Cockroach allergy

Cockroach Allergy
8th September 2017
Thansinee Saetae, MD.
Pediatric Allergy and Immunology Unit
King ChulalongkornMemorial Hospital

• Cockroach species
• Cockroach allergen
• Cockroach allergy
• Cockroach allergy and inner city asthma
• Cockroach environmental control
• Cockroach immunotherapy

Taxonomy of cockroaches
Portnoy Et Al, J Allergy Clin Immunol, 2013

• Over 4,000 cockroach species have been identified.
• However, only a few species live in people's homes and have been the focus for
cockroach allergen-related research.
• These cockroaches include American cockroach (Periplaneta americana), German
cockroach (Blattella germanica), oriental cockroach (Blatta orientalis), brown-
banded cockroach (Supella longipalpa) and smoky brown cockroach (Periplaneta
fulliginosa)
• In particular, both German and American cockroaches are the predominant
species that infest human dwellings.
• 9 German cockroach allergens (Bla g 1-8 and Bla g 11)
• 10 American cockroach allergens (Per a 1-3, Per a 5-7, Per a 9-12)
Cockroach species
Do Et Al. Allergy. 2016 April ; 71(4): 463–474. doi:10.1111/all.12827.

Cockroaches
http://www.domyownpestcontrol.com

American Cockroach
• American Cockroaches are more common in warmer climates.
• They prefer to nest outdoors, yet close buildings and are very
common in sewer systems.
• American Cockroaches can fly
• They are reddish-brown in color.
• American Cockroaches are considered large roaches and vary
from 1.1 to 2 inches in length.
• The can squeeze into a space no thicker than a quarter.
• Female American Cockroaches can produce up to 150
offspring per year.
• They are very fast runners and can move up to 50 body lengths
per second.
• American Cockroaches are nocturnal and mostly active at
night
• They will eat just about anything, include paper, hair, cloth and
dead insects
http://www.combatbugs.com

German Cockroach
• German Cockroaches are prevalence in houses,
apartments& hotels and are known for infestations.
• The are considered small roaches and range from ½ of
an inch to 5/8 of an inch long.
• They eat sweet, grease, meat and garbage.
• Their lifespan is about 200 days.
• One female can produce up to 100,000 cockroaches in
one year, the fastest of any common pest cockroach
species.
• Newborn German Cockroaches become adults as little
as 36 days.
• The can fit to a crack as thin as a dime.
• Although German Cockroaches have fully developed
wing, they do not fly.
http://www.combatbugs.com

Cockroach allergen
Do et al. Page 23
Table 1
Characteristics and functions of allergens from German and American cockroaches
Allergen
M.W.
(*) Function/Homology IgE Prevalence Major Linear IgE
Epitopes
GeneBank Accession #
Bla g 1 46 • Lipids-associated and/or binding protein
(118) (i.e. palmitic, oleic, and steric acids)
• Nonspecific transport of lipid molecules
in cockroach
• Non-enzymatically active aspartic
protease (34, 40, 119)
20-40% a.a. 1-111, 289-403,
and 394-491 (32)
AF072219
AF072221
L47595
AF072220
Bla g 2 36 • Glycoprotein, decorated glycans indicated
to be important for IgE binding (55, 73)
• Binds to human beta-defensin 3 (44)
40-70% a.a. 1-75 and 146-225
(45)
U28863
Bla g 3
79
(*) • Homologous to hemocyanin and
American cockroach allergen Per a 3 (120)
n.r. n.r. GU086323
Bla g 4 21 • Ligand binding protein, members of the
calycin protein family (121)
17-40% a.a. 34-73, 78-113,
and 118-152 (34)
U40767
Bla g 5 23 • Sigma class glutathione S-transferase (35,
36, 122)
35-68% a.a. 176-200 (37) U92412
Bla g 6 21 • Homologous to muscle protein troponin C
with four calcium-binding domains (35)
14% Dependent upon
calcium level, a.a.
96-151 (123)
DQ279092
DQ279093
DQ279094
Bla g 7 31 • German cockroach tropomyosin (124)
• Can induce TIM4, CD80, and CD86 and
increased IL-13 secretion in human DCs
(125)
• Potential involvement in DCs-induced
Th2 polarization (47)
18% n.r. AF260897
Bla g 8 n.r. • Calcium binding protein
• Myosin light chain (47)
n.r. n.r. DQ389157
Bla g 11 57 • α-amylase DQ355516
KC207403
Per a 1 45 • Homologous to the mosquito precursor
protein, ANG12, which may be involved in
9-100% a.a. 358-446 (38) AF072222
U78970
• Groups 1, 2, 10 are excreted
into the feces.
• Others are found
predominantly in the bodies.
Groups 6, 7, 8 Allergens
homologous to proteins
involved in contraction
Groups 3, 5, 9 Functions
associated with metabolism

Cockroach allergen
with four calcium-binding domains (35) calcium level, a.a.
96-151 (123)
DQ279093
DQ279094
(125)
18% n.r. AF260897
n.r. n.r. DQ389157
Bla g 11 57 • α-amylase DQ355516
KC207403
Per a 1 45 • Homologous to the mosquito precursor
protein, ANG12, which may be involved in
digestion (123)
9-100% a.a. 358-446 (38) AF072222
U78970
U69957
U69261
U69260
Per a 2 42 • Inactive aspartic protease-like (126)
• 42-44% homology to Bla g 2
81% a.a. 57-86, 200-211,
and 299-309 (17)
GU188391
Per a 3 72 • Homologous to insect hemolymph
proteins, arylphorin/hemocyanin (127)
26-95% a.a. 400-409, 466-471,
580-595, and 595-605
(39)
L40818
L40820
L40819
L40821
Per a 5
(**) 25 • Glutathione S-transferase (128) 25% n.r. AY563004
Per a 6 17 • Homologous to insect troponin Cs and
vertebrate calmodulins (129)
14% n.r. AY792950
Per a 7 33 • Tropomyosin (123)
• Induce reduction of IL-12 production and
expression of TLR9 in P815 mastocytoma
cells (130)
13-54% n.r. Y14854
AF106961
Per a 9 43 • Arginine kinase (51) 80-100% p. LTPCRNK AY563004
Per a 10 28 • Serine protease and insect trypsins (131) 82% n.r. AY792954
Per a 11 55 • α-amylase (132) 83% n.r. n.r.
Per a 12 45 • Chitinase (133) 64% n.r. n.r.
(*)
AuthorManuscriptAuthorManuscript
Do et al. Page 23
Table 1
Characteristics and functions of allergens from German and American cockroaches
Allergen
M.W.
(*) Function/Homology IgE Prevalence Major Linear IgE
Epitopes
GeneBank Accession #
Bla g 1 46 • Lipids-associated and/or binding protein
(118) (i.e. palmitic, oleic, and steric acids)
• Nonspecific transport of lipid molecules
in cockroach
• Non-enzymatically active aspartic
protease (34, 40, 119)
20-40% a.a. 1-111, 289-403,
and 394-491 (32)
AF072219
AF072221
L47595
AF072220
Bla g 2 36 • Glycoprotein, decorated glycans indicated
to be important for IgE binding (55, 73)
• Binds to human beta-defensin 3 (44)
40-70% a.a. 1-75 and 146-225
(45)
U28863
Bla g 3
79
(*) • Homologous to hemocyanin and
American cockroach allergen Per a 3 (120)
n.r. n.r. GU086323
Bla g 4 21 • Ligand binding protein, members of the
calycin protein family (121)
17-40% a.a. 34-73, 78-113,
and 118-152 (34)
U40767
Bla g 5 23 • Sigma class glutathione S-transferase (35,
36, 122)
35-68% a.a. 176-200 (37) U92412
Bla g 6 21 • Homologous to muscle protein troponin C
with four calcium-binding domains (35)
14% Dependent upon
calcium level, a.a.
96-151 (123)
DQ279092
DQ279093
DQ279094
(125)
18% n.r. AF260897
n.r. n.r. DQ389157
Groups 10, 11, and 12:
digestive enzymes
Groups 9: Arginine kinase
Per a 9 was identified as a
major cockroach allergen

Cockroach allergy
• Cockroach allergy has been established as an important cause of
asthma for over 50 years.
• Subsequent studies established a causal relationship between
cockroach allergy and asthma by demonstrating bronchoconstriction
following inhalation of cockroach extract by cockroach allergic
asthmatic patients.
Kang Et Al. J Allergy Clin Immunol. 1979;63:80–6.

