house dust mite allergy

House dust mite

AllergyLalita Tearprasert; M.D.

Scope

• Introduction

• HDM allergens and Cross-reactivity

• HDM & Respiratory allergic diseases

• Mechanisms of HDM allergen induced sensitization

• Diagnosis of HDM Allergy

• Preventive and Therapeutic Approaches for HDM Allergy

Introduction

• Major perennial indoor allergen cause Asthma, AR, AD

• 50 – 85% of asthmatics are typically HDM allergic

• Prevalence data for HDM allergen sensitization vary from 65 to130 million

persons (1-2%) in the general population worldwide

• Geographic variation

• In1967, Spieksma and Voorhorst established that the dust mite,

Dermatophagoides pteronyssinus, was an important source of house dust allergens in the Netherland

Thomas A.E. Plattes-Mills. Middleton's Allergy 8th Edition. 453-469.Gregory and Lloyd.Trends Immunol. 2011; 32(9): 402–411.

Phylum Arthropoda

Domestic mite: Any species of mite found in house

Dust mite:Family Pyroglyphidae

- Dermatophagoides

- Euroglyphus

Thomas A.E. Plattes-Mills. Middleton's Allergy 8th Edition. 453-469.

Storage mite(flour,grain, barn, hay):

Family Acaridae & Glycyphagidae

(Tropical mite : Blomia tropicalis)

J. Portnoy et al. / Ann Allergy Asthma Immunol 111 (2013) 465-507.

Domestic

mite

Family Pyroglyphidae• Dermatophagoides (Subfamily Dermatophagoidinae)

- Dermatophagoides pteronyssinus (Dp)/ European HDM- Dermatophagoides farinae (Df)/ American HDM

• Euroglyphus (Subfamily Pyroglyphinae)- Euroglyphus maynei (Em)

>> England, Europe, the southern United state>> Em frequently co-inhabits with Dp and Df in some geographical areas

>> Many patients sensitive Dp, Df are also sensitive to Em>> Extracts of Em for diagnosis and immunotherapy are not

commercially available

House dust mite

The two most common HDM species worldwide : Dp, Df

Fernández-Caldas et al. Chem Immunol Allergy, 2014, vol 100, 234–242.Morgan S. et al.Int Arch Allergy Immunol 2015;166:267–272.

• D. pteronyssinus (Dp) tends to be most abundant.

• Only a few countries have either predominantly D. pteronyssinus or D. farinae.

- Australia, New Zealand, England and Mauritius have D. pteronyssinus

with few other HDM

- Singapore has a bias to D. pteronyssinus but with B. tropicalis

- Most of South Korea has a bias to D. farinae especially in the northwest

- Italy also has D. farinae -biased

• In Asia; Singapore, Malaysia, Hong Kong and the Phillipines have

D.pteronyssinus as the dominant pyroglyphid HDM.

Thailand and Taiwan and have more D. pteronyssinus than D. farinae

Distribution of Dermatophagoides species

Wayne R Thomas. Asian Pac J Allergy Immunol 2010;28:211-24.

In Thailand

N.Malainual et al. Clinical and Expiramental Allergy ,1995, Volume 25, 554-560.

• Eight-legged, Sightless

• 0.3 mm. in length

• Absorbing water through Hygroscopic substance

extrude from leg joints

• Habitat with 3 key macromolecules derived from

organic debris

- keratin (human skin scales) --> food source

- cellulose (textile fibers)

- chitin (fungal hyphae and mite cuticles)


Caldereon, et al. J Allergy Clin Immunol. July 2015;136:38-48.

• Excrete fecal particles

- contain allergenic digestive enzyme

- chitinous peritrophic membrane (not waterproof)

- size 10-35 micron (similar to pollen grain)

- carry allergen 0.2 ng

- airborne and easily inhaled

Life cycle- Egg to adult : 1 month

- Adult living an additional 1-3 months.

