6. • Fel d 1 is a 38 kD tetrameric glycoprotein with a structure similar to
that of uteroglobulin.
• IgE from over 90 % of cat-sensitized individuals reacts with this major
cat allergen.
• Fel d 1 is produced in sebaceous, anal, and salivary glands and
transferred to the fur by grooming.
• Airborne Fel d 1 is mostly associated with larger particles (>9 μm)
• 23 % of airborne Fel d 1 is carried on small particles (<4.7 μm diameter) that
stay suspended in the air for several days, favoring distribution of the
allergen in the environment.
Pomés A et al. Curr Allergy Asthma Rep. 2016;16:43
7. • Others relevant cat allergens
• Fel d 3: Cysteine protease inhibitor react with 10 % of IgE from cat-allergic patients.
• Fel d 6: Cat IgM is less well documented.
Pomés A et al. Curr Allergy Asthma Rep 2016;16:43
Grönlund H et al. Int Arch Allergy Immunol 2010;151:265–274
Konradsen et al. J Allergy Clin Immunol 2015;135:616-25.
Sarbjit S. Saini. Middleton's 8th edition.
90%
63%
37%
15-40%
40%
High IgE levels to Fel d 1 could be a marker of increased asthma risk.
High IgE levels to Fel d 4 have been associated with atopic dermatitis.
8. • A proportion of the airborne allergen (10% to 40%) was being carried on
smaller particles (less than 5 μm in diameter).
• The aerodynamic behavior of these particles and show that they are
dynamically equivalent to spheres of 1 to 7 μm in diameter.
• It is important to realize that a flat “flake” of dander may potentially have an
aerodynamic size smaller than its real size.
• Approximately 60% of airborne Fel d 1 settles out within 2 days of
disturbance, leaving smaller particles that can remain airborne for up to 14
days or longer.
J. Portnoy et al. Ann Allergy Asthma Immunol 2012;2018:223.e1–223.e15
Sarbjit S. Saini. Middleton's 8th edition.
9. • The presence of a cat can increase airborne Fel d 1 within 30 minutes.
• Indeed, recent estimates suggest that the quantities of cat allergen inhaled
are 10 to 50 times higher than mite allergen.
• The size of these particles has some important consequences.
• Small particles fall slowly and can be kept airborne by any movement in the house.
• Increased ventilation helps to remove small particles from a house.
• Air filtration with a room air cleaner may be a useful method of reducing exposure
to allergen on small particles.
J. Portnoy et al. Ann Allergy Asthma Immunol 2012;2018:223.e1–223.e15
Sarbjit S. Saini. Middleton's 8th edition.
10. • More than 90% of all people who have respiratory tract symptoms
related to cat exposure have IgE antibodies specific for Fel d 1.
• Measurements of Fel d 1 in the environment provide an excellent
model for cat exposure relevant to asthma or rhinitis.
• Peptides derived from Fel d 1 have been proposed as an alternative
to cat extract for immunotherapy.
• Fel d 1 itself has no important cross-reactivities and indeed has very
little homology with any known allergens except Can f 4.
Sarbjit S. Saini. Middleton's 8th edition.
11. • Other allergens from cat are more important in relation to food
allergy than to inhalant symptoms.
Fel d 2, Cat albumin
cross-reactsimmunologically with several different
mammalian albumins, including those of dog, pork,
and beef à adult-onset allergic reactions to pork
Pork-Cat Syndrome
Patients with this syndrome sensitized to albumins
from animal dander report symptoms after the
consumption of pork because of the cross-reactivity
of albumins from different species.
Konradsen et al. J Allergy Clin Immunol 2015;135:616-25.
Sarbjit S. Saini. Middleton's 8th edition.
12. • Fel d 5w, cat IgA
• The alpha-gal–specific IgE antibodies were strongly associated with delayed
anaphylaxis to red meat.
• IgE antibodies to alpha-gal will bind to cat IgA (Fel d 5w), beef thyroglobulin
• The presence of IgE antibodies to alpha-gal can lead to misleading results on
IgE assays or skin tests using cat extracts.
