; full response to itraconazole over 1 year.
d Case III: 56-year-old man; diving instructor; increasingly severe late-onset asthma; continuous obstruction with FEV1 of 45% of
predicted value despite 40 mg of prednisone per day; culture of bronchoalveolar lavage fluid grew Aspergillus and Nocardia
species; successful treatment with voriconazole and Augmentin for 1 year
TABLE II. Clinical and immunologic differences among 3 common forms of allergic disease
Peanut-induced anaphylaxis EoE
Delayed anaphylaxis to mammalian meat
(alpha-gal syndrome)
Relevant allergens Ara h 1, Ara h 2 (peanut) Bos d 4, Bos d 5 (cow’s milk)
Wheat proteins
Alpha-gal*
Route of sensitization Skin Esophagus (?)
Skin unlikely
Skin
(Tick bites)
Risk factors Eczema Unknown Outdoor activity
Lipitor (?)
Serum IgE antibody High-titer IgE to peanut proteins
(5-500 IU/mL)
Low-titer or negative IgE to cow’s
milk proteins (<0.1-2 IU/mL)
High-titer IgE to alpha-gal (often 10%
to 30% of total IgE)
Treatment Diet free of peanut
Oral immunotherapy
Diet free of cow’s milk with swallowed
cromolyn 4 times daily
Diet free of mammalian products
Prevention Prevent eczema
Feed peanut from 3 mo
Not known Avoid tick bites
Timing of reaction
to foods
15-60 min to local and generalized
swelling§
12-24 h 3-6 h after eating red meat
*Chung et al28 and Commins et al.29
Erwin et al.47
Erwin et al.79
§Du Toit et al.48
J ALLERGY CLIN IMMUNOL
JUNE 2016
1666 PLATTS-MILLS ET AL
Europe.26,27 In evaluating cases of reactions attributed to red
meat, we found patients with negative results to alpha-gal but positive
results to pork, and weak results to beef. In these cases the
pork response was explained by IgE specific for pork albumin.
Absorption studies provided evidence that cat albumin was
responsible for the initial sensitization and that food reactions
were due to cross-reactivity.27 Patients with IgE to alpha-gal
can have delayed reactions to foods containing gelatin, such as
marshmallows or jelly babies.63 This occurs because gelatin
made from mammals can carry alpha-gal; however, in addition,
there are patients who are allergic to the protein epitopes on
gelatin. The gelatins cross-react extensively, and this has given
rise to anaphylactic reactions to vaccines containing gelatin.64
Most recently, we have seen a case reporting delayed reactions
to mammalian products, including cow’s milk and beef, who
was negative to alpha-gal. In this case the dominant assay result
was to milk, and the specific protein was BSA.65 What matters
here is that testing IgE to specific proteins and/or to the oligosaccharide
alpha-gal makes it possible to identify the relevant allergens
in many cases.
RELEVANCE OF THE ROUTE OF SENSITIZATION TO
THE SPECIFICITY AND TITER OF IgE ANTIBODY
RESPONSES
For many years, there have been questions about whether
sensitization to allergens could occur through routes other than
the inhaled or oral routes. The obvious example was atopic
dermatitis, in which the skin is already damaged and IgE
antibodies to inhalant allergens can reach high levels.66,67
Furthermore, patients with severe atopic dermatitis often have
IgE specific for foods, bacterial antigens, and also fungi, particularly
yeasts, such as Pityrosporum ovale.
68,69 During the last
15 years, the evidence for sensitization through the skin has
become much clearer. In relation to peanut allergy, it is well established
that sensitization correlates with eczema and that use of
topical treatments that incorporate peanut proteins increases the
risk of sensitization. The success of early introduction of oral peanut
in decreasing sensitization has added further evidence.48,70
Perhaps equally striking is the outbreak of wheat sensitization
among women in Japan who use a mildly abrasive face preparation
that contains wheat proteins.71-73
Given that the oral route can be tolerogenic and that there are
obvious advantages to not becoming allergic to food, the question
arises whether the skin route can break tolerance induced through
the oral route. This question became more complicated with the
discovery that sensitization to alpha-gal was common in large
areas of the United States.28,56 It is now clear that tick bites are the
dominant cause of this novel form of allergy in the United States
and that this syndrome provides another example of high-titer IgE
production in which the skin is the route of sensitization.59,62
Because we all make IgM and IgG2 specific to alpha-gal as part
of an innate response to gut bacteria, it could be argued that the
IgE response to alpha-gal must have broken tolerance. However,
we have remarkably little understanding of either the immunology
of IgE responses to oligosaccharides or the relevance of
T cells in the response to tick bites. Initial studies in collaboration
with Dr Rispens in Amsterdam suggested that the response to
FIG 3. IgE antibodies in patients with EoE compared with those with 2 anaphylaxis syndromes: peanut and
alpha-gal. Although IgE to milk, wheat, egg, and soy are common in children with EoE, the titers are
generally low or very low.
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PLATTS-MILLS ET AL 1667
alpha-gal does not include IgG4.
74 Recently, we have extended
those observations to confirm that neither the natural responses
to this oligosaccharide nor the IgE-dominated response include
IgG4.