Allergens induce release of cytokines
and chemokines by the epithelium
IL-6
IL-8
IL-25
IL-33
CCL20
GM-CSF
PAR-2
TLR2
CLR
T CD4+
Th2
IgE
DC
B
AhR
Inhalation
10
1-12
2
10
CD86
CD40
IL-12, IFN-
IL-4, IL-5, IL-13, IL-6, TNF-
10, 7
1-12
MC
AhR
Curr Allergy Asthma Rep (2017) 17: 25
Cockroach Allergens: A Heterogeneous Group
of Proteins
Twelve groups of cockroach allergens are currently listed in
the official Allergen Nomenclature database maintained by
the World Health Organization/International Union of
5
I
o
f
g
p
TLR2
CD86
CD40
IL-12, IFN-
IL-4, IL-5,
MC
Fig. 1 Proposed mechanisms of cockroach allergy. 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. Mechanisms involved in the process include (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, (c) allergen
interaction with different receptors (some of which contribute to the
u
a
t
i
l
r
m
Allergens induce release of cytokines
and chemokines by the epithelium
IL-6
IL-8
IL-25
IL-33
CCL20
GM-CSF
TLR2
CLR
T CD4+
Th2
IgE
DC
B
AhR
2
CD86
CD40
IL-12, IFN-
IL-4, IL-5, IL-13, IL-6, TNF-
10, 7
MC
AhR
Fig. 1 Proposed mechanisms of cockroach allergy. 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. Mechanisms involved in the process include (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, (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. TLR toll-like receptors, CLR C-type
lectin receptors including mannose receptors, AhR aryl hydrocarbon
receptor, DC dendritic cell, T CD4+ and Th2 T cells, B B cell, MC
mast cell
Proposed mechanisms of cockroach allergy
Pomés Et Al. Curr Allergy Asthma Rep (2017) 17: 25

Glycan in cockroach allergens may be a major
determinant for immunogenicity
Figure 1.
Glycans in cockroach allergens. Surface epitopes mapped from a murine monoclonal
antibody against the cockroach allergen Bla g 2 was found to contain a carbohydrate moiety
(references 33, 44) and the prevention of glycosylation significantly reduces IgE binding to
Bla g 2 (references 21). (A) MALDI-TOF mass spectrum of N-linked glycans prepared from
purified natural Bla g2 glycoprotein (adopted from Tsai et al, 2013) demonstrated a
predominance of (B) tri-antennary core di-fucose modified glycans with mannose-,
Do et al. Page 18
Figure 1.
Glycans in cockroach allergens. Surface epitopes mapped from a murine monoclonal
antibody against the cockroach allergen Bla g 2 was found to contain a carbohydrate moiety
(references 33, 44) and the prevention of glycosylation significantly reduces IgE binding to
Bla g 2 (references 21). (A) MALDI-TOF mass spectrum of N-linked glycans prepared from
purified natural Bla g2 glycoprotein (adopted from Tsai et al, 2013) demonstrated a
predominance of (B) tri-antennary core di-fucose modified glycans with mannose-,
galactose-, and/or N-acetyl glucosamine- (GlcNAc) terminated moiety. (C) These tri-
antennary core di-fucose modified glycans are predicted to decorate Bla g 2 (1YG9) at
asparagine (ball-and-stick) 268 and 317 (N268, N317). Glycan compositions were assigned
based on the measured m/z values with the m/z values of the putative composition of
permethylated glycans. **is undermethylated glycans. *is unknown peaks.
anuscriptAuthorManuscriptAuthorManuscript
• Surface epitopes of the cockroach allergen Bla g 2 was found to contain a carbohydrate moiety.
• The prevention of Bla g 2 glycosylation significantly reduces IgE binding,Th2 cytokine, IL-13
production, and increased IL-10

Mechanism underlying the cockroach
allergen-induced allergic inflammation
Do et al. Page 19
AuthorManuscriptAuthorManuscriptAuthorManuscript
1. Cockroach allergens gain access to the lungs
by lodging across the nasal and oral cavity.
2. Direct activate epithelial cells and induce the
production of epithelial cells derived
cytokines and chemokines.
3. Activate innate immune cells.
4. Imbalanced adaptive immune response and
development of cockroach sensitization and
allergic asthma.
5. Protease cockroach extract can damage the
epithelium leading to an increased
penetration of allergens and activation of
innate immune cells via TLRs, AhR and CLRs.
1
2
34
5

Protease-activated receptor-2 (PAR-2) and
environment allergen-induced asthma
• Serine protease activity (in German cockroach), which can induce pro-
inflammatory cytokines production, especially TNF-⍺ and IL-8, from
challenged airway epithelial cells via PAR-2.
• PAR-2, a major member in family of proteolytically activated G-coupled
receptors, is expressed on a variety of cell types located throughout the
airways.
• Dual oxidase-2(DOUX2)-ROS pathway in airway epithelial cells plays a
crucial role in mediating the activation of PAR-2 stimulated airway
reactivity, inflammation, oxidative stress and apoptosis in cockroach
allergen-induced mouse model of asthma.
• Proteases may link the innate and adaptive immune responses via PAR-2
activation and signaling.

Toll-like receptors (TLRs) mediate allergen-
induced sensitization and inflammation
• TLR4 activation in airway epithelial cells by house dust mite has been
demonstrated to be sufficient in promoting allergic sensitization via
the release of innate cytokines such as IL-25, IL-33, and TSLP.
• TLR signaling is critical in mediating antigen-induced immune
responses.
• German cockroach frass contains a 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.
• TLR2 and TLR8 were up-regulated in patients with cockroach allergy in
comparison to healthy individuals.

C-type lectin receptors (CLRs) recognize
glycans in allergens
• CLRs are implicated to be crucial in the recognition allergenic glycans present on
allergens and have been evolved to facilitate the endocytosis and presentation of
pathogens.
• Signaling through CLRs has been shown to induce T-cell activation, tolerance and
modification of cellular responses via cross-regulation of the TLR-mediated effect.
• Allergenic glycan-CLR signaling may be important for allergenic immune
responses.
• We previously reported a functional interaction for MRC1 and cockroach
allergens in antigen binding, antigen recognition and downstream immune
responses.
• The deletion of MRC1 in mice (MR−/−) may exacerbate cockroach allergen-
induced lung inflammation and play a role in regulating allergen-induced
macrophage polarization.

Figure 3.
Schematic diagram of the proposed mechanisms for miR-511-3p in modulating allergic
inflammation in asthma. MRC1 transcribes the primary intronic miR-511, and followed by
the miRNA machinery to generate the mature miR-511-3p sequence. The miR-511-3p can
directly targets several genes (e.g., ROCK2, PTEN, and LTBP1) and shape the balance of
M1 and M2 macrophage polarization and skew the immune response. In addition,
miR511-3p may also modulate the expression of several indirect targets. MRC1,
macrophage receptor, AGO, Argonaut.
Do et al. Page 20
C-type lectin receptors (CLRs) recognize
glycans in allergens
Figure 3.
Schematic diagram of the proposed mechanisms for miR-511-3p in modulating allergic
inflammation in asthma. MRC1 transcribes the primary intronic miR-511, and followed by
the miRNA machinery to generate the mature miR-511-3p sequence. The miR-511-3p can
directly targets several genes (e.g., ROCK2, PTEN, and LTBP1) and shape the balance of
M1 and M2 macrophage polarization and skew the immune response. In addition,
miR511-3p may also modulate the expression of several indirect targets. MRC1,
macrophage receptor, AGO, Argonaut.
Do et al. Page 20
• An intronicmiRNA encoded within MRC1 is
processed by the miRNA machinery to
generate the mature miR-511-3p sequence.
• miR-511-3p regulate the balance of M1 and
M2 macrophage polarization, subsequently
leading to allergic diseases and asthma.
• miR-511-3p has been shown to directly
target ROCK2, a serine-threonine kinase that
regulates the cell cytoskeleton contractility.
• ROCK2 can phosphorylate IRF4 and promote
alternative activation of macrophages.

Air pollution boosts cockroach allergy and
asthma
• Exposure air pollution, particularly diesel exhaust and other combustion-
related byproducts, can increase the likelihood of developing cockroach
allergy.
• Prenatal exposure to cockroach allergen was associated with a greater risk
of allergic sensitization and this risk was increased by exposure to
nonvolatile PAHs.
• Exposure to traffic-related air pollutants during childhood (i.e., PAH) is
associated with the development and exacerbation of asthma with
increasing likelihood of sensitization to cockroach allergens in urban inner-
city children.
• However, the underlying molecular mechanism remains unknown.