• IgE antibodies to alpha-gal do not create a risk for asthma or other inhalant
symptoms.
Sarbjit S. Saini. Middleton's 8th edition.
14. • Dogs can be a potent source of allergen,
• appears to be less common than cat allergy as a cause of asthma.
• Many dogs are kept outside and become dirty (actually, much worse),
so washing dogs is a common practice.
• A common sources of dog allergens are dander and saliva.
• Four of six currently identified dog allergens are lipocalins.
• Can f 1, Can f 2, Can f 4, and Can f 6
Sarbjit S. Saini. Middleton's 8th edition.
Pomés A et al. Curr Allergy Asthma Rep. 2016;16:43
15. • About ∼70 % of dog- allergic individuals have IgE antibodies specific to
the major dog allergen Can f 1.
• Can f 1 is detectable in one third of homes without a dog.
• The size distribution of particles associated with Can f 1 is similar to
that of Fel d 1.
• A wide variability in Can f 1 levels can be found between dog breeds,
• but there is no evidence for a hypoallergenic breed.
Pomés A et al. Curr Allergy Asthma Rep. 2016;16:43
16. • Can f 5 (prostatic kallikrein, arginine esterase), derived from dog urine is
also considered a major allergen, with up to 70% of dog- allergic patients
having Can f 5-specific IgE.
• 38 % of dog-allergic patients were monosensitizedto Can f 5.
• Other relevant dog allergens
• Can f 2 (lipocalin)
• react with 20–30% of IgE from dog- allergic patients.
• Can f 4 (lipocalin)
• react with 15–50% of IgE from dog- allergic patients.
• Can f 6 (lipocalin)
• react with 38% of IgE from dog- allergic patients.
• Can f 3 (dog albumin)
• react with 81 % of IgE from dog- allergic patients.
Significant inhalant allergens
Sarbjit S. Saini. Middleton's 8th edition.
Mattsson et al. J Allergy Clin Immunol 2009;123:362-8.
Pomés A et al. Curr Allergy Asthma Rep. 2016;16:43
20. • The immune response to domestic animal allergens includes
• T cells
• IgE antibodies
• different isotypes of antibodies.
• At present, both the significance of IgE antibodies and the techniques
for measuring IgE antibody levels are better established than the
techniques for describing any other aspect of the immune response.
Konradsen et al. J Allergy Clin Immunol 2015;135:616-25.
21. • T-cell responses
• A wide range of studies have been carried out on T-cell responses
to cat allergens using both the protein Fel d 1 and overlapping
peptides derived from Fel d 1.
• These studies demonstrated that responses to Fel d 1 are, broadly
speaking, of a TH2 type.
• Although it is possible that there are patients who have symptoms
related to cat or dog allergen exposure on the basis of a T-cell
response without an associated IgE antibody response, this has
not been demonstrated.
Konradsen et al. J Allergy Clin Immunol 2015;135:616-25.
22. • IgG antibody responses
• There are mixed data about the isotypes other than IgE and IgG4.
• Many publications report detectable IgG4 antibodies in most allergic and
non-allergic subjects in contrast to extensive earlier data.
• Although the results might not be relevant to the clinical evaluation of
patients, they are important to understanding the immune response to cat
allergens in those atopic children who live in a house with a cat but do not
become symptomatic on exposure to cat allergens.
Konradsen et al. J Allergy Clin Immunol 2015;135:616-25.
23. • IgG antibody responses (Cont.)
• The dissociation of allergen-specific IgE and IgG responses to cat,
dog, and horse was reported,
• indicating that nonsequential class-switch mechanisms are operative in
patients with animal allergy and might explain why naturally occurring
allergen-specific IgG is not always protective.
• Measurement of IgG antibodies might also be relevant to understanding
why some subjects experience increased symptomson entering a house
with an animal after a period of decreased exposure.
Konradsen et al. J Allergy Clin Immunol 2015;135:616-25.