55 There is excellent evidence that oral desensitization of
children with immediate hypersensitivity to milk or peanut can increase
or induce IgG4 antibodies.48,70,75,76 Our current view is
that the skin is an excellent route for inducing IgE to, for example,
schistosomes, ticks, and peanut but in general is a poor route for
inducing or boosting IgG4 antibodies. The exception might be
multiple bee stings. The early data on IgG4 argued that this
response required prolonged exposure. We would add that the
oral route might be the best route for boosting high levels of
IgG4 in an already sensitized subject and that the esophagus might
be an important route for this response (Fig 4).
CONCLUSIONS
The 3 areas on which we have focused here were chosen
because they illustrate the difficulty of understanding the role of
allergens in diseases in which the relationship between exposure
and the disease is not obvious to the patient. In these studies the
ability to measure IgE levels to allergen extracts, purified
proteins, and novel allergens has been central to understanding
the nature of the condition. Our first experience with this process
came from investigating the epidemic of asthma in children in the
United Kingdom at a time when it was already clear that many of
these children were allergic to dust mites. The proof that Der p 1
was a major target for IgE was an essential part of the definition of
this protein as a major mite allergen.77 In turn, this was essential
to proposing assays of Der p 1 in dust as a surrogate for microscopic
counting of dust mites.6,15
Although sensitization to yeasts and dermatophytes was well
known before the discovery of IgE, the level of scientific or
clinical acceptance was ‘‘meager.’’ Purification of Aspergillus
species allergens allowed measurements of IgG and IgE antibodies.
Sensitization to Trichophyton species provides another
example of the overall problem because very few of the patients
have considered the possible relevance of the fungal infection
TABLE III. Relevance of specific IgE antibodies to the treatment of allergic disease
Disease IgE assay and skin test Role of IgE Treatment* Immunotherapyz
Hay fever
Asthma
Seasonal allergens
Indoor and outdoor allergens
Primary
Central
Avoidance
A. Avoidance
B. Omalizumab
SCIT
SCIT
Late onset and
severe asthma
AERD
Vocal chord
Indoor allergens
Fungal
Not clear
Not relevant
Central
Mixed
Voice therapy, etc
A. Avoidance
B. Omalizumab
Anti-fungal
—
SCIT
?
Food allergy
Immediate reactions
Peanut, etc Primary Avoidance OIT
EoE Cow’s milk, wheat. Probably none Avoidance SCIT?
Alpha-gal Syndrome Alpha-gal, beef. Primary Avoidance —
*Antihistamines and local steroids, for example, are asked for all these diseases.
Dependent on identifying specific allergen or allergens.
OIT, Oral immunotherapy; SCIT, subcutaneous immunotherapy.
FIG 4. Contrast between 3 body surfaces that are relevant to the induction and maintenance of immune
responses for food allergens: skin (keratinized squamous epithelium), esophagus (nonkeratinized squamous
epithelium), and columnar epithelium in the intestines. We recognize that the lymphoid tissues
draining the upper airways and mouth are also important for response to food allergens.
J ALLERGY CLIN IMMUNOL
JUNE 2016
1668 PLATTS-MILLS ET AL
on their feet to their disease. Purification of the relevant proteins
was an important part of understanding the immune response that
starts in the skin.41 Clinically, the availability of the newer antifungals
has completely changed the equation. We would stress
that these cases continue to appear and that without considering
fungal sensitization and using oral antifungal treatment, they
will continue to be treated with high doses of steroids.
The 2 new syndromes of food allergy illustrate well the
problems with diagnosis and treatment of allergic diseases in
which allergen exposure does not give rise to immediate
symptoms.
With EoE, the clearest guide to the relevance of foods comes
from the response to diet and particularly from the exacerbations
that can occur after reintroduction of specific foods. However, the
esophageal symptoms do not reappear for 24 hours or more. Skin
tests are generally not convincing in defining the important
sensitivity. By using serum IgE assays, the presence of IgE to
cow’s milk proteins is clear.53 Nonetheless, it seems unlikely that
IgE antibodies play a direct role in the disease. The most recent
findings about IgG4 antibodies to milk proteins add further evidence
about the relevance of these proteins.
During the first years of the 21st century, many of the patients
with alpha-gal syndrome presented to allergists and were
consistently advised that their symptoms were not due to food
allergy. This was because:
A. the onset of allergic reactions to meat in adult life was
considered rare;
B. skin prick tests to meat showed 2- to 3-mm wheals at best
(intradermal skin test results were positive); and
C. the patients reported long delays after eating red meat
before the symptoms started.
Without a specific assay for IgE antibodies to alpha-gal, it
would have been very difficult to connect the dots.78 Equally,
establishing that the IgE binding to meat extracts was IgE specific
for an oligosaccharide provided a further enigma until it became
clear that sensitization was occurring through the skin.
Today it is clear that the skin is an important route for IgE
responses, that a large proportion of allergic disease involves
conditions in which the relationship of exposure to disease is not
obvious, and that the ability to measure IgE and IgG4 antibody
levels to specific proteins can provide an important part of the
diagnosis and management (Table III).
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J ALLERGY CLIN IMMUNOL
(Instituto Nacional de la Diabetes y las Enfermedades Digestivas y Renales)
- En inglés y español
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Efectos a largo plazo de la intoxicación alimentaria (Departamento de Salud y Servicios Humanos)
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