cockroach allergy.pdf

Cockroaches
Allergy
Yada Sirisa, MD
Division of Allergy, Immunology and Rheumatology Unit,
Departement of Pediatrics
King Chulalongkorn Memorial Hospital

Outline
• Cockroach species
• Cockroach allergen
• Pathophysiology: Cockroach allergy
• Cockroach allergy and inner city asthma
• Cockroach enviromental control
• Cockroach immunotherapy
Picture from: www.rentokil.co.id/en/cockroaches/cockroach-life-cycle

Cockroaches
• Cockroaches can spread disease, cnotaminate our food, cause allergies, and
even exacerbate asthma attacks in people
• Cockroach allergy: important health problem in the Unite States, especially in
inner-cities, and is associated with chronic exposure and IgE sensitization,
results in developemnt of asthma
• WHO: carriers of the organisms causing diarrhea, dyentery, cholera, leprosy,
typhoid fever, and viral diseases such as poliomyelitis
Middleton's’ Allergy: Principle and Practice, 9th edition

Cockroaches
• There are many species of cockroaches found in Florida, generally, these species can
be grouped into two categories: indoor cockroaches and outdoor cockroaches
• Several species of cockroaches are common in houses : Blattella germanica &
Periplaneta americana
• The German cockroach prefers cool and dry climates (Europe and USA)
• The American cockroach is common in hot and humid conditions (Brazil and Thailand)

Cockroaches
• Prevalence of cockroach allergy ranges from 17 to 41% in the United States
• 60-80% of inner-city children with asthma are sensitized to cockroach
• Subsequent studies established a causal relationship between cockroach allergy and
asthma by demonstrating bronchoconstriction following inhalation of cockroach extract
by cockroach allergic asthmatic patients

Toxonomy of cockroaches
* Significant indoor allergen
Portnoy J, et al. J Allergy Clin Immunol. 2013 Oct;132(4):802-8.e1-25.

Blattaria
* Significant indoor allergen
B. germanica
P. americana
S. longipalpa
B. orientalis

Cockroach species
• Few species live in people's homes and have been the focus for cockroach allergen-related
research including American cockroach (Periplaneta americana), German cockroach
(Blattella germanica), Oriental cockroach (Blatta orientalis), brown- banded cockroach (Supella
longipalpa) and smoky brown cockroach (Periplaneta fulliginosa)
• German and American cockroaches are the predominant species that infest human dwellings
- 9 German cockroach allergens (Bla g 1-8 and Bla g 11)
- 9 American cockroach allergens (Per a 1-3, Per a 6-7, Per a 9-12)
Pomés A, et al. Curr Allergy Asthma Rep. 2017 Apr;17(4):25.

• American cockroaches are more common in warmer climates
• Live and breed outdoors, yet close buildings and are very
common in sewer systems
• American cockroaches can fly in short distances
• American cockroaches are nocturnal and mostly active at night
• They will eat just about anything, including paper, hair, cloth and
dead insects
American cockroach
(Periplaneta americana)
www.combatbugs.com

• German cockroaches are prevalent in houses, apartments,
restaurants & hotels
• They eat sweets, soap, toothpaste, grease, meat and garbage
• They can fit into a crack as thin as a dime and cannot fly
German cockroach
(Blatella germanica)
www.combatbugs.com

• They have a greasy sheen and strong, unpleasant, roachy odor
and they actually emit a foul odor due to the numerous
bacterial and viral pathogens on their bodies
• They prefer to live outdoors and near water but will go indoors
during the summer time
Oriental cockroach
(Blatta orientalis)
www.combatbugs.com

• Brown banded cockroaches feed on household items like books,
envelopes, stamps, wallpaper, and draperies
• They are reported to spread at least 33 kinds of bacteria, six kinds of
parasitic worms and at least seven other kinds of human pathogens
• Brown banded cockroaches are usually nocturnal, or active primarily
at night and avoid water and are more common in warmer, dryer
climates
Brown banded cockroach
(Supella longipalpa)
www.combatbugs.com

การควบคุมพาหะนําโรค แมลงสาบ สํานักงานกรมอนามัยสิ7งแวดล้อม

Cockroaches in Thai patients
• Cockroaches have been established as the second
most important allergen, producing allergic disease,
especially in low socioeconomic populations
• Allergens of P. americana were detectable in all
homes studied, with the highest levels in the kitchen
area (72.15% of six spices of cockroaches)
• P. americana was the most common cockroach and may be the species causing allergic
diseases, especially asthma, In Thailand, which differs from the USA and Europe
Tungtrongchitr A, et al. Asian Pac J Allergy Immunol. 2004 Jun-Sep;22(2-3):115-21.