Aryl hydrocarbon receptor mediates allergen-
induced exacerbation of asthma
• Environmental pollutantssuch as DEP and PAH can activate AhR signaling leading
to changes in target gene transcription (e.g., cytochrome P450 cyp1a1, cyp1b1)
and a variety of immunotoxicologicaleffects.
• Bacterial compounds can also act as potential AhR ligands and that recognition of
these virulence factors by AhR contributes to host defense against invading
microbial pathogens.
• A critical role of AhR 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.

AhR in modulating environmental pollutant
and allergen-induced allergic inflammation
Page 21
• Damaged airway epithelial cells release cytokines and
chemokines (e.g., TGFβ1), which can recruit MSCs and some
other inflammatory cells to the epithelial damaged sites for
tissue repairing/inflammation.
• The recruited MSCs activated through AhR by environmental
pollutants or cockroach allergens or both synergistically release
anti- inflammatory factors (e.g., iNOS, IDO, and TGFβ1) and
suppress airway inflammation.
• Activated MSCs may modulate macrophage differentiation
through AhR and inhibit airway inflammation.

Genetic determinants in the development of
cockroach allergy
• Linkage between the HLA-linked marker DRB1*0101 and DRB1*0102
• Genome wide quantitative-trait loci (QTL) analysis of 533 Chinese families with
asthma, provided evidence of linkage at a possible QTL D4S1647 for skin
reactivity to cockroach defined by skin prick tests.
• Linkage between IgE and cockroach sensitization was found on chromosome
5q23 where TSLP is located.
• Single-nucleotide polymorphisms (SNPs) in several genes including mannose-
binding lectin (MBL), IL-12A, TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1,
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.
• Environmental exposure has been suggested to play a critical role in asthma by
interacting with genetic factors in genetically susceptible individuals.

Cockroach allergy and inner city asthma
• A large population of inner-city children with asthma, 6 to 17 years
old, was followed prospectively while receiving guidelines-based.
• FEV1 bronchodilator responsiveness, severity of rhinitis and markers
of atopy, particularly total serum IgE levels, mold sensitization, and
the total number of allergen sensitizations, were significant factors
which distinguished difficult to control from easy to control asthma.
• The study highlights the importance of phenotyping inner-city
children with asthma for identifying those who require high-dose
asthma controller therapy.
Pongracic Et Al. J Allergy Clin Immunol. 2016;138(4):1030–41

The New England Journal of Medicine
THE ROLE OF COCKROACH ALLERGY AND EXPOSURE TO COCKROACH
ALLERGEN IN CAUSING MORBIDITY AMONG INNER-CITY CHILDREN
WITH ASTHMA
DAVID L. ROSENSTREICH, M.D., PEYTON EGGLESTON, M.D., MEYER KATTAN, M.D., DEAN BAKER, M.D., M.P.H.,
RAYMOND G. SLAVIN, M.D., PETER GERGEN, M.D., HERMAN MITCHELL, PH.D., KATHLEEN MCNIFF-MORTIMER, M.P.H.,
HENRY LYNN, PH.D., DENNIS OWNBY, M.D., AND FLOYD MALVEAUX, M.D., PH.D.,
FOR THE NATIONAL COOPERATIVE INNER-CITY ASTHMA STUDY*
ABSTRACT
Background It has been hypothesized that asth-
ma-related health problems are most severe among
children in inner-city areas who are allergic to a spe-
cific allergen and also exposed to high levels of that
allergen in bedroom dust.
Methods From November 1992 through October
1993, we recruited 476 children with asthma (age,
four to nine years) from eight inner-city areas in the
United States. Immediate hypersensitivity to cock-
roach, house-dust-mite, and cat allergens was meas-
ured by skin testing. We then measured major aller-
gens of cockroach (Bla g 1), dust mites (Der p 1 and
Der f 1), and cat dander (Fel d 1) in household dust
using monoclonal-antibody–based enzyme-linked im-
munosorbent assays. High levels of exposure were
defined according to proposed thresholds for caus-
ORBIDITY due to asthma is dispro-
portionately high among inner-city
residents,1 for reasons that are not com-
pletely understood. Proposed explana-
tions include increased exposure to allergens,2 poor
air quality,3 psychosocial problems,4 and inadequate
access to good medical care.4
Allergens involved in causing asthma include those
derived from house-dust mites,5 animal dander,6 and
mold spores.7 In particular, it has been suggested
that exposure to cockroach allergen may be an im-
portant factor in asthma in inner-city areas,8 since
cockroaches are ubiquitous and are highly allergen-
ic.9,10 However, a clear causal relation among allergy
to cockroaches, increased levels of cockroach aller-
M

• The rate of hospitalization for
asthma was high among the
children who were sensitive to
cockroach allergen and exposed
to high levels of this allergen in
their bedrooms (group 4) as for
the other three groups (0.37 vs.
0.11, P 0.001)
• Similarly, more unscheduled
visits, days of wheezing and
their care givers had to change
their own plans because of the
children’s asthma
0.37
4.04
15.52
2.56
WITH ASTHMA
ABSTRACT
ing disease. Data on morbidity due to asthma were
collected at base line and over a one-year period.
Results Of the children, 36.8 percent were allergic
gen, and asthma has not been demonstrated.
As part of the National Cooperative Inner-City
Asthma Study, we performed a comprehensive anal-
ysis of factors that might be associated with the se-
M
Rosenstreich Et Al, N Engl J Med 1997;336:1356-63.

• No significant association
between morbidity due
to asthma and high
bedroom level of dust-
mite or cat allergen.
• Rate of hospitalization
for asthma among 4
groups of children were
similar.
WITH ASTHMA
ABSTRACT
ing disease. Data on morbidity due to asthma were
collected at base line and over a one-year period.
gen, and asthma has not been demonstrated.
As part of the National Cooperative Inner-City
Asthma Study, we performed a comprehensive anal-
M
Rosenstreich Et Al, N Engl J Med 1997;336:1356-63.