26. E.A. Erwin et al. Ann Allergy Asthma Immunol 2014;112:545-550
• Non-sensitized individuals with IgG to Fel d 1 experienced
a significant decrease in IgG titers with decreased
exposure to cat allergen (p=0.02).
• For those students (n = 21) who were followed up for a
second year, levels of IgG antibody to Fel d 1 had
decreased further.
• Non- sensitized individuals, IgG4 also decreased (P < .001)
during 8 months of decreased cat exposure.
• None of the individuals having IgG to Fel d 1 without
sensitization to cat developed a positive serum IgE
antibody assay or a positive skin prick test result to cat
during 1 year or 2 years.
Changes in Antibody Titers to Fel d 1 in Non-sensitized Individuals
27. E.A. Erwin et al. Ann Allergy Asthma Immunol 2014;112:545-550
• Specific IgE titers to cat did not decrease
significantly during prolonged, decreased
exposure to cat allergen.
• IgG antibody to Fel d 1 decreased significantly during
the 8-month study period (P < .001)
Antibody Changes in Cat Sensitized Individuals
29. • Conclusion: Under conditions of marked decrease in exposure,
• No participants developed new-onset sensitization.
• Among the individuals sensitized at study entry, there were major decreases
in the ratio of IgG to IgE.
E.A. Erwin et al. Ann Allergy Asthma Immunol 2014;112:545-550
31. • The major cat allergen, Fel d 1, remains airborne for many hours
after any disturbance.
• As a result, estimates of the quantities of cat (or dog) allergens
inhaled in a house with an animal are much higher, at approximately
1 μg/day, than comparable estimates of Der p 1 inhaled of 10
ng/day.
• In addition, the particles of dander carrying cat allergens appear to be
“sticky,” which means that they are consistently carried on clothing
from houses with an animal to other buildings.
Sarbjit S. Saini. Middleton's 8th edition.
33. • In 1998, Hesselmar and Bjorksten reported that children raised in a
house with a cat were less likely to become allergic to cats.
• This result was greeted with astonishment;however, several other groups of
investigators found strong evidence supporting that observation.
• Many of the “non-allergic” children who lived in a house with a cat had made
IgG and IgG4 antibodies to Fel d 1.
• This response is of interest in that it has more of the features of a “modified
Th2” response than of a shift to Th1.
• The effect of exposure to a cat in early life can be both allergen-
specific and long-lasting.
Sarbjit S. Saini. Middleton's 8th edition.
43. Lodrup Carlsen KC et al. PLoS One 2012;7:e43214.
Conclusion:
• Pet ownership in early life did not appear to either increase or reduce the risk
of asthma or allergic rhinitis symptoms in children aged 6–10.
• Advice from health care practitioners to avoid or to specifically acquire pets for
primary prevention of asthma or allergic rhinitis in children should not be given.
44. • An issue of some clinical importance is whether the effect of a dog in
the house is the same as the effect of a cat.
• High levels of endotoxin in the home were inversely related to
allergen sensitization.
• Several detailed studies have shown that a cat in the home does not increase
endotoxin either in floor dust or in airborne form.
• The presence of one or more dogs in the house does increase airborne
endotoxin, and in some studies, early exposure to dogs appeared to have an
inhibitory effect on allergy in general.
Sarbjit S. Saini. Middleton's 8th edition.
45. • Although undoubtedly individual differences will affect the response
to animal exposure, two very different mechanisms may be involved.
• The first is the shift, induced by higher exposure, to germinal center
production of B cells, which favors IgG4 production and may be a major
component of the allergen-specific tolerance induced by early exposure to
cat allergens.
• The second mechanism is increased endotoxin or increased bacterial
diversity in the home, with consequent effects on the microbiomeof the
child during early development.
• The second mechanism would not be allergen- specific and is more likely with a dog
than with a cat.
Sarbjit S. Saini. Middleton's 8th edition.