Allergen components in German cockroaches
Molecular Allergology User’s Guide EAACI 2022

Allergen components in American cockroaches

Group of cockroach allergens
Group 1 • There is cross reactivity between Bla g 1, Per a 1 and homologous proteins from other
cockroach species such as P.fuliginosa and B.orientalis and from other insects
• The protein is most prevalent in the midgut, so the presence of Bla g 1 in fecal particles, together
with Bla g 2, a good marker of cockroach allergen exposure
Group 2 • Bla g 2 is an unusual (inactive) aspartic protease with strong allergenic properties
• There is three times more Bla g 2 in cockroach feces compared with the whole extract
• It was originally found to be the allergen with the highest IgE antibody prevalence among 5
cockroach allergens in a US population
Group 3 • High homology to insect hemolymph proteins
• Per a 3 induces IL-4 expression from allergic patients and correlates with skin reactivity and
clinical symptoms
Group 4 • Bla g 4 and Per a 4 are lipocalins; very stable and hydrophobic cavity that binds small ligands
such as retinoids, glucocorticoids, and pheromones

Group 5 • Bla g 5 is a sigma class glutathione S-transferase (GST) that has a high IgE response in
cockroach sensitized individuals
• Cross-reactivity with GSTs of several sources (Der p 8 and Tyr p 8)
• Lack of significant IgE cross-reactivity among GSTs from cockroach, mite and Ascaris
Group 6 • Homologues to insect troponin C
• IgE binding to Bla g 6 has calcium dependent indication that IgE preferably binds to one of the
conformers
Group 7 • Invertebrate tropomyosin are important pan-allergeis among dust mites, chironomids, silverfish,
crustaceans, nematodes and mollusks
• IgE binding frequency to cockroach tropomyosin are very different in some populations and this
may reflect differences in environmental conditions
Group 8 • Bla g 8 shares 81-84% amino acid sequence identity with the myosin light chain of several
insects and the shrimp Litopenaeus vannamei

Group 9 • Per a 9 and Bla g 9 were identified as major allergens in Thai and US patients, respectively
• Arginine kinase homologues have also been reported in the shrimp P.monodon (Pen m 2), D.
pteronyssinus (Der p 20)
Group 10 • Per a 10; serine protease isolated from P. americana
• Cross-reactivity between cockroach and mite serine protease (Der f3, Der p 3, Der p 6 and Der p
9) is unlikely due to low amino acid identities among these molecules
Group 11 • Bla g 11; novel allergen, Per a 11 allergen has been described in China
Group 12 • Per a 12 and Bla g 12; Chitinases, essential for digestion of chitin
• Their amino acid identities with the house dust mite chitinases Der p 15 and Der f15
Group 13 • Per a 13; Glyceraldehyde-3-phosphate dehydrogenases

Cross reactivity of cockroach allergen
• In Southern China and Korea, sensitization to cockroach allergens has been reported,
sometimes associated with co-sensitization to shrimp and moth
• Bla g 7 and Per a 7, two of the cockroaches’ tropomyosin, are pan-allergens and
positive correlation between shrimp, cockroach, and dust mite IgE levels

Wang L, et al. Allergy. 2022 Sep 25.
Population: All subjects were recruited from the Allergy Clinic, Department of Oto-Rhino-Laryngology,
Siriraj Hospital, Bangkok, Thailand from 2020 - 2021
Methods: High-quality genome assembled using nanopore, Illumina, and Hi-C sequencing techniques
to approach genomic, transcriptomic, and proteomic
Using enzyme-linked immunosorbent assay, selected allergens were tested in Thai patients allergic to
P. americana

Wang L, et al. Allergy. 2022 Sep 25.
Result:
• A comprehensive allergen profile has been
characterized, with seven novel groups of allergens,
including enolase (Per a 14), cytochrome C (Per a
15), cofilin (Per a 16), alpha-tubulin (Per a 17),
cyclophilin (Per a 18), porin3 (Per a 19), and
peroxiredoxin-6 (Per a 20), showing IgE sensitivity
in enzyme-linked immunosorbent assay
• A new isoallergen of tropomyosin (Per a 7.02) and
multiple potential isoallergens of Per a 5 were
revealed using bioinformatics and proteomic
approached
• Additionally, comparative analysis of P. americana
with the closely related Blattodea species revealed
the possibility of cross-reaction
Conclusion: The high-quality genome and
proteome of P. americana are beneficial in studying
cockroach allergens at the molecular level
Seven novel allergen groups were identified