- Adult females lay up to 40-80 eggs

• Temperature : 65-80°F (20-25°C)

• Relative humidity (RH) : 70-75%

>> carpets, sofas, mattresses, or clothing

Optimum growth condition

Thomas A.E. Plattes-Mills. Middleton's Allergy 8th Edition. 453-469.Yu SJ, et al.Asia Pac Allergy 2014;4:241-252.


• Environmental factors of temperature and RH is reflected in seasonal fluctuations

in dust mite numbers and allergen levels in different parts of the world.

• Summer is warm and dump so mite population can expand.

• The most important facilitative factor for mite growth is RH.

- Once humidity decreases below 50%, mite proliferation and survival

is decreased.

- Mites can survive for weeks before they die.

- As humidity falls, it may take months for mites to die and longer for

allergen levels to decrease in carpets, sofas, or mattresses.

- An elevated RH for as briefly as little as 1.5 hours per day (cooking, bathing),

the mite can survive. 2 to 3 hours per day, mites can reproduce.

HDM allergens

Gregory and Lloyd.Trends Immunol. 2011; 32(9): 402–411.

• Mite allergens are present in mite bodies, secretion and excretion

• Fecal particles contain the greatest proportion of mite allergen

• Airborne mite allergen is detected only during or shortly after

disturbance of dust. Fell rapidly after disturbance.

• Little or no airborne allergen (e.g., less than 1 ng/m3) is

present in undisturbed conditions.

• Indicate that mite allergen is predominantly airborne on

particles greater than 10 µm in diameter.

• Fecal particles become airborne and easily inhaled.




• Exposure to mite allergens is in the form of fecal particles contain - Mite-derived proteins

- Endotoxin derived from bacteria >> potent TLR-4 agonist

- Mite DNA and bacterial DNA (unmethylated) >> activate TLR-9. - Chitin peritrophic membrane >> Chitin and its breakdown products can act on

TLR-2 and dectin-1

Potential adjuvants

Mite Allergen Group

M. RAULF et al. Allergo J Int 2015; 24: 68–80. Fernández-Caldas et al. Chem Immunol Allergy, 2014, vol 100, 234–242.

33 groups

Major allergens (frequency of patients sensitized and amount of specific IgE)

- Group 1 (Der p 1 and Der f 1)

- Group 2 (Der p 2 and Der f 2)

• Allergens from mites include commonly encountered functions

of allergens from a wide variety of sources- Proteases (Group1, 3, 6, 9, 20)- Lipid-binding proteins (Group 2, 7, 13, 14)

- Contractile proteins (Group 10, 11, 16, 17, 24)

- Glycosidases and carbohydrate-binding proteins (Group 4, 12, 15, 18, 23) - Glutathione S-transferase (Group 8)

- Unidentified function

• Most mite allergens are enzymes

J. Portnoy et al. / Ann Allergy Asthma Immunol 111 (2013) 465-507.Rubaba Hamid Shafique, M.Phil et al. Allergy Rhinol 3: 74–90, 2012.

Mite Allergen functions

Group 1

Caldereon, et al. J Allergy Clin Immunol. July 2015; 38-48Schulz O. et al. J. Exp. Med. 1998, 271-275

Cysteine proteases

- Destroy the epithelial tight junctions

- Innate immune response :recognized by

PAR-2 and TLRs --> PAMPs

- Adaptive immune : Promote Th2

- Activating mast cells independently of IgE

• Glycoprotein 25 kDa, Heat-labile

• Peptidase enzyme/ Proteolytic enzyme

(Identity with plant enzyme papain)