48. Practice Parameter
Environmental assessment and exposure control: a practice parameter—furry animals
Chief Editors: Jay Portnoy, MD, Kevin Kennedy, MPH, James Sublett, MD
Members of the Joint Task Force on Practice Parameters: David Bernstein, MD, Joann Blessing-Moore, MD, Linda Cox, MD, David Khan, MD, David Lang, MD, Richard Nicklas,
MD, John Oppenheimer, MD, Jay Portnoy, MD, Christopher Randolph, MD, Diane Schuller, MD, Sheldon Spector, MD, Stephen A. Tilles, MD, Dana Wallace, MD
Practice Parameter Work Group: James Sublett, MD, cochair, Kevin Kennedy, MPH, cochair, Charles Barnes, PhD, David Bernstein, MD, Jonathan Bernstein, MD, Carl Grimes,
Elizabeth Matsui, MD, Jeffrey D. Miller, MD, J. David Miller, PhD, Wanda Phipatanakul, MD, MS, James Seltzer, MD, P. Brock Williams, PhD
Invited Reviewers: Jack Armstrong, Hans Gr×nlund, PhD, Kraig W. Jacobson, MD, Jill A. Poole, MD, Matthew A Rank, MD, Megan Taylor, MD
This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy,
Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology.
The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) have jointly accepted responsibility for
establishing “Environmental Assessment and Remediation: A Practice Parameter.” This is a complete and comprehensive document at the current time. The medical environment is a
changingenvironment,andnotallrecommendationswillbeappropriateforallpatients.Becausethisdocumentincorporatedtheeffortsofmanyparticipants,nosingleindividual,including
thosewhoservedontheJointTaskForce,isauthorizedtoprovideanofficialAAAAIorACAAIinterpretationofthesepracticeparameters.Anyrequestforinformationaboutoraninterpretation
of these practice parameters by the AAAAI or ACAAI should be directed to the executive offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. These
parameters are not designed for use by pharmaceutical companies in drug promotion.
Reprints: Joint Council of Allergy, Asthma and Immunology, 50 N Brockway St, #3-3 Palatine, IL 60067.
Disclosures: The following is a summary of interests disclosed on Work Group members’ Conflict of Interest Disclosure Statements (not including information concerning family member
Ann Allergy Asthma Immunol 108 (2012) 223.e1–223.e15
Contents lists available at SciVerse ScienceDirect
• A desire for companionship often override the medically prudent advice to
avoid exposure to dogs and cats for a sensitized person.
• The bottom line is that patients love their pets. They are part of the family.
• Pet ownership is likely to persist.
• Allergists need to be able to advise their patients how to live with the pet
while remaining as healthy as possible.
50. • Because 1 or more cat allergens are present in all cats, patients should not
be advised that it is safe to obtain a nonallergenic cat. (C)
• Measurement of cat allergens in settled dust should not be used as a
surrogate for airborne exposure. (C)
• Carpetsare the major reservoir for pet allergens in homes with pets
• Dust from living rooms contains significantly higher concentrations of both Fel d 1
and Can f 1 than dust from bathrooms, kitchens, and bedrooms, although the beds
may contain even higher concentrationsof Fel d 1.
• To reduce transport of cat allergen, people should consider changing their
clothes when traveling from a high cat allergen environment to a low cat
allergen environment. (C)
J. Portnoy et al. Ann Allergy Asthma Immunol 2012;2018:223.e1–223.e15
51. • Because 1 or more dog allergens are present in all dogs, patients
should not be advised that it is safe to obtain a nonallergenic dog. (C)
• Dogs should be excluded from rooms in which reduced exposure is
desired. (C)
• The number of dogs in the home is not related to dog allergen levels.
• Homes with outdoor dogs have higher dog allergen levels than homes
without any dogs but lower levels than homes with indoor dogs.
• Upholstered chairs in hospitals are an important reservoir of cat and dog
allergen.
• Special daycare centers with children who don’t have dogs or cats have
lower concentrations of both dog and cat allergen than daycare centers with
children who live with a dog or cat.