Cockroach exposure independent of sensitization
status and association with hospitalizations for
asthma in inner-city children
Felicia A. Rabito, PhD*; John Carlson, MD, PhD†; Elizabeth W. Holt, PhD*; Shahed Iqbal, PhD*; and
Mark A. James, PhD‡
Background: Children with asthma living in urban environments experience disproportionately high asthma hospitalization
rates. Excessive exposure to perennial allergens, including cockroach and house dust mite (HDM), have been implicated, but data
are limited.
Objective: To examine the relation between cockroach and HDM exposure and measures of asthma morbidity and health care
utilization.
Methods: Participants included 86 atopic asthmatic children living in New Orleans, Louisiana. Sensitization status was
determined by means of serum specific IgE testing, and vacuum dust samples were collected for allergen analysis. Logistic
regression analysis was used to assess the odds of persistent wheezing, emergency department visits, and asthma hospitalization
in those with high vs low levels of allergen exposure.
Results: Approximately 44% and 40% of children were exposed to Bla g 1 levels greater than 2 U/g and HDM levels greater
than 2 ␮g/g, respectively, and 24% reported at least 1 hospitalization in the previous 4 months. The median Bla g 1 level was
significantly higher in the homes of children hospitalized compared with those with no hospital admissions (7.2 vs 0.8 U/g). In
multivariable models, the odds of hospitalization were significantly higher in children exposed to Bla g 1 levels greater than 2
U/g (adjusted odds ratio, 4.2; 95% confidence interval, 1.24–14.17), independent of sensitization status. Exposure to HDMs was
not associated with any measure of morbidity.
Conclusions: Exposure to cockroach allergen was strongly associated with increased hospitalization in children with asthma.
This effect cannot be explained entirely by IgE-mediated inflammation. Controlled interventional trials are needed to determine
whether isolated cockroach abatement improves asthma control.
Ann Allergy Asthma Immunol. 2011;106:103–109.
INTRODUCTION
An estimated 7 million US children currently have asthma,
with the highest burden borne by low-income black children
living in urban environments.1
The annual asthma hospital-
ization rate for black children is 33.5 per 10,000.2
Inner-city
children are exposed to high levels of indoor allergens in
cities across the United States,3–6
and allergen avoidance is a
major component of asthma control advocated by physi-
cians.7
However, results of intervention trials8–12
assessing the
effectiveness of allergen reduction techniques have been
mixed. There is strong evidence linking allergen exposure
and sensitization to the diagnosis of asthma, but there is
conflicting evidence as to whether current exposure is asso-
ciated with asthma morbidity.
Allergens found in household dust that have been linked to
asthma include those derived from pet dander, rodent excre-
ment, mold spores, plant pollens, and arthropod feces, with
the relative importance of particular allergens depending on
the geographic location and socioeconomic condition of the
study population. Abundant evidence4,6,13–16
confirms that ex-
posure to house dust mites (HDMs) is independently associ-
ated with allergic sensitization; however, exposure to HDM
The odds of reporting previous hospitalization were 4.2 times higher in children exposure to Bla g 1
greater than 2 U/g than in those exposed to 2 U/g or less (95% CI, 1.24–14.17 U/g), independent of
sensitization status.
Rabito Et Al. Ann Allergy Asthma Immunol. 2011;106:103–109.
Cockroach exposure independent of sensitization
status and association with hospitalizations for
asthma in inner-city children
Felicia A. Rabito, PhD*; John Carlson, MD, PhD†; Elizabeth W. Holt, PhD*; Shahed Iqbal, PhD*; and
Mark A. James, PhD‡
Background: Children with asthma living in urban environments experience disproportionately high asthma hospitalization
rates. Excessive exposure to perennial allergens, including cockroach and house dust mite (HDM), have been implicated, but data
are limited.
Objective: To examine the relation between cockroach and HDM exposure and measures of asthma morbidity and health care
utilization.
Methods: Participants included 86 atopic asthmatic children living in New Orleans, Louisiana. Sensitization status was
determined by means of serum specific IgE testing, and vacuum dust samples were collected for allergen analysis. Logistic
regression analysis was used to assess the odds of persistent wheezing, emergency department visits, and asthma hospitalization
in those with high vs low levels of allergen exposure.
Results: Approximately 44% and 40% of children were exposed to Bla g 1 levels greater than 2 U/g and HDM levels greater
than 2 ␮g/g, respectively, and 24% reported at least 1 hospitalization in the previous 4 months. The median Bla g 1 level was
significantly higher in the homes of children hospitalized compared with those with no hospital admissions (7.2 vs 0.8 U/g). In
multivariable models, the odds of hospitalization were significantly higher in children exposed to Bla g 1 levels greater than 2
U/g (adjusted odds ratio, 4.2; 95% confidence interval, 1.24–14.17), independent of sensitization status. Exposure to HDMs was
not associated with any measure of morbidity.
Conclusions: Exposure to cockroach allergen was strongly associated with increased hospitalization in children with asthma.
This effect cannot be explained entirely by IgE-mediated inflammation. Controlled interventional trials are needed to determine
whether isolated cockroach abatement improves asthma control.
Ann Allergy Asthma Immunol. 2011;106:103–109.
INTRODUCTION
An estimated 7 million US children currently have asthma,
with the highest burden borne by low-income black children
living in urban environments.1
The annual asthma hospital-
ization rate for black children is 33.5 per 10,000.2
Inner-city
children are exposed to high levels of indoor allergens in
cities across the United States,3–6
and allergen avoidance is a
major component of asthma control advocated by physi-
mixed. There is strong evidence linking allergen exposure
and sensitization to the diagnosis of asthma, but there is
conflicting evidence as to whether current exposure is asso-
ciated with asthma morbidity.
Allergens found in household dust that have been linked to
asthma include those derived from pet dander, rodent excre-
ment, mold spores, plant pollens, and arthropod feces, with
the relative importance of particular allergens depending on

control or prevention, airway inflammation
assessed by fraction of exhaled nitric oxide
(FeNO), and asthma-related quality of life.
Potentially modifiable biological and
chemical exposures resulting from indoor
sources were considered for inclusion as poten-
tial causes of asthma morbidity. Infectious
agents and outdoor-generated pollutants that
penetrate buildings were excluded. Studies
on new onset of asthma, asthma prevalence,
or experimental biologic markers of asthma
were excluded.
Only studies of human health effects
were included. Eligible study designs were
controlled (experimental) exposure studies,
environmental intervention studies, and
a variety of observational designs: prospec-
tive or retrospective (longitudinal) cohort,
case–control, and cross-sectional. Case studies
and case series were ineligible. Detailed
inclusion and exclusion criteria are described
in the Supplemental Material, “Study
inclusion criteria.”
Indoor Environmental Exposures and Exacerbation of Asthma: An Update
to the 2000 Review by the Institute of Medicine
Watcharoot Kanchongkittiphon,1,2,3* Mark J. Mendell,4,5* Jonathan M. Gaffin,1,2 Grace Wang,6 and
Wanda Phipatanakul1,2
1Division of Allergy and Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA; 2Harvard Medical School, Boston,
Massachusetts, USA; 3Department of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 4Indoor Air Quality
Program, California Department of Public Health, Richmond, California, USA; 5Indoor Environment Group, Lawrence Berkeley National
Laboratory, Berkeley, California, USA; 6American Institutes for Research, San Mateo, California, USA.
*These authors contributed equally to this work.
BACKGROUND: Previous research has found relationships between specific indoor environmental
exposures and exacerbation of asthma.
OBJECTIVES: In this review we provide an updated summary of knowledge from the scientific literature
on indoor exposures and exacerbation of asthma.
METHODS: Peer-reviewed articles published from 2000 to 2013 on indoor exposures and
exacerbation of asthma were identified through PubMed, from reference lists, and from authors’ files.
Articles that focused on modifiable indoor exposures in relation to frequency or severity of exacerba-
tion of asthma were selected for review. Research findings were reviewed and summarized with
consideration of the strength of the evidence.
RESULTS: Sixty-nine eligible articles were included. Major changed conclusions include a causal
relationship with exacerbation for indoor dampness or dampness-related agents (in children);
associations with exacerbation for dampness or dampness-related agents (in adults), endotoxin,
and environmental tobacco smoke (in preschool children); and limited or suggestive evidence for
association with exacerbation for indoor culturable Penicillium or total fungi, nitrogen dioxide,
rodents (nonoccupational), feather/down pillows (protective relative to synthetic bedding), and
(regardless of specific sensitization) dust mite, cockroach, dog, and dampness-related agents.
DISCUSSION: This review, incorporating evidence reported since 2000, increases the strength of
evidence linking many indoor factors to the exacerbation of asthma. Conclusions should be considered
provisional until all available evidence is examined more thoroughly.
CONCLUSION: Multiple indoor exposures, especially dampness-related agents, merit increased
attention to prevent exacerbation of asthma, possibly even in nonsensitized individuals.
Additional research to establish causality and evaluate interventions is needed for these and other
indoor exposures.
control or prevention, airway inflammation
assessed by fraction of exhaled nitric oxide
(FeNO), and asthma-related quality of life.
Potentially modifiable biological and
chemical exposures resulting from indoor
sources were considered for inclusion as poten-
tial causes of asthma morbidity. Infectious
agents and outdoor-generated pollutants that
penetrate buildings were excluded. Studies
on new onset of asthma, asthma prevalence,
or experimental biologic markers of asthma
were excluded.
Only studies of human health effects
were included. Eligible study designs were
controlled (experimental) exposure studies,
environmental intervention studies, and
a variety of observational designs: prospec-
tive or retrospective (longitudinal) cohort,
case–control, and cross-sectional. Case studies
and case series were ineligible. Detailed
inclusion and exclusion criteria are described
in the Supplemental Material, “Study
inclusion criteria.”
Indoor Environmental Exposures and Exacerbation of Asthma: An Update
to the 2000 Review by the Institute of Medicine
Watcharoot Kanchongkittiphon,1,2,3* Mark J. Mendell,4,5* Jonathan M. Gaffin,1,2 Grace Wang,6 and
Wanda Phipatanakul1,2
1Division of Allergy and Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA; 2Harvard Medical School, Boston,
Massachusetts, USA; 3Department of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 4Indoor Air Quality
Program, California Department of Public Health, Richmond, California, USA; 5Indoor Environment Group, Lawrence Berkeley National
Laboratory, Berkeley, California, USA; 6American Institutes for Research, San Mateo, California, USA.
*These authors contributed equally to this work.
BACKGROUND: Previous research has found relationships between specific indoor environmental
exposures and exacerbation of asthma.
OBJECTIVES: In this review we provide an updated summary of knowledge from the scientific literature
on indoor exposures and exacerbation of asthma.
METHODS: Peer-reviewed articles published from 2000 to 2013 on indoor exposures and
exacerbation of asthma were identified through PubMed, from reference lists, and from authors’ files.
Articles that focused on modifiable indoor exposures in relation to frequency or severity of exacerba-
tion of asthma were selected for review. Research findings were reviewed and summarized with
consideration of the strength of the evidence.
RESULTS: Sixty-nine eligible articles were included. Major changed conclusions include a causal
relationship with exacerbation for indoor dampness or dampness-related agents (in children);
associations with exacerbation for dampness or dampness-related agents (in adults), endotoxin,
and environmental tobacco smoke (in preschool children); and limited or suggestive evidence for
association with exacerbation for indoor culturable Penicillium or total fungi, nitrogen dioxide,
rodents (nonoccupational), feather/down pillows (protective relative to synthetic bedding), and
(regardless of specific sensitization) dust mite, cockroach, dog, and dampness-related agents.
DISCUSSION: This review, incorporating evidence reported since 2000, increases the strength of
evidence linking many indoor factors to the exacerbation of asthma. Conclusions should be considered
provisional until all available evidence is examined more thoroughly.
CONCLUSION: Multiple indoor exposures, especially dampness-related agents, merit increased
attention to prevent exacerbation of asthma, possibly even in nonsensitized individuals.
Additional research to establish causality and evaluate interventions is needed for these and other
indoor exposures.
• There is sufficient evidence of casual
relationship between cockroach allergen
exposure and exacerbation of asthma in
individuals specially sensitized to
cockroaches, especially adults.
• There is limited or suggestive evidence of
association between cockroach allergen
exposure and exacerbation of asthma in
children non sensitized to cockroaches.
Kanchonghittiphon Et Al. Environmental Health Perspectives 2015; 123(1):6–20.