Cockroach Allergy
• Environmental exposure to cockroach has been linked to cockroach sensitization and asthma
• In particular, the combination of exposure and sensitization to cockroach appears to have a
greater effect on morbidity and severity of asthma than exposure and sensitization to other
allergens including dust mites or pets, among inner-city children and young adults with asthma
• Environmental interventions targeted at reducing cockroach allergen exposure have provided
conflicting results

Cockroach Allergen induced
allergic inflammation
• Cockroach allergens gain access to the lungs by lodging across the nasal and oral cavity
• Directly activate epithelial cells and induce the production of epithelial cell-derived cytokines
an chemokines and active innate immune response
• Proteases in cockroach extract can damage the epithelium leading to an increased
penetration of allergens and activation of innate immune cells via TLRs, AhR and CLRs à
imbalanced adaptive immune response
Do DC, et al. Allergy. 2016 Apr;71(4):463-74.

Cockroach Allergen induced
allergic inflammation
1. Direct: activate epithelial cells
2. Indirect: induce the production of
epithelial cell-derived cytokines an
chemokines and active innate immune
response
1
2

Pathophysiology
• Cockroach allergens, belonging to 12 different
groups, are carried by particles that are
inhaled to the human lung, where they activate
innate and adaptive immune responses
• A disruption of epithelial integrity by proteases
(such as Per a 10) that facilitate allergen
penetration
• B activation of release of pro- inflammatory
cytokines from the epithelium in a PAR-2
dependent manner by proteases
A
B

Pathophysiology
• C allergen interaction with different receptors
(some of which contribute to the uptake of
allergens by dendritic cells -TLR, CLR-), and
subsequent activation of the adaptive immunity
with production of IgE antibodies that bind to the
high affinity IgE receptors on mast cells
• (Numbers indicate the allergen group number)
C

Allergen-induced asthma
• PAR-2: a major member in family of proteolytically activated G-coupled receptors
• Serine protease activity: can induce pro-inflammatory cytokines production (TNF∝
and IL-8) via PAR-2 à airway reactivity, inflammation, oxidative stress and apoptosis
• TLR2 ligand that can directly activate cells of the innate immune system, leading to
the release of MMP-9 and decreased acute allergic responses in experimentally
induced asthma (in mice)
• Allergenic glycan-CLR signaling may be important for allergenic immune responses

Air pollution in cockroach allergy
• Exposure air pollution, particularly diesel exhaust and other combustion-related byproducts,
can increase the likelihood of developing cockroach allergy
• Environmental pollutants (DEP and PAH) can activate Ah signaling leading to changes in
target gene transcription and a variety of immunotoxicologic effects.
• Role of Ah in controlling mast cell differentiation, growth, and function and cockroach
allergens induced immune responses.
• AhR deficiency led to exacerbation of lung inflammation when exposed to cockroach allergen
in our well-established asthma mouse model

• Environmental pollutants and cockroach allergens ››
Damaged airway epithelial cells release cytokines and
chemokines (e.g., TGFb1), which can recruit MSCs and
some other inflammatory cells to the epithelial damaged
sites for tissue repairing/inflammation
• The recruited MSCs activated through AhR > release
anti-inflammatory factors (e.g., iNOS, IDO, and TGFb1)
and suppress airway inflammation
• Activated MSCs may modulate macrophage
differentiation through Ah and inhibit airway inflammation
AhR in modulating environmental pollutant and
allergen-induced allergie inflammation

Genetic determinants in the
development of cockroach allergy
• Linkage between the HLA-linked marker DRB1*0101 and DRB1*0102
• Environmental exposure has been suggested to play a critical role in asthma by
interacting with genetic factors in genetically susceptible individuals
• Linkage between IgE and cockroach sensitization was found on chromosome 5q23
where TSLP is located

Genetic determinants in the
development of cockroach allergy
• Single-nucleotide polymorphisms (SPs) in several genes including mannose- binding lectin
(MBL), IL- 12A, TLR6, STAT6, SLC25A46, HLA-DQB1, IL1 RL1, LPP, MYC, IL2 and HLA-
B were associated with cockroach allergy
• Boston Birth Cohort and identified several genes that are associated with cockroach
sensitization including JAK1, JAK3, IL5RA, FCER1A, and ADAM33 with the strongest
association for FCER1A