J. Portnoy et al. Ann Allergy Asthma Immunol 2012;2018:223.e1–223.e15
57. • Washing cats or dogs at least weekly can reduce airborne cat Fel d 1
or dog Can f 1; however, the clinical benefit is yet to be proven and
the effect of washing is not sustained. (B)
• Some woven microfiber bed encasings, generally those with a mean
pore size of 6 m or less, block cat allergen from penetrating the fabric
though the respiratory health benefit from their use is unclear. (C)
• Nonwoven microfiber encasings collect allergen on their surface
over time, including cat and mite allergens. Because they cannot be
washed, they are unsuitable for allergen avoidance. (C)
J. Portnoy et al. Ann Allergy Asthma Immunol 2012;2018:223.e1–223.e15
59. Sarbjit S. Saini. Middleton's 8th edition.
houses ha
some alle
nates.At p
ling hum
surfaces w
ronments
Althou
generally
good evid
clear evid
shows tha
influence
are a com
measurem
Limulus a
toxin.99
In
reduce or
experiment will produce a measurable fall in FEV1 in sensitive
patients. Thus if such a patient was in a house with an airborne
• Removal of cat from the home*
• Measures to reduce allergen with cat in situ
1. Reduce reservoirs for cat allergen (e.g., carpets, sofas).
2. Use vacuum cleaners with effective filtration system.
3. Increase ventilation or use high-efficiency particulate air
(HEPA) filters to remove small airborne particles.
4. Wash cat weekly, if possible.
BOX 28-3 AVOIDANCE MEASURES FOR CAT
ALLERGENS
*Reducing allergen levels requires about 12 to 16 weeks after cat is
removed.
61. • Although the best treatment for animal allergy is avoidance.
• This is not always possible.
• Exposure to both dog and cat allergen has been shown to be ubiquitous
and can occur even without an animal in the home.
• Making avoidance even more difficult.
• Because immunotherapy has been shown to be effective for cat and dog
• The decision to include dog or cat allergen in an allergen immunotherapy extract
should be considered in those circumstances in which there is exposure.
Cox et al. J Allergy Clin Immunol 2011;127:S1-55
62. • The major allergen content of cat extracts is relatively low, requiring
larger amounts to be given than for pollens or house dust mite.
• The major allergen content of most dog extracts is too low to allow
effective dosing, even with undiluted manufacturers’ extracts.
• However, in one study using an extract containing approximately 161 mg/mL
Can f 1 (Hollister-Stier Laboratories, Spokane, Wash), there was a significant
dose response of immunologic parameters similar to that demonstrated with
other allergens.
Cox et al. J Allergy Clin Immunol 2011;127:S1-55
65. • Fel d 1 is an ideal model allergen for the development of new strategies for
allergen-specific treatment of allergy and asthma.
• Fel d 1 hypoallergens
• Peptide-based immunotherapy:
• T-cell epitope-containing peptides
• Engineered Fel d 1 proteins with immunomodulatory function:
• Formulations consisting of Fel d 1 coupled to an immunomodulatory protein or carrier.
• Results reported from studies evaluating these approaches in experimental in
vitro and in vivo systems as well as in clinical trials with Fel d 1 peptides bear
promise that safer, more specific and efficient ways to treat cat-allergic patients
will be available in the future.
Grönlund H et al. Int Arch Allergy Immunol 2010;151:265–274
66. Study design:
• Randomized, double-blind, placebo-controlled, parallel-group clinical trial
Subjects:
• 18- 65 years, had a history of rhinoconjunctivitison exposure to cats for at least 1 year
Study medication: Cat-PAD: 6-nmol, 3 -nmol
Cat-PAD: Cat-peptide antigen desensitization
• an equimolar mixture of 7 peptides
• derived from Fel d 1
• Peptide immunotherapy uses synthetic peptides consisting of
T-cell epitopes derived from major allergens and autoantigens
to induce antigen-specific tolerance.
• Delivery of T-cell epitopes intradermallyis thought to lead to
the induction of T cells with a regulatory phenotype, which
results in downregulation of the response to antigen.