• Allergen sensitization (linked
sequentially to allergic inflammation,
pulmonary physiology and rhinitis
severity), and environmental tobacco
smoke exposure had the largest effects
on asthma severity
• Vitamin D, stress and obesityshowed
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
Liu Et Al. J Allergy Clin Immunol. 2016;138(4):1042-50Mediation analyses (Table E4) revealed modest indirect DISCUSSION
FIG 2. Direct and indirect effects of all pathways. Estimates are standardized direct effects that are
interpreted as the SD increase in the dependent domain for every 1-SD increase in the independent domain.
Estimates with associated P values that are less than .05 are denoted by asterisk and solid lines. Thick lines
further denote statistically signiﬁcant pathways by tests of indirect effects and mediation. Statistically insig-
niﬁcant estimates are denoted by dashed lines. All estimates are adjusted for age, sex, and race.
IN IMMUNOL
NUMBER 4
LIU ET AL 1047
Pathways through which asthma risk factors
contribute to asthma severity in inner-city children
Andrew H. Liu, MD,a,b
Denise C. Babineau, PhD,c
Rebecca Z. Krouse, MS,c
Edward M. Zoratti, MD,d
Jacqueline A. Pongracic, MD,e
George T. O’Connor, MD, MS,f
Robert A. Wood, MD,g
Gurjit K. Khurana Hershey, MD, PhD,h
Carolyn M. Kercsmar, MD,h
Rebecca S. Gruchalla, MD, PhD,i
Meyer Kattan, MD,j
Stephen J. Teach, MD, MPH,k
Melanie Makhija, MD,e
Dinesh Pillai, MD,k
Carin I. Lamm, MD,j
James E. Gern, MD,l
Steven M. Sigelman, RN, MHA,m
Peter J. Gergen, MD, MPH,m
Alkis Togias, MD,m
Cynthia M. Visness, PhD,c
and
William W. Busse, MDl
Denver and Aurora, Colo; Chapel Hill, NC; Detroit, Mich; Chicago, Ill; Boston, Mass; Baltimore, Md;
Cincinnati, Ohio; Dallas, Tex; New York, NY; Washington, DC; Madison, Wis; and Bethesda, Md
GRAPHICAL ABSTRACT

• Cluster analysis using baseline and
longitudinal variables was
performed in 616 inner-city
children with asthma followed
prospectively for a year.
• Five clusters were identified by
indicators of asthma and rhinitis
severity, pulmonary physiology,
allergy (sensitization and total
serum IgE), and allergic
inflammation.
• Severe asthma often co clustered
with highly allergic children.
• However, a symptomatic
phenotype with little allergy or
allergic inflammation was also
identified.
ZorattiEt Al. J Allergy Clin Immunol. 2016;138(4):1016–29
A B C D E
FeNO at V0 (ppb)7
Blood eosinophil count at V0 (cells/mm3)8
Total serum IgE at V0 (kU/L)7
Number of allergen sensitizations (panel of 22)6
at V0
Rhinitis symptom score5
at Screening
Rhinitis medication score4
at Screening
Bronchodilator response (%) at Screening
Airway obstruction3
(V0−V6)
Mean of controller treatment step (V0−V6)
Mean of CASI − Exacerbations2
(V0−V6)
Mean of CASI − Night symp & albuterol use1
(V0−V6)
Mean of CASI − Day symp & albuterol use1
(V0−V6) 0.11 (0.13) 0.51 (0.36) 0.16 (0.23) 0.19 (0.25) 0.65 (0.39)
0.10 (0.19) 0.58 (0.51) 0.14 (0.22) 0.08 (0.15) 0.64 (0.44)
0.05 (0.12) 0.31 (0.35) 0.12 (0.24) 0.32 (0.52) 0.76 (0.73)
14.1 (1.78) 14.6 (2.07) 20.4 (2.14) 26.4 (2.24) 27.1 (2.20)
121
[100, 210]
200
[100, 300]
300
[190, 500]
331
[200, 505]
400
[235, 570]
6.60 (8.41) 12.2 (11.6) 10.1 (9.48) 16.2 (16.1) 19.5 (16.4)
83.5 (5.67) 79.0 (8.81) 81.3 (6.37) 78.2 (8.14) 74.8 (8.25)
1.14 (1.12) 1.98 (1.82) 8.82 (4.28) 13.0 (4.21) 14.1 (4.26)
39.4 (3.56) 71.4 (4.32) 259 (3.37) 576 (3.43) 616 (3.18)
6.63 (6.07) 8.60 (5.53) 5.20 (5.45) 14.0 (3.04) 12.5 (5.11)
7.40 (5.66) 9.03 (5.79) 6.37 (5.96) 10.5 (5.15) 11.6 (6.21)
1.39 (1.38) 4.19 (1.52) 1.93 (1.60) 3.41 (1.69) 4.68 (1.28)
Asthma
severity
Pulmonary
physiology
Rhinitis
severity
Allergen
sensitization
Allergic
inflammation
Lowest HighestIntermediate
1. Composite Asthma Severity Index (CASI) component − Day and night symptoms includes measures of asthma symptoms and albuterol use in the last 2 weeks (scoring range between 0 and 3).
2. CASI component − Exacerbations includes hospitalizations and/or oral corticosteroid bursts in the last 2 months.
J ALLERGY CLIN IMMUNOL
OCTOBER 2016
1020 ZORATTI ET AL
Asthma and lower airway disease
Asthma phenotypes in inner-city children
Edward M. Zoratti, MD,a
Rebecca Z. Krouse, MS,b
Denise C. Babineau, PhD, MS,b
Jacqueline A. Pongracic, MD,c
George T. O’Connor, MD, MS,d
Robert A. Wood, MD,e
Gurjit K. Khurana Hershey, MD, PhD,f
Carolyn M. Kercsmar, MD,f
Rebecca S. Gruchalla, MD, PhD,g
Meyer Kattan, MD,h
Stephen J. Teach, MD, MPH,i
Steven M. Sigelman, RN, MHA,j
Peter J. Gergen, MD, MPH,j
Alkis Togias, MD,j
Cynthia M. Visness, PhD,b
William W. Busse, MD,k
and
Andrew H. Liu, MDl,m
Detroit, Mich; Chapel Hill, NC; Chicago, Ill; Boston, Mass; Baltimore and Bethesda, Md; Cincinnati,
Ohio; Dallas, Tex; New York, NY; Washington, DC; Madison, Wis; and Denver and Aurora, Colo
GRAPHICAL ABSTRACT
Background: Children with asthma in low-income urban areas
have high morbidity. Phenotypic analysis in these children is
lacking, but may identify characteristics to inform successful
tailored management approaches.
Objective: We sought to identify distinct asthma phenotypes
among inner-city children receiving guidelines-based
management.
Methods: Nine inner-city asthma consortium centers enrolled
717 children aged 6 to 17 years. Data were collected at baseline
and prospectively every 2 months for 1 year. Participants’
asthma and rhinitis were optimally managed by study
physicians on the basis of guidelines. Cluster analysis using 50
baseline and 12 longitudinal variables was performed in 616
participants completing 4 or more follow-up visits.
Results: Five clusters (designated A through E) were
distinguished by indicators of asthma and rhinitis severity,
pulmonary physiology, allergy (sensitization and total serum
From a
Henry Ford Health System and Wayne State University School of Medicine, De-
troit; b
Rho Federal Systems Division, Chapel Hill; c
Ann and Robert H. Lurie Chil-
dren’s Hospital of Chicago, Chicago; d
Boston University School of Medicine,
Boston; e
Johns Hopkins University School of Medicine, Baltimore; f
Cincinnati Chil-
dren’s Hospital, Cincinnati; g
the University of Texas Southwestern Medical Center,
Dallas; h
the College of Physicians and Surgeons, Columbia University, New York;
i
the Children’s National Health System and the George Washington University School
of Medicine and Health Sciences, Washington; j
the National Institutes of Allergy and
Infectious Diseases, Bethesda; k
the University of Wisconsin School of Medicine and
Public Health, Madison; l
National Jewish Health, Denver; and m
Children’s Hospital
Colorado and University of Colorado School of Medicine, Aurora.
This project has been funded in whole or in part with federal funds from the National Institute
of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH),
Department of Health and Human Services (under contract nos., HHSN272200900052C
and HHSN272201000052I, and 1UM1AI114271-01). Additional support was provided by
the National Center for Research Resources (NCRR), and the National Center for
R. A. Wood has received grants from the NIH, DBV, and Aimmune; has consultant
arrangements with Sanofi and Stallergenes; is employed by Johns Hopkins University;
and has received royalties from Up To Date. C. M. Kercsmar has received a grant from
the NIH and was the chair of Data Safety Monitoring Board on GSK-funded, Food and
Drug Administration–mandated trial evaluating the safety of inhaled corticosteroid
1 long-acting beta-agonist versus inhaled corticosteroid alone in children
(ClinicalTrials.gov Identifier: NCT01462344). R. S. Gruchalla is employed by the
Center for Biologics Evaluation and Research and has consultant arrangements with
the Massachusetts Medical Society. M. Kattan has received a grant from the NIH-
NIAID and is on the advisory board for Novartis Pharma. S. J. Teach has received
grants from the NIH-NIAID, Novartis, Patient Centered Outcomes Research Institute,
Fight for Children Foundation, EJF Philanthropies, and the NIH-National Heart, Lung,
and Blood Institute; has consultant arrangements with Novartis; and has received roy-
alties from Up To Date. W. W. Busse has received a grant from the NIH-NIAID; has
received partial study funding and provision of study drug and placebo from Novartis;
is a member of the Data Safety Monitoring Boards for Boston Scientific and Circassia;
is a member of the Study Oversight Committee for ICON; and has consultant arrange-