• Location: Gut

• Der p1, Der f1

• Der p 1: significant role in IgE antibody responses

1.) Cleavage of CD23 (FCeRII on B cells) ----> IgE

2.) Cleavage of CD25 (IL-2R on T cells) ----> Th2 response

• Group 3 : Trypsin-like enzyme - also found in insect venoms

- Der p 3 quite similar to the cockroach Bla g 10

• Group 6 : Chymotrypsin• Group 9 : Collagenolytic serine protease

Group 3,6,9

Serine proteases

• Trypsin - Destroy the epithelial tight junctions

- Trigger PAR-2 ---> results in the initiation of multiple G-protein

coupled signaling cascades- Promote Th2


• Innate immune: TLR4 (on DCs, airway epithelium, and airway smooth muscle cells)

bind endotoxin

• Adaptive immune: Promotion of TH2

polarization and inflammatory cell recruitment

Group 2

• Glycoprotein 15 kDa, Heat-stable

• Molecular mimicry of MD-2 protein

(lymphocyte antigen 96)

• Lipid-transfer or lipid-carrying proteins

• Location: Intracellular

• Der p2, Der f2

MD-2 like

lipid-binding protein

Caldereon, et al. J Allergy Clin Immunol. July 2015; 38-48.J. Portnoy et al. / Ann Allergy Asthma Immunol 111 (2013) 465-507.

Associated with Oral mite syndrome

• Occurs because of shared similar or identical IgE-binding epitopes

• Der p highly cross-reactivity with Der f

- Group 2 allergens are very similar to each other in structure,

with greater than 90% sequence homology, indeed,

no mAb assays currently available can distinguish Der p 2 from Der f 2

• B. tropicalis cross-react partially with other dust mites

>> designated Blo t 5 because it has sequence homology with Der p 5

G. Reese et al.Int Arch Allergy Immunol 1999;119:247–258.Thomas A.E. Plattes-Mills. Middleton's Allergy 8th Edition. 453-469.

Cross-reactivity

Group10

Tropomyosin

• Muscle protein

• coiled- coil structure, two

parallel alpha-helical

• Location: Muscle

• Der p10, Der f10

• Invertebrates

- Crustaceans (shrimp, lobster,

crab, craw-fish)

- Arachnids (house dust mites)

- Insects (cockroaches)

- Mollusks (e.g. squid)

• 5% to 15% of patients who are

highly sensitized to dust mite also

are sensitized to crustaceans

G. Reese et al.Int Arch Allergy Immunol 1999;119:247–258.J. Portnoy et al. / Ann Allergy Asthma Immunol 111 (2013) 465-507.

• Found

- Invertebrate >> Allergic

- Vertebrate >> Non-allergic

• Shrimp (Pen i 1, Pen a 1, Met e 1) identity 81-90%

• Cockroachs (Per a 7, Bla g 7) identity 80%

• Other Crustacean

- Crab: Cha f 1

- Lobster: Pan s 1, Hom a 1 identity 81-90%

• Mollusk (Cra g 1, Tur c 1, Tod p 1)

• Helminth (Ascaris, Filaria and Anisakis simplex)

G. Reese et al.Int Arch Allergy Immunol 1999;119:247–258

Tropomyosin• Der p10, Der f10

Threshold level

• Most studies accept

- Sensitization threshold level 2 μg/g. of dust (100 mites/g.)

- Threshold levels for for developing symptoms

in already sensitized individuals 10 μg/g. of dust (500 mites/g.)

- For nonallergic children higher threshold level 20 μg/g. of dust

World Health Organization (WHO).Bull World Health Organ 1988;66:769-80.Thomas A.E. Plattes-Mills. Middleton's Allergy 8th Edition. 453-469.

HDM & Respiratory allergic diseases

1. Two-side monoclonal antibody (mAb) based enzyme

immunoassay (ELISA) -- --> Gold standard

- most common available : Der p1, Der f1/ Der p2, Der f2/ Blo t5

2. Guanine (the major nitrogenous excretory product of arachnids)

3. Mite count

Methods of estimating dust-mite allergens

A. Custovic.Allergy 1998; 53 (Suppl 48): 71-76

• Environmental assessment and exposure control of dust mites:

a practice parameter 2013

• Advise patients to minimize exposure of susceptible children to dust mite allergens

to decrease their risk of developing mite-specific IgE. Because intermittent

exposure to mite allergens can lead to sensitization. (Strength of recommendation: strong, A evidence)

• Advise patients to minimize exposure of dust mite sensitized children to dust mite allergens to decrease their risk of developing asthma and possibly rhinitis.