Gao P. et al. Clin Dev Immunol. 2012;2012:563760.
A. Cockroach-derived proteases can disturb airway
epithelial integrity and lead to an increased penetration
of cockroach allergen, which can activate innate
immune cells (e.g., dendritic cells (DCs)) via binding to
Toll-like receptors (TLRs) or C-type lectin receptors
B. The activated DCs can direct cells of the adaptive
immune system to a promotion of Th2 cell response
and subsequently increase risk of sensitization
C. Genetic factors, particularly genetic variants in TLRs,
CLRs, CD14, either alone or in interaction with
cockroach exposure, confer the susceptibility to
increased risk of cockroach sensitization and
subsequently inflammation in the lung and asthma
The mechanism of cockroach
allergen-induced allergic
sensitization
A
B
C

Cockroach Allergy and
Inner-city asthma
• Cockroach and mouse represent a significant percentage
of allergic sensitization greater effect on morbidity and
severity of asthma than dust mites or pets
• Allergen sensitization and its consequences is associated
with high asthma morbidity, particularly among children
living in urban environments and low-income area

Inner-city asthma
• Cockroach exposure at threshold levels greater than 1–2 U/gram of allergen in settled dust
increases the risk of allergic sensitization
• In addition to asthma morbidity, early exposure to cockroach in children with atopic parents
may increase the risk of developing asthma
• Compared to children without exposure, those exposed to cockroach allergens levels
greater than 2 U/g of settled dust were 35.9 times more likely to have asthma
Bassirpour G, et al. Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):535-41.

Inner-city asthma
• Immediate and late phase asthmatic reactions have been demonstrated in cockroach-sensitized
asthmatics after bronchial challenge with the cockroach allergen
• Total IgE measurement and assessment of IgE to environmental allergens (cockroach, mouse)
are among the priorities for identifying inner-city children with difficult-to-control asthma

Liu AH, et al. J Allergy Clin Immunol. 2016 Oct;138(4):1042-1050.
Conceptual model to describe how 8 risk-factor
domains are linked to asthma severity
Result: Allergen sensitization (allergic inflammation,
pulmonary physiology and rhinitis severity), and
environmental tobacco smoke exposure had the
largest effects on asthma severity

Liu AH, et al. J Allergy Clin Immunol. 2016 Oct;138(4):1042-1050.
Result: Vitamin D, stress and obesity showed no significant association
The model supported the concept that multiple pathways contribute significantly to asthma severity
However, allergen sensitization appears to be the originating domain in the pathophysiologic chain
Conclusion: In children with asthma and rhinitis, allergen sensitization, allergic inflammation, pulmonary
physiology, ETS exposure, and rhinitis severity are related through specific pathways to asthma severity

Pongracic JA, et al. J Allergy Clin Immunol. 2016 Oct;138(4):1030-1041.
Population: Asthma Phenotypes in the Inner City (APIC) was a prospective longitudinal study of 6- to 17-
year-old children with asthma living in 9 urban areas
Method: assessment at screening and had asthma and rhinitis managed based on National Asthma
Education and Prevention Program Expert Panel Report and Allergic Rhinitis and its Impact on Asthma
(ARIA) 2008 guidelines–derived treatment algorithms with assessment and medication adjustments every
2 months for 1 year (V0, V1, V2, V3, V4, V5, and V6)

Results:
• Among 619 recruited participants, 40.9% had difficult-to-
control asthma, 37.5% had easy-to-control asthma and
21.6% fell into neither group
• At baseline, FEV1 bronchodilator responsiveness was the
most important characteristic distinguishing difficult- from
easy-to-control asthma
• Markers of rhinitis severity and atopy were among the
other major discriminating features
• Over time, difficult-to-control asthma was characterized by
high exacerbation rates, particularly in spring and fall,
greater day and night symptoms, especially in fall and
winter, and compromised pulmonary physiology despite
ongoing high dose controller therapy

Conclusions:
• Despite good adherence, difficult-to-control
asthma showed little improvement in
symptoms, exacerbations or pulmonary
physiology over the year
• Besides pulmonary physiology measures,
rhinitis severity and atopy were associated
with high dose asthma controller therapy
requirement
Clinical implication:
Clinical baseline characteristics related to
pulmonary physiology, rhinitis severity, and atopy
prospectively distinguish difficult-to-control from
easy-to-control asthma