Cockroach environmental control
1. Exposure to cockroach allergen in homes should be minimized to
reduce the risk of cockroach sensitization. (StrRec, B Evidence)
2. Exposure to cockroach allergens should be minimized to reduce the
risk that sensitized children will develop allergic disease. (Rec, C
Evidence)
3. Cockroach allergen exposure should be minimized to reduce the risk
of asthma morbidity in already sensitized subjects. (Rec, B Evidence)
4. Patients with possible cockroach allergy should be asked whether
they have seen cockroaches in their homes. (Rec, C Evidence)
Environmental assessment and exposure reduction of cockroaches:
A practice parameter PORTNOY ET AL . J ALLERGY CLIN IMMUNOL 2013

5. 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.
(StrRec, D Evidence)
6. 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. (StrRec, D Evidence)
7. The extent and duration of a cockroach infestation should be monitored
by using strategically placed sticky traps. (StrRec, D Evidence)

8. Pesticides should be used judiciously and ideally should be applied by a
professional exterminator as part of an integrated pest management
program. (Rec, C Evidence)
9. Boric acid is an effective pesticide; however, surviving cockroaches can
produce more allergen after exposure. (Rec, C Evidence)
10. Measurement of cockroach allergen in dust can be considered for
building occupants at increased risk of cockroach sensitization or sensitivity
though routine clinical use of this information has not been sufficiently
studied. (Opt, D Evidence)
11. Reservoirs of cockroach contaminants should be cleaned or removed to
prevent additional exposure to occupants. (StrRec, A Evidence)

12. Integrated pest management with a combination of interventions
appears to be the most effective method for preventing and
eliminating cockroach infestations. (StrRec, B Evidence)
13. Integrated pest management should be used to decrease cockroach
exposure to reduce asthma morbidity. (StrRec, A Evidence)
14. Immunotherapy with cockroach extracts can be considered;
however, it has only been evaluated in a limited number of studies, an
effective dose is not known, and it is not clear how effective the
treatment is for asthma or rhinitis. (Opt, C Evidence)

• Although, cockroach exposure control strategies may be helpful, they
are difficult to maintain and exposure may continue outside the
home.
• Effective cockroach immunotherapy has the potential of modifying
the course of asthma and providing sustained clinical benefit.
Bassirpour and Zoratti. Curr Opin Allergy Clin Immunol. 2014 December ; 14(6): 535–541

Unique features of cockroach allergy that may
impact the efficacy of immunotherapy
• 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)

Limitations of current cockroach allergen extracts
• 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.
Bassirpour and Zoratti, Curr Opin Allergy Clin Immunol. 2014 December ; 14(6): 535–541

• 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

• Immunotherapy with cockroach extracts has been evaluated in a limited
number of studies.
• 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.
• If immunotherapy with cockroach extract is prescribed, only glycerinated
extracts should be used.
Cockroach immunotherapy
Allergen immunotherapy: A practice parameter third update
COX ET AL . J ALLERGY CLIN IMMUNOL JANUARY 2011

The Role of Immunotherapy
in Cockroach Asthma
Bann C. Kang, M.D., F.A.A.A.I., F.A.C.P.,'
Jessie Johnson, B.S., Cinda Morgan, B.S.N.,
and Jin Lai Chang, Ph.D.
Department of Medicine
Mt. Sinai Hospital Medical Center- Rush Medical School
Chicago, Illinois
ABSTRACT
To evaluate the preventive role of immunotherapy in
severe perennial asthma, we investigated cockroach
asthma as a model. Twenty-eight subjects with bronchial
asthma due to cockroach hypersensitivity (BACR) were
divided into two groups in alternating order: 15 were
started with cockroach antigen immunotherapy (CRa-IT)
and 13 were given control immunotherapy. Eleven in the
former group and two in the latter group completed the
study after 5 years. The changes in symptoms and medica-
tion scores were assessed; blocking antibody factor in the
paired p r eand postimmuneserum of the two groups was
measured and compared. Cellular sensitivity (HR50)was
measured using the basophil-rich leukocytes (BRLs) ob-
tained from the two treated asthma groups, and the result
was compared with that of the untreated cockroach
asthmatic cells.
The average symptom score changed from 7.2 * 2.7
to 1.2 f 0.4 in the CRa-IT group. The control-IT group
showed no change. The medication score changed from
11.4 f 1.6 to 5.2 f 1.4 in the CRa-IT group only (p <
0.011. The mean blocking antibody factor in the immune
*Addressreprint requeststo: Bann C. Kang, M.D.,Divi-
• 28 Subjects with severe perennial asthma
• Positive allergen skin test or/and bronchial provocation test to cockroach allergen
• Cockroach allergen immunotherapy group (N=15)
• 11/15 complete study
• Control allergen immunotherapy group (N=13)
• 2/13 complete study
Kang Et Al. Asthma. 1988;25:205–18.