(Strength of recommendation: strong, A evidence)

Sensitization & Development respiratory disease

Sporik R et al. N Engl J Med (1990);323: 502-7.

Active asthma was very strongly associated with

both atopy & sensitivity to HDM

Significant relation between high levels of expose

and early onset of wheezing (P=0.001)

Casas et al.European journal of allergy and Clinical Immunology.Allergy 70 (2015); 820-827.

Early life exposure plays a role in the development

of sensitization

Lodge,et al.J Allergy Clin Immunol 2011;128:782-8.

• Birth cohort of 620 children

oversampled for familial allergy

• SPTs to 6 allergens at ages 6, 12, and 24 months

• Wheeze and eczema were recorded during

the first 2 years

• Current wheeze was recorded at age 12 years

• New-onset sensitization by 2 years or sensitization at both 1 and 2 years were both strong predictors

of wheeze at age 12 years

Lodge,et al.J Allergy Clin Immunol 2011;128:782-8.

HDM sensitization was associated with current wheeze at age 12 years

Danansuriya et al. World Allergy Organization Journal (2015) 8:19

• Students with current asthmawere having13 times

higher risk of atopy to HDM

compared to their healthy siblings

• House dust mite and the cockroach are

the most important aeroallergen

sensitizers in Thai allergic rhinitis

patients, since more than half the

patients were skin test positive to the

house dust mite and the cockroach.

• 85% of mite-sensitive patients were

skin test positive to both species of

Dermatophagoides, indicating

substantial cross reactivity.

Pumhirun et al.Asian Pac J Allergy Immunol (1997) 15: 183-185

• 2 Main route

1.) Innate immune system --> Epithelial cells, Dendritic cells

2.) CD4+ TH2 cells induce and IgE-dependent allergic response

Mechanism of HDM allergen induced sensitization


Innate epithelial cytokines

Dendritic cells

Th2


Innate immune system : Epithelial cell

Group 1(cystein protease): PAR-2

Group 2 (MD-2 like LBP): TLR-4

Endotoxin : TLR-4

B-glycan : Dectin-1

Chitin : TLR-2, Dectin-1

Mite&Bac. DNA : TLR-9

Potential enhancement of the allergic response by

HDM

Caldereon, et al. J Allergy Clin Immunol. July 2015;136:38-48.

Der p 1: significant role in IgE antibody responses

1.) Cleavage of CD23 (FCeRII on B cells) ----> IgE

2.) Cleavage of CD25 (IL-2R on T cells) ----> Th2 response

Group 1(cystein protease): PAR-2

Group 2 (MD-2 like LBP): TLR-4

Endotoxin : TLR-4

B-glycan : Dectin-1

Chitin : TLR-2, Dectin-1

Mite&Bac. DNA : TLR-9

• Skin testing and/or specific IgE

• Nasal provocation testing (NPT) : perennial AR due to HDM when the

patient history provides inconclusive information

Diagnosis of HDM allergy

M. RAULF et al. Allergo J Int 2015; 24: 68–80

• D. farinae ,D. pteronyssinus, Mite mix extracts are standardized.

• Commercially available in many country ex. the United States, Europe, Maxico.

• Content of extracts varies depending on whether purified mite bodies or total spent

culture is used as the source material

- Mite bodies greater than 99% purity and are almost exclusively used in the

United States >> 40 µg/mL of Der p 1 and 30 µg/mL of Der p 2

- Spent cultures containing adult mites, eggs, larvae, fecal particles, and culture medium are often used in Europe >> at least 10 times more group 1 than group 2

Dust mite extracts



1. ) Environment control

- Recommend avoidance for SPT positive to HDM

2. ) Immunotherapy - Subcutaneous (SCIT), Sublingual (SLIT)

Preventive and Therapeutic Approaches

Fernández-Caldas et al.History of Allergy. Chem Immunol Allergy, 2014, vol 100, 234–242.