Pomés A, et al. J Allergy Clin Immunol. 2019 Oct;144(4):935-944.
Population: Cockroach-sensitized 10-year-old children from the
URECA cohort with either positive cockroach-specific IgE levels
or positive cockroach-specific skin prick test responses, or both
Objective: To perform a cockroach allergen component analysis
to determine the allergens and antibody levels and patterns of
sensitization associated with asthma and rhinitis.
URECA: Observational birth cohort of
560 infants from 4 research centers
with 1 parent with a history of allergic
rhinitis, eczema, and/or asthma at least

Methods:
• Antibody (IgE, IgG, and IgG4) levels to total cockroach and 8 cockroach allergens were determined in 2
groups of cockroach -sensitized 10-year-old children with (n =19) or without (n 28) asthma and rhinitis
• Allergen specific antibody levels were measured in streptavidin ImmunoCAPs loaded with each of the
recombinant allergens from groups 1, 2, 4, 5, 6, 7, 9, and 11, and total cockroachspecific IgE levels were
measured with the ImmunoCAP

Result:
• IgE antibody levels to cockroach allergens and
extract differed between subjects with and without
asthma and rhinitis
• Specifically, recognition of more cockroach
allergens with higher allergen -specific IgE levels
was associated with disease
• There was a good correlation between the sum of
allergen-specific IgE and total cockroach IgE levels

Conclusions :
• Component analysis of 8 cockroach allergens revealed significant differences in IgE reactivity associated
with the presence of asthma and rhinitis
• Allergen - specific IgE titers and sensitization profiles were associated with asthma and rhinitis
Components associated with asthma and rhinitis

Pomés A, et al. Front Immunol. 2021 Feb 10;11:621700.
Population: A cohort of 23 subjects sensitized to cockroach in US
Method: Measurement of Allergen-Specific IgE Antibody Levels and Activation Induced Marker (AIM) Assay
Result:
• The prevalence of IgE sensitization were 43.5% for Bla g 3 and 17.4% for chitinase
• The IgE prevalence of Bla g 3 (43.5%) was above the average of IgE prevalence for the 10 allergens
tested (38.7 ± 13.0%), and for Bla g 1, Bla g 4, Bla g 5, and Per a 7
• No correlation was observed between the prevalence of IgE sensitization and the frequencies of the T
cell response to 10 cockroach allergens at the population level in the cohort tested or between allergen-
specific IgE antibody levels and magnitude of the T cell response at individual level

Conclusion:
• Although it has been shown that higher T cell reactivity is associated with allergen sensitization and asthma
• An important implication of the current study is that knowledge of individual reactivity profiles will help to
interpret outcomes of cockroach immunotherapy, according to the allergens present in the cockroach
extract used for treatment
• A diagnostic analysis of each patient will provide information that could allow future tailored immunotherapy
according to the proteins that are relevant for each patient
Pomés A, et al. Front Immunol. 2021 Feb 10;11:621700.

Environmental controls: Cockroah
• Species are common in houses:
• Blattella germanica (German cockroach)
• Periplaneta american (American cockroach)
• Allergen derived from feces, saliva, debris from dead animals
• Major allergens in feces extract > body extract 6 times
• Highest levels of cockroach allergens: kitchen
• Dose-response relationship between cockroach allergen exposure and sensitization
• Sensitized threshold: Bla g 1/Bla g 2 >2 unit/g (risk for develop asthma : 35x)
Pediatric allergy&Primary immune deficiency diseases. Indoor allergens. 35-60.

• Poison bait
- Boric acid (damage foregut)
- Hydramethylnon, abamectin, fiproni
• Careful housekeeping to enclose all sources of food for the insects
• Cleaning to remove any accumulated allergen
sealing as many access points to the house as possible
Pediatric allergy&Primary immune deficiency diseases. Indoor allergens. 35-60.

• Exposure to cockroach allergen in homes should be minimized to reduce the risk of
cockroach sensitization
• Exposure to cockroach allergens should be minimized to reduce the risk that sensitized
children will develop allergic disease
• Cockroach allergen exposure should be minimized to reduce the risk of asthma morbidity in
already sensitized subjects
Recommendations for environmental control

Tungtrongchitr A, et al. Asian Pac J Allergy Immunol. 2004 Jun-Sep;22(2-3):115-21.
• Patients with possible cockroach allergy should
be asked whether they have seen cockroaches
in their homes
• Patients with suspected atopy and likely
cockroach exposure should be evaluated for
sensitization to cockroach allergens by skin
prick testing or measurement of specific IgE
directed toward cockroach-derived allergens