Intervention:
• IT : SCIT with mixed CR extracts (German,
American and Oriental)
• 20 to 30 weeks of weekly injections,
conventional methods
• Test group
• IT with CR extracts + other allergens to
which patients were sensitized.
• 4 to 5 years
• Control group
• IT with all relevant allergens except CR
52 months
in Cockroach Asthma
Chicago, Illinois
ABSTRACT
asthmatic cells.
sionof Allergy and Immunology, Universityof Kentucky
Medical Center, 800 Rae Street, Lexington,KY 40636.
Outcome:
Clinical outcome : Symptom and
Medication scores
Immunologic outcome :
• Total IgE, sIgE CR
• Leukocyte Preparation and
Anaphylactic Histamine Release
Assay Blocking
• Antibody Determination

• CRa-IT group:
• The symptom score changed from 7.2 +/-2 . 7 to 1.2 +/- 0.4
• The medication score changed from 11.4 +/- 1.6 to 5.2 +/-1.4
• Total IgE levels and sIgE in the groups showed no significant change (p < 0.5).

Table 3. Effect of Pre- and Postimmune Serum Factors Produced by CRa-IT and
Control-IT on Leukocyte Histamine Release Assay (HR50) Using Untreated Asthmatic BRLs
GROUP
(NO. OF
CRa-ITC 5.15 1 0 - ~ * 2.03 x 1 0 - ~ 1.34 x 10-1 f 0.32 x lo-'
HR50 ASSAYS) PREIMMUNEa POSTIMMUNE~
(15)
5.83 2.16Control-ITd 5.16 10-5 f 1.33 10-5
(3)
ap > 0.2 by unpaired t-test.
bp c 0.05by unpaired t-test.
cp < 0.001 by paired t-test.
dp > 0.1 by paired t-test.
Mean E: standard error.
212
loo[90
Kang et al.
106 10-5 10-4 10-3 10-2 10-1 100
Amount of cockroach antigen,pg/ml
Figure1. The antigen-specificblocking antibody inhibitedthe anaphylactic
leukocytehistamine releasability.B a s were collectedfrom an asthmatic
subject (B.E.).C. C. received CRa-ITfor 20 months, a cumulative dose of
30,900 PNU:Mpreimmune serum; Mpostimmune serum. F. I.
receivedantigenlTotherthanCRafor 19months:C----Wpreimmuneserum;
0----0postimmune serum.
The post CRa serum blocked the
anaphylactic histamine release
of the BRLs 260-fold of the pre-
CRa-IT serum (1.34x10-1 from
5.15x10-4 pg/ml; p < 0.01)

Conclusion
• Clinical outcome:
• Reduction in symptom and medication scores
• Immunologic outcome:
• Increase in CR-specific blocking antibody and blunting of
in vitro basophil histamine release
in Cockroach Asthma
Chicago, Illinois
ABSTRACT
asthmatic cells.
sionof Allergy and Immunology, Universityof Kentucky

• Double-blind, placebo-controlled study
• 42 cockroach(P. americana) sensitized patients of asthma, rhinitis or both
• IT 24
• Placebo 18
• 2 years follow up
Clinico-immunological changes post-immunotherapy
with Periplaneta americana
Deepsikha Srivastava*,†
, Shailendra Nath Gaur‡
, Naveen Arora*
and Bhanu Pratap Singh*
*
Allergy and Immunology Section, Institute of Genomics and Integrative Biology, CSIR, Delhi, India, †
Department of
Biotechnology, University of Pune, Ganeskhind, Pune, India, ‡
Department of Pulmonary Medicine, V. P. Chest Institute,
University of Delhi, Delhi, India
ABSTRACT
Background Cockroach proteins induce allergies including asthma in predisposed individuals. Well-designed
controlled studies are required to show the effect of cockroach immunotherapy (IT). This study is aimed to
assess changes in clinical and immunological parameters post-IT with Periplaneta americana extract.
Materials and methods A double-blind, placebo-controlled trial of cockroach IT was performed for 1 year in 50
patients of asthma, rhinitis or both. The efficacy of IT was assessed by change in skin reactivity and clinical
parameters such as symptom ⁄ drug score, airway reactivity and immunological parameters namely IgE, IgG1
and IgG4, IL-4 and IFN-c by enzyme-linked immunosorbent assay and western blotting using patients’ sera at
baseline and after 1 year of treatment.
Results Immunotherapy with cockroach extract demonstrated significant improvement in clinical parameters of
active group patients compared with baseline values and placebo group. Specific IgE levels showed a modest
reduction, while IgG4 levels increased significantly in active IT group after 1 year. IgE immunoblotting demon-
strated reduction in intensity and number of specific bands, whereas IgG4 binding showed more number and
distinct bands following IT. Active group patients showed correlation between increase in IgG4 ⁄ IgG1 ratio and
reduction in symptom score post-IT.
Conclusions Immunotherapy with cockroach extract improved clinical and immunological status of asthma and
rhinitis patients. Clinical improvement in patients after IT is associated with immunological changes.
Keywords Asthma, ELISA, immunoblot, immunotherapy, Periplaneta americana, rhinitis.
Eur J Clin Invest 2011; 41 (8): 879–888

Intervention
• IT: SCIT of an aqueous 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.
Outcome at 1 year, 2 year
• Clinical outcome: Airway reactivity, Symptom ⁄ drug score.
• Immunological outcome: sIgE CR, IgG4, IgG1, Changes in IgE binding against cockroach allergens
(immunoblotting)
, Naveen Arora*
*
Department of
ABSTRACT
Eur J Clin Invest 2011; 41 (8): 879–888
D. SRIVASTAVA ET AL. Eur J Clin Invest 2011; 41 (8): 879–888

Symptom score
IT group: statistically significant reduction
immunoblot. Here, 72- and 78-kDa components are represent-
ing Per a 3 of P. americana identified earlier. Per a 9 separated at
43 kDa and Per a 7 at 37 kDa in previous studies, whereas in
IgE binding to other allergenic components also reduced in
some patients post-IT. Five patients showed decreased intensit
to 72- and 78-kDa components. Two patients showed decrease
IgE binding to 37- and 23-kDa proteins. One patient showed
decreased IgE binding to 43-kDa protein. Four patients did not
show any change in IgE binding with protein components,
while patient numbers 3 and 18 showed increased IgE bands
post-IT (Table 4; Fig. 4).
Figure 2 Scattered diagram of the total symptom score of
active group ‘T0’ [baseline i.e. before immunotherapy (IT)], ‘T1’
(after 1 year of IT) and ‘T2’ (after 2 year of IT) and placebo group
at ‘T0’ (baseline i.e. before IT) and ‘T1’ (after 1 year of IT). ‘T’
stands for time. Symptom score was analysed for active IT
group patients in comparison with baseline value and placebo
group patients after 1 year of treatment. P < 0Æ05 was
considered statistically significant.
Table 4 Immunoblot results for specific IgE and IgG4 at T0 and
T1 of active group patients
Protein bands
(molecular weight in kDa)
IgE IgG4
No. of
patients
No. of
patients
T0 T1 T0 T
97 7 7 5 1
72 and 78 (Per a 3) 13 8 9 1
43 (Per a 9) 11 10 3
37 (Per a 7) 10 8 5
28 (Per a 10) 16 10 5 1
23 11 13 4 1
T0, baseline [i.e. before immunotherapy (IT)]; T1, after 1 year of IT.
Clinical OutcomeMedian 154 Median 157
Median 47 Median 96
Airway reactivity (P20FEV1)
• IT group: 18 of 24 patients showed
significant increase in PC20FEV1
compared with baseline values
and placebo group, 8 of 24
patients tolerated highest dose of
histamine after 1 year of IT.
• Placebo group:15 of 18 patients
showed decrease in PC20FEV1
indicating rise in airway reactivity.
Medication score
IT group:
reduction after 1 year and highly
significant reduction after 2 years

IT group
• Specific IgG4: increase significantly
• IgG1: some increase
• IgG4 ⁄ IgG1 ratio: increase
• Cytokines:(Data not shown)
• IL-4: decreased
• IFN-gamma: not show much change
er-
e
i-
year
Figure 3 Correlation of IgG4 ⁄ IgG1 ratio with clinical improve-
ment (Change in symptom score T0–T1) in active immunother-
apy group patients.
Immunologic Outcome

• IgE immunoblotting:
• mostly decrease or same
• IgG4 immunoblotting
• higher intensity and more
number of bands after 1 year
her-
ore
ari-
year
nt.
f
, ‘T1’
group
T’
Figure 3 Correlation of IgG4 ⁄ IgG1 ratio with clinical improve-
ment (Change in symptom score T0–T1) in active immunother-
apy group patients.
Table 4 Immunoblot results for speciﬁc IgE and IgG4 at T0 and
T1 of active group patients
Protein bands
(molecular weight in kDa)
IgE IgG4
No. of
patients
No. of
patients
T0 T1 T0 T1
97 7 7 5 10
72 and 78 (Per a 3) 13 8 9 13
43 (Per a 9) 11 10 3 6
37 (Per a 7) 10 8 5 8
28 (Per a 10) 16 10 5 11
23 11 13 4 10
T0, baseline [i.e. before immunotherapy (IT)]; T1, after 1 year of IT.
Immunologic Outcome