Environmental control

Avoidance

1.) Physical

2.) Chemical

• A special mite-impermeable

membrane was used in PE and CE

group

• Regular bedsheets were applied to

all groups

• PE group : mattresses were

encased on tops and sides only

CE group : complete mattress

encasement was undertaken

• Mattress encasing with a special membrane was highly efficacious in the reduction of mite

allergen (90%).• Complete mattress encasing in a tropical environment does not offer any advantage over

partial encasing in the reduction of mite allergen

Vichyanond et al. Allergy 1999, 54, 736-741.

Cover mattresses and pillows with impermeable cover

• The ideal mite cover should have at least 2

important characteristics

1.) block the leakage of mite

allergens from the inside of the

bedding

2.) prevent mites from penetrating

through the covers in either

direction

Mahakittikun et al. J Allergy Clin Immunol 2006;118:1164-8.


• Environmental assessment and exposure control of dust mites: a

practice parameter 2013

- Woven microfiber fabrics with a mean pore size smaller than 10 micron

can effectively block passage of Der p 1 (Strong, B evidence)

- Dust mite allergens (Der f 1 and Der p 1) were decreased to below

detectable limits by fabrics with a pore size smaller than 10 micron



Remove carpets, stuffed animals, and clutter from bedroom

• Removing carpets is more effective in the long term than any currently available carpet

cleaning measure.

• Designing the house with polished floors and wooden or vinyl or leather furniture, to limit the

sites where mites can grow and to reduce dust collectors so as to make cleaning easier.



• The most effective way to manage reservoirs of mite allergens is to remove them completely

from the environment. That means removing carpets, drapes, and upholstered furniture and

sealing mattresses, box springs, and pillows in mite-impermeable covers



Wash bedding regularly 130° F

• 130°F (55°C) can kill mites and allergen removed by washing generally reappears within 1

month

• Washing bedding at 130°F (55°C) once weekly is effective

• Environmental assessment and exposure control of dust mites: a practice parameter

2013

- Most mites that are killed in the washing process die by drowning. Although higher temperature

kills slightly more mites.

- There is evidence that temperatures lower than 130°F are adequate, high temperature is

not necessary.

- Home hot water should be kept below 120°F prevent danger to children.

- Wash bedding weekly in warm water, without aiming for a specific and potentially dangerous

temperature. This will remove most, not all, mites and mite allergens. Clothing also should be

washed after use. (strong, B evidence)



• Vacuum weekly (wearing a mask) using vacuum cleaner with a double-

thickness bag or a high-efficiency particulate air (HEPA) filter.

• Regular (at least weekly) vacuuming is essential for preventing buildup

of mite allergens in homes with carpets.

• Vacuuming does not remove all live mites, mite allergens in the form of

fecal particles can be removed.

Vacuuming

Vacuuming



Reduce humidity

• Reduce humidity below 45% relative humidity (or 6 g H2O/ kg air)

• Environmental assessment and exposure control of dust mites:

a practice parameter 2013

- Advise patients that relative humidity in the home should be kept

between 35% and 50% to decrease the growth of dust mites (Strong, B evidence)

- Encourage dust mite-allergic patients to obtain and use a hygrometer to

measure humidity in their home. (Strong, D evidence)

J. Portnoy et al. / Ann Allergy Asthma Immunol 111 (2013) 465-507

Reduce humidity

• Remove excessive : Using a dehumidifier and/or air conditioning

- Dehumidifier needs to be emptied regularly or set to drain continuously,

and it should be located in areas where dampness is likely to occur.

- Air conditioners need to run long enough to remove sufficient moisture from the air to decrease RH.


• killing mites

• Benzyl benzoate Moist powder and foam.