• Factors that facilitate the growth and persistence of cockroach
populations, such as food and water, paths of ingress, and
microenvironments that can provide shelter, should be mitigated to
reduce the cockroach carrying capacity of the environment
• The extent and duration of a cockroach infestation should be
monitored by using strategically placed sticky traps

• Pesticides should be used judiciously and ideally should be applied
by a professional exterminator as part of an integrated pest
management program
• Boric acid is an effective pesticide; however, surviving cockroaches
can produce more allergen after exposure
• Reservoirs of cockroach contaminants should be cleaned or
removed to prevent additional exposure to occupants

• Integrated pest management with a
combination of interventions appears to be the
most effective method for preventing and
eliminating cockroach infestations
• Integrated pest management should be used to
decrease cockroach exposure to reduce
asthma morbidity

Environment assessment algoritm

• The combination of cockroach exposure and allergic sensitization is a key factor
contributing to asthma morbidity, particularly in urban areas where high-level
cockroach allergen exposure is common and asthma burden is high
• Although, cockroach exposure control strategies may be helpful, they are difficult to
maintain and exposure may continue outside the home
• In contrast, effective cockroach immunotherapy has the potential of modifying
the course of asthma and providing sustained clinical benefit

• Cockroach allergic patients present variable allergen sensitization profiles due to the
influence of sensitization to cross-reactive antigens
- USA: sensitization to Bla g 2, Bla g 4, and Bla g 5
-Taiwan: sensitization to Bla g 2, Bla g 4, vitellogenin, Bla g 1 & arginine
kinase, Bla g 5 & Bla g 7 and enolase
- Brazil: sensitization to Per a 7 (cross-reactivity to mite tropomyosin,
tropomyosin from intestinal parasites, particularly Ascaris lumbricoides)
Unique features of cockroach allergy that may impact
the efficacy of immunotherapy

• Allergen extracts contain a complex mixture of major and minor allergens
• The lack of an immunodominant allergen and the complex patterns of IgE response
to multiple cockroach allergens
• Currently available commercial extracts tend to have low and variable potency
Limitations of current cockroach allergen extracts

• The use of standardized cockroach extracts of reliable potency and contents would
facilitate diagnosis and treatment of cockroach allergy
• Cockroach allergic patients present variable allergen sensitization profiles
• The availability of individual recombinant and natural cockroach allergens will
facilitate the diagnosis of individual profiles of IgE reactivity and the identification of
specific allergens affecting each cockroach allergic patient
Recombinant cockroach allergen for diagnosis

• A limited number of clinical trials using cockroach allergen extracts showed
improvement in both immunological and clinical parameters
• Although commercially available extracts are relatively low in potency,
immunotherapeutic doses should be achievable
• In conjunction with aggressive avoidance measures, particularly in patients living in
the inner city who have perennial allergic symptoms and specific IgE antibodies to
cockroach allergens
Cockroach immunotherapy

• Immunotherapy (IT) is currently performed with crude extracts and there are reports
supporting its effectiveness
• Subcutaneous IT was more effective at modifying immune parameters than
sublingual IT, although both types proved to be safe
• Potential cockroach allergen immunotherapy has been tested in mouse models for
prophylaxis (Bla g 2 DNA vaccine) or treatment (liposome entrapped Per a 9) of airway
inflammation

• Cockroach extracts for immunotherapy are not standardized and are highly
variable in allergen content
• The allergen content in German cockroach extracts and the sensitization profiles
determine in vitro extract potency for IgE reactivity, the selection of appropriate
extracts to be used for immunotherapy is important

Kang BC, et al. J Asthma. 1988;25(4):205-18.
Intervention Group
IT: SCIT with mixed
CR extracts (German,
American and oriental)
20-30 weeks of weekly
injection (convential
methods)
Test group
IT with CR extracts with
other allergens to which
patients were sensitizaed
Control group
IT with all relevant
allergens except CR

Kang BC, et al. J Asthma. 1988;25(4):205-18.
Outcomes Conclusion
Clinical outcome:
Symptom and medication scores
Immunologic outcome:
• Total IgE, sIgE CR
• Leukocyte preparation and
anaphylactic histamine release
assay blocking
• Antibody determination
Clinical outcome:
Reduction in sympton and
medication scores
Immunologic outcome:
Increase in CR-specific blocking
antibody and blunting of invitro
basophil histamine release