Patel et al. J Allergy Clin Immunol 2013;131:103-9
67. • Intervention: 3 groups
• Primary efficacy measurement: the mean change in TRSSs at 50 to 54
weeks from 1 hour onward on days 2 to 4 of the posttreatment challenge
(PTC) compared with baseline values
Patel et al. J Allergy Clin Immunol 2013;131:103-9
70. • Results:
• Greater efficacy with 4 administrations of a 6-nmol dose 4 weeks apart
• The treatment effect of 6 nmol persisted 1 year after the start of treatment
and was significantly different from
• 3-nmol (P= 0.0342) and placebo (P= 0.0104)
• Conclusions:
• A short courseof Cat-PAD improves the ocular and nasal components of
rhinoconjunctivitis symptoms in subjects with cat allergy, with the treatment
effect persisting 1 year after the start of treatment.
Patel et al. J Allergy Clin Immunol 2013;131:103-9
73. • Studies investigating dog allergen immunotherapy during the past 40 years
have failed to demonstrate any clearly reproducible clinical evidence to
confirm its effectiveness in ameliorating symptoms of rhinitis and asthma.
• Variability of Dog Extracts
• In 1996 report noted that
• Can f 1 levels in these extracts ranged from 3.8 to 170 mg/mL.
• The major dust mite allergens, Der p 1 and Der p 2, were detectable in all commercial dog
extracts.
• The possibility of false positives with skin prick testing for dog allergy.
• In 2001 compared the newest AP dog extract to the traditional aqueous dog extract
• 48% tested positive to AP dog. Only 28%tested positive to conventional dog extracts.
• All patients who tested positive to conventional extracts also were positive to AP dog, with a
significantly larger mean wheal diameter.
• 41% who tested positive to AP dog tested negative to conventional dog extracts.
• These data perpetuated questions about false negative.
D.M. Smith and C.A. Coop. Ann Allergy Asthma Immunol 2016;116:188-193
74. • Stability of Dog Extracts
• In 1998 showed that
• Can f 1 was relatively thermostable, with 50% of the allergen remaining after 60 minutes
of 140 C dry heat.
• In 2009, the stability and compatibility of AP and conventional dog extracts
were investigated
• Can f 1 levels remained at 94% to 119% and Can f 3 retained 79% to 94% potency for 3
days when kept between 21 C and 45 C, showing standard shipping methods without
refrigeration are acceptable for extracts.
• The extracts with 50% glycerin retained their potency, whereas the extracts with no
more than 10% glycerin showed significant degradation.
D.M. Smith and C.A. Coop. Ann Allergy Asthma Immunol 2016;116:188-193
75. • Current Prescribing Trends
• A nationwide survey in 2006 showed the perspective of how allergists across
the United States were integrating these conflicting and confusing data and
using them in daily practice.
• Responses showed the maintenance weight-to-volume ratio varied widely from 1:10 to
1:1,000 with the most common concentration being 1:100 (24.3%).
• Most allergists believe that dog immunotherapy will provide at least some relief from
allergic rhinitis (91.9%) and asthma (89.6%)
• 86% would be willing to offer immunotherapy to treat occupational allergy.
• This rate decreases to 81% if the patient is unable to remove the dog for purely
emotional reasons.
• To compare with 1987 when only 65% of board-certified allergists in private
practice perceived improvement in allergic rhinitis or asthma symptoms with
cat or dog immunotherapy.
D.M. Smith and C.A. Coop. Ann Allergy Asthma Immunol 2016;116:188-193
76. • Future research is necessary to produce more potent and complex extracts that
could be tailored to an individual patient’s pattern of dog sensitization.
• The first step would be to produce a standardized extract for clinical use.
• Additional trials could be designed to evaluate the efficacy of dog allergen
immunotherapy in improving clinical end points for patients.
• Properly powered studies with consistent allergen extracts also would facilitate
identification of the optimal dose required to produce these effects.
• The current recommendation on immunotherapy dosing for nonstandardized
dog extracts is 15 ug of Can f 1 per dose.
• 0.5-mL dose using full-strength (1:100 w/v) AP dog extract
D.M. Smith and C.A. Coop. Ann Allergy Asthma Immunol 2016;116:188-193