- The active powder kills 90% of mites in culture within 12 hours

and 100% in 24 hours

- Reapplied at 2-3 month intervals



- Acaricides are not recommended for use on mattresses, particularly

given the likelihood of exposure to the chemical

- Limited efficacy at decreasing allergen levels

(moderate, B evidence)

Acaricides

Ex. Benzyl benzoate,pyrethroids, natamycin (an antifungal), pirimiphosmethyl



Treat carpets with benzyl benzoate or tannic acid

• Protein-denaturing agent

• Reduce allergen levels in house dust : 1% and 3% solutions

• Does not kill mites, so the effect can only be temporary. Reapplied at 1-2 week intervals

• TA was very effective at reducing mite allergen levels in dust, though it required up to 4

hours to exert its full effect.

Tannic acid

Woodfolk et al. Allergy Clin lmmunol. Volume 94, Number 1, 1994, 19-26.


Treat carpets with benzyl benzoate or tannic acid

• Environmental assessment and exposure control of dust mites: a practice

parameter 2013

- Do not recommend tannic acid for decreasing mite allergens in carpet

dust because it is only marginally effective : concentrations of tannic

acid as low as 0.1% were found to inhibit the ELISA assays

(Moderate, C evidence)

Immunotherapy

Akkoc et al. Allergy Asthma Immunol Res. 2011 January;3(1):11-20.

• Recommend 3 to 5 years

• Effective dose - SCIT : 7 mg of Der p 1 per dose for European extracts

500-2,000 AU per dose for US extracts

(US >> Der p1:Der p2 = 1:1, Europe >> Der p1:Der p2 = 10:1)

- SLIT : 4,200 AU containing approximately 70 mg of Der f 1 given daily

• Frequency of administration once maintenance is reached- SCIT : Ranged from weekly to monthly

- SLIT : Daily to 3 times per week

• No evidence to support giving lower doses more frequently or higher doses less

frequently to obtain similar efficacy

• Dust mite extracts are compatible with pollen and animal dander extracts and can be

mixed with fungal and cockroach extracts provided they are kept in glycerin at a

concentration of at least 10%

Immunotherapy


Practice parameter 2013

• Retrospective study

• 39 patients (23 boys,16 girls)

• Children with asthma and rhinitis who

were allergic to house dust mite

• 3 years of SLIT with 50 % Der p and

50 % Der f in a standardized extract

Conclusion

• SLIT is effective in children who have

allergic airway disease which cannot be

controlled effectively with allergen

avoidance measures only

Y Nuhoglu, et al. J Investig Allergol Clin Immunol 2007; Vol. 17(6): 375-378.

Cingi C. et al. Eur Arch Otorhinolaryngol. 2014.

• 186 patients with AR who had positive SPT for HDMs

• Administered SLIT using for 1 year

• Evaluation of the patients regarding

- symptom scores

- clinical findings

- Rhinitis Quality of Life Questionnaire (RQLQ)

• At baseline, 6 and 12 months of therapy.

HUI Y. et al. Expiramental and therapeutic medicine 7: 630-634, 2014.

• 90 asthmatic children (with or without

allergic rhinitis) with a mild to moderate

HDM allergy (aged, 5-14 years) were

recruited

• SCIT combined with standardized

management (ICS) for 36 months.

• Suggest that long-term SCIT may

alleviate asthma symptoms and reduce

the required dose of ICS.

In thailand

• A double blind, self-controlled study between the

SMAV and standardized commercial mite allergen

vaccine

• 17 normal Thai adult males and non-pregnant or non-

lactating females aged 18-60 years

Result

- No significant difference in wheal and flare

diameter

- Significant correlation between wheal diameter

- Suggested that SMAV could be used for SPT

instead of using the more expensive imported

commercial vaccine

Visitsunthorn, et al.ASIAN PACIFIC JOURNAL OF ALLERGY AND IMMUNOLOGY (2010) 28: 41-45.

Thank you

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