Srivastava D, et al. Eur J Clin Invest. 2011 Aug;41(8):879-88.
Intervention Outcome at 1,2 years
IT: SCIT of an aqeous solution of standardized
American cockroach extract for 1 year
Placebo: injections of phosphate buffered saline
weekly at the build-up phase
Every 3 month at maintenance dose was reached
Clinical outcome
Airway reactivity, symptom and drug score
Immunological outcome
sIgE CR, IgG4, IgG1
Change in IgE binding against cockroah
allergens (immunoblotting)

Result: Clinical outcome
Airway reactivity (PCFEV1)
• IT group: 18/24 patients showed significant increase in PC20
FEV1 compared with baseline values and placebo group, 8/24
patients tolerated highest dose histamine after 1 year of IT
• Placebo group: 15 of 18 patients showed decrease in PC20
FEV1 indicating rise in airway reactivity
Symptom score: statistically significant reduction
Medication score: reduction after 1 year and highly significant
reduction after 2 years
Conclusion: Clinical outcome
• Improvement in clinical scores after 1 year and reduction in
symptoms and medication use after 2 years

Result: Immunologic outcome
• Specific IgG4 and IgG4/IgGI ratio: increase after 1 and 2 years
•Cytokines: decrease in IL4 but not show much change in IFN ∝
• IgE immunoblotting: showed modest reduction
• IgG4 immunoblotting: higher intensity and more number of
bands after 1 year
Conclusion: cockroach IT for 1–2 years is
potentially effective treatment for cockroach
allergy in patients with asthma and rhinitis

Cockroach immunotherapy: 4 pilot studies

Pilot 1 SCSS: Sublingual Cockroach Safety Study
Wood RA, et al. J Allergy Clin Immunol. 2014 Mar;133(3):846-52.e6.
• Open-label study to assess the safety of cockroach SLIT in adults and children
• The primary outcome: Rate of related adverse events and serious adverse events in the course of
treatment
• Population: 27 patients with perennial rhinitis with or without asthma 5-55 years
• Intervention:
- SLIT with German CR extract
- Underwent 1 day,8 dose escalation to Maintenance dose, followed by daily dose for 14 days
- CR allergen dose per day: Bla g 2 = 4.2 ug, Bla g 1 = 50 ug
• Clinical outcome: 7 reports (No SAE)
- Mild to moderate events (5): oral or throat pruritus, skin rash, nausea
- 1 subject discontinued due to oral symptoms and vomiting
- 1 subject had throat irritation and cough, graded as severe
• Immunological outcome: Not applicable

Pilot 2 BioCSI: Biomarkers of Cockroach Sublingual Immunotherapy
• Double-blind, randomized placebo controlled, multicenter study
• The primary outcome: Determine whether cockroach SLIT would induce a 3-fold group mean difference
in levels of cockroach IgE, a biomarker of allergen immunotherapy, over 6 months
• Population: 54 adults patients with perennial allergic rhinitis with or without asthma
• Intervention:
- SLIT with German CR extract 420 microliter daily
- Dose escalation on day 1 (day 2 if needed), Maintenance for 6 months
- CR allergen dose per day: Bla g 2 = 4.2 ug, Bla g 1 = 50 ug
• Clinical outcome: Not applicable
• Immunological outcome:
- Increase in CR-specific IgE levels
- No significant increase in CR-specific IgG4

Pilot 3 BioCSI2: Biomarkers of Cockroach Sublingual Immunotherapy 2
• Randomized, Double-blind, placebo controlled, low dose and higher dose, multicenter study
• The primary outcome: Determine whether the high dose of cockroach SLIT would induce a 3-fold group
mean difference in levels of cockroach IgE, a biomarker of allergen immunotherapy, over 3 months.
• Population: 89 children with perennial allergic rhinitis with or without asthma
• Intervention: SLIT with German CR extract
- Dose escalation low dose on day 1 (day 2 if needed), for high dose over 2-4 wks maintenance for 3 months
- CR allergen dose per day: Low dose 420 UL (Bla g 2 = 4.2 ug, Bla g 1 =50 ug)
High dose 840 UL(Bla g 2 = 16.8 ug, Bla g 1= 202 ug) twice daily
• Clinical outcome: Not applicable
• - Increase in CR-specific IgE levels in low and high dose
• - High dose: increase CR-specific IgG4, Low dose: no increase CR-specific IgG4
• - Increase in FAB activity in the low dose group