, Naveen Arora*
*
Department of
ABSTRACT
Eur J Clin Invest 2011; 41 (8): 879–888
Conclusion
• Improvement in clinical scores and in bronchial hyper reactivity after 1 year.
• Reduction in symptoms and medication use after 2 years.
• Immunologic outcome:
• Increase in CR-specific IgG4 after 1 and 2 years

Four pilot studies were conducted:
(1) an open-label study to assess the safety of cockroach sublingual
immunotherapy (SLIT) in adults and children
(2) a randomized, double-blind biomarker study of cockroach SLIT versus
placebo in adults
(3) a randomized, double-blind biomarkerstudy of 2 doses of cockroach
SLIT versus placebo in children
(4) an open-label safety and biomarker study of cockroach subcutaneous
immunotherapy (SCIT) in adults
Development of cockroach immunotherapy by the Inner-City
Asthma Consortium
Robert A. Wood, MDa, Alkis Togias, MDb, Jeremy Wildfire, MSc, Cynthia M. Visness, PhDc,
Elizabeth C. Matsui, MD, MHSa, Rebecca Gruchalla, MDd, Gurjit Hershey, MDe, Andrew H.
Liu, MDf, George T. O’Connor, MD, MSg, Jacqueline A. Pongracic, MDh, Edward Zoratti,
MDi, Frederic Little, MDg, Mark Granada, MDg, Suzanne Kennedy, PhDc, Stephen R.
Durham, MDj, Mohamed H. Shamji, PhDj, and William W. Busse, MDk
aDepartment of Pediatrics, Johns Hopkins University School of Medicine, Baltimore
bDivision of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious
Diseases, National Institutes of Health
cRho Federal Systems Division, Chapel Hill
dDepartments of Medicine and Pediatrics, University of Texas Southwestern Medical School,
Dallas
eDepartment of Pediatrics, Cincinnati Children’s Hospital, Cincinnati
fNational Jewish Health and University of Colorado Denver School of Medicine, Denver
gDepartment of Medicine, Boston University School of Medicine, Boston
hDepartment of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago
iDepartment of Medicine, Henry Ford Health System, Detroit
jImperial College, London
kDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison
Abstract
Background—Cockroach allergy is a key contributor to asthma morbidity in children living in
PAAuthorManuscriptNIH-PAAuthorManuscript
Wood et al. J Allergy Clin Immunol. 2014 March ; 133(3): 846–852.e6

• open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and
children
• The primary outcome:
• The rate of related adverse events and serious adverse events in the course of treatment
• 27 patients with perennial rhinitis with or without asthma
• Intervention:
• SLIT with German CR extract
• Dose escalation on day 1, Maintenance for 14 days
• CR allergen dose per day: Bla g 2: 4.2, Bla g 1 : 50 ug
• Mild to moderate events: oral or throat pruritus, skin rash, nausea
• 1 subject discontinued due to oral symptoms and vomitting
• 1 subject had throat irritation and cough, graded as severe
• No SAE
• Immunological outcome:
• Not applicable
Sublingual Cockroach Safety Study

• Double-blind, placebo controlled, multicenter
• The primary objective:
• To 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.
• 54 adults patients with perennial allergic rhinitis with or without asthma
• Intervention:
• Dose escalation on day 1 (day 2 if needed), Maintenance for 6 months
• CR allergen dose per day: Bla g 2: 4.2, Bla g 1 : 50 ug
• Clinical outcome: Not applicable
• Increase in CR-specific IgE levels
• No significant increase in CR-specific IgG4
Biomarkers of Cockroach Sublingual Immunotherapy

• Double-blind, placebo controlled, low dose and higher dose, multicenter
• To 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.
• 89 children with perennial allergic rhinitis with or without asthma
• Intervention:
• Dose escalation for low dose on day 1 (day 2 if needed), for high dose over 2-4 weeks Maintenance for 3 months
• CR allergen dose per day:
• Low dose: Bla g 2: 4.2 ug Bla g 1 : 50 ug
• High dose: Bla g 2: 16.8 ug Bla g 1 : 202 ug
• 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
Biomarkers of Cockroach Sublingual Immunotherapy 2

• Open label, single site
• To determine safety and as a proof of concept of the immunologic effect of German CR
• 10 adult patients with perennial allergic rhinitis with or without asthma
• Intervention:
• SCIT with German CR extract
• Escalation over 11 weeks to maintenance with 0.6 mL of a 1:20 concentration of extract for 15 weeks
• 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
Subcutaneous Immunotherapy in Cockroach-sensitive Adults

4 Cockroach Immunotherapy Protocols
NIH-PAAuthorManuscriptNIH-PA Wood et al. Page 13
TABLE I
Summary of study design for the 4 cockroach immunotherapy protocols
Treatment
SCSS BioCSI BioCSI2 SCITCO
SLIT SLIT SLIT SCIT
Design Open label, single site DBPC, multicenter DBPC, low and higher dose,
multicenter
Open label, single site
CR antigen dose per day Bla g 2: 4.2 μg
Bla g 1: 50 μg
Bla g 2: 4.2 μg
Bla g 1: 50 μg
Low dose
Bla g 2: 4.2 μg
Bla g 1: 50 μg
High dose:
Bla g 2: 16.8 μg
Bla g 1: 202 μg
Bla g 2: 6 μg
Bla g 1: 120 μg
Primary outcome Adverse events Change in cockroach-specific
IgE level
Change in cockroach-specific
IgE level
Adverse events
Treatment duration 14 d 6 mo 3 mo 6 mo
Ages of participants Children and adults Adults Children Adults
Sample size 27 54 89 10
CR, Cockroach; DBPC, double-blind, placebo-controlled.

IgE and IgG4 level and blocking antibody activity responsesPage 12
All 3 biomarkers showed
significant change from
baseline during the 6
months treatment period

Conclusion
• These pilot studies suggest that immunotherapy with cockroach allergen is
more likely to be effective with SCIT.
• 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.
Development of cockroach immunotherapy by the Inner-City
Asthma Consortium
Robert A. Wood, MDa, Alkis Togias, MDb, Jeremy Wildfire, MSc, Cynthia M. Visness, PhDc,
Elizabeth C. Matsui, MD, MHSa, Rebecca Gruchalla, MDd, Gurjit Hershey, MDe, Andrew H.
Liu, MDf, George T. O’Connor, MD, MSg, Jacqueline A. Pongracic, MDh, Edward Zoratti,
MDi, Frederic Little, MDg, Mark Granada, MDg, Suzanne Kennedy, PhDc, Stephen R.
Durham, MDj, Mohamed H. Shamji, PhDj, and William W. Busse, MDk
aDepartment of Pediatrics, Johns Hopkins University School of Medicine, Baltimore
bDivision of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious
Diseases, National Institutes of Health
cRho Federal Systems Division, Chapel Hill
dDepartments of Medicine and Pediatrics, University of Texas Southwestern Medical School,
Dallas
eDepartment of Pediatrics, Cincinnati Children’s Hospital, Cincinnati
fNational Jewish Health and University of Colorado Denver School of Medicine, Denver
gDepartment of Medicine, Boston University School of Medicine, Boston
hDepartment of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago
iDepartment of Medicine, Henry Ford Health System, Detroit
jImperial College, London
kDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison
Abstract
H-PAAuthorManuscriptNIH-PAAuthorManuscript

• Sensitization with exposure to cockroach allergen contributes to asthma
morbidity.
• Lack of an immunodominantallergen, the complex patterns of IgE response to
multiple cockroach allergens and relatively low in potency of commercially
available extracts are the problems.
• The individual recombinant and natural cockroach allergens will facilitate the
diagnosis and the identification of specific allergens affecting each cockroach
allergic patient.
• Cockroach immunotherapy modulates immune responses and appears to provide
clinical benefit.
• Recent studies which immunotherapy with cockroach allergen is more likely to be
effective with SCIT, and provided the basis for larger-scale efficacy studies of
immunotherapy for cockroach allergy.

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