Pilot 4 SCITCO : Subcutaneous Immunotherapy in
Cockroach-sensitive Adults
• Open label, single site study
• The primary outcome: Determine safety and as a proof of concept of the immunologic effect of German CR
• Population: 10 adult (18-55)patients with perennial allergic rhinitis with or without asthma
• Intervention:
- SCIT with German CR extract
- Escalation over twice/wk 11 wks to 1:20 concentration of extract 0.6 mL for maintenance 15 wks
• Clinical outcome: Mild reaction common, not affecting dose, no SAE
- Increase in CR-specific IgE (similar to SLIT)
- Increase CR-specific IgG4 (more vigorous and consistent than with SLIT)
- Reduction in FAB activity

Cockroach immunotherapy protocols: 4 pilot studies

IgE and IgG4 level and blocking antibody activity responses
SCITCO
All 3 biomarkers showed
significant change from
baseline during the 6-month
treatment period

Conclusion
• SCIT is immunologically more active than SLIT, especially with regard to IgG4 levels
and blocking antibody responses
• No safety concerns were raised in any age group
• These pilot studies suggest that immunotherapy with cockroach allergen is more likely to
be effective with SCIT

• Allergen extracts of German cockroach (Blattella germanica) potential use in diagnostics
• Allergen immunotherapy are highly variable in their individual allergenic protein content
• Cockroach allergen composition and concentration both differed, presumably depending
on whether fecal pellets and body parts of juvenile versus adult insects were extracted
• Feces contain high concentrations of Bla g 1 and Bla g 2 but no Bla g 5 compared with
whole-body extracts
Kleine-Tebbe J, et al. J Allergy Clin Immunol. 2019 Apr;143(4):1342-1344.

• German cockroach allergen extracts
display variable potencies
• Heterogeneous IgE repertoires and
complex allergen composition contribute to
the complexity
• For routine diagnostic and treatment use
need to be verified and documented to
ensure they contain appropriate allergens
and concentrations of the major sensitizing
molecules for the study population

• The allergist should be aware of different performance characteristics of commercially available
cockroach extracts from different companies and those designed for skin prick tests or allergen-
specific IgE testing and the potentially variable results caused by absent, low-level, or as yet
unidentified B.germanica allergens
• The performance characteristics and value of component-resolved diagnostics should also be
considered
• For the future, the challenge involves the question of how to properly standardize cockroach
allergen extracts. necessary to establish an optimal AIT dose that effectively balances the efficacy
and safety of the final product

Glesner J, et al.J Allergy Clin Immunol. 2019 Apr;143(4):1474-1481.e8.
• Cockroach extracts for immunotherapy are currently not standardized
• The doses of extract used for cockroach immunotherapy by the Inner-City Asthma Consortium were
calculated based on content of the cockroach allergens Bla g 1 and Bla g 2
• Maintenance dose for cockroach subcutaneous immunotherapy was established as 120 mcg of Bla g 1
and 6 mcg of Bla g 2
• Bla g 1 and Bla g 2 have consistently been used as markers of environmental exposure to cockroach

The current study extends the analysis of IgE
reactivity to 3 additional cockroach allergens
(from groups 6, 9, and 11)
• Bla g 6 is a troponin C
• Bla g 9, had not been listed as an allergen in the
World Health Organization
• ∝-Amylases (Bla g11) from both B.germanica and
P.americana were recently described in Korea and
China, with an IgE prevalence of 41% and 83%,
respectively
• Variability in content among German cockroach extracts prepared from different sources
and using different protocols. (whole body, feces, frass)

Content of cockroach allergen extracts

Sookrung N , et al. Current Protein & Peptide Science 2020; 21(2)
Cockroach allergy and Immunotherapy

Decision algorithm for cockroach allergy
Decision algorithm for
cockroach allergy

Cox L, et al. J Allergy Clin Immunol. 2011 Jan;127(1 Suppl):S1-55.
Allergen extract
Mixed cockroaches

• Cockroach allergy is associated with high morbidity and increased
severity of asthmatic patients, living in low-income inner-city
environments
• Continued indoor exposure to low levels of cockroach allergens may
lead to sensitization and subsequent development of symptoms
• Immunotherapy using cockroach crude non-standardized, low
potency extracts has been attempted, with promising results but
limited reports of outcomes
Conclusion: Cockroach Allergy

• Both sublingual and subcutaneous cockroach immunotherapy
were shown to be safe in adults and children
• Progress in molecular cloning and expression of recombinant
allergens has led to improved knowledge of the structure and
function of cockroach allergens, which is fundamental for
developing novel strategies for diagnosis and therapy of cockroach
allergic patients
Conclusion: Cockroach Allergy

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