Page 1

Natural Course of House Dust Mite Allergy

Thomas A E Platts-Mills, FRS University of Virginia

Disclosures: We are grateful to NIAID AI-20565 and Thermo Fisher for grant support. Dr Platts-Mills is a consultant to IBT/Viracor


Natural course of house dust mite allergy

• Why is the dust mite “the best allergen in the world”? • Sensitivity to mite in the developing world is not related to asthma, but serum IgE antibody is low titer • A major effect of “hygiene” (clean water, antihelminthic drugs, and “homes”) is the development of high titer IgE antibodies • High titer IgE antibodies to mite establish the risk for asthma and dramatically increase the risk for acute episodes associated with rhinovirus infections


Mite Fecal Particles a Der p 1 ~ 0.2ng….. cysteine protease b,c Der p 2 ~ 0.1ng….. mimics MD2 d Mite DNA……….TLR-9 e Bacterial DNA......TLR-9 Endotoxin….…….TLR-4 and MD2 f Chitin……………..TLR-2 and Dectin 1 g

Tovey et al Nature 1982 a

a Tovey et al Nature 1982, 289: 592. b Gough et al J Exp Med 1999, 190:1897. c Wan et al J Clin Invest 1999, 104:123. d Trompette et al Nature 2009, 457:589. e Satinover et al JACI 2007 f Eisenbarth et al J Exp Med 2002, 196:1645. g Lee et al Current Op Imm 2008, 20: 684. Ribbon structure of Der f 1, Chrusz et al J Mol Biol 2009


Atopy, Mite Sensitization and Exposure to Dust Mites in Early Childhood as Risk Factors for Asthma at Age 11 Early* Current Asthma wheezing Never* Yes No only wheezed

Relative risk

Atopy at age 11

16/17 19/50

10/25

9/25 14.6 p<0.005

Mite sensitization at age 11 Exposure to >10Âľg Der p 1 at age 2

16/17 12/50

4/25

8/25 19.7 p<0.001

12/13 30/46

16/23

14/23

4.8 p=0.05

Current asthma = wheeze in the last year & bronchial reactivity to histamine. * Subgroups of no current asthma.

Sporik et al, NEJM 1990; 323: 502.


New Zealand: the attractive part of Australasia • Wheezing ~20%; mite sensitization dominates risk for asthma*. • From an ISAAC based study on 1,500 children we studied 112 with wheezing and 112 controls.$ • Of the 55 with asthma living in a home with a cat, 34 were sensitized to mite, but not cat. • Cat ownership (50%) was associated with decreased sensitization to cat, but had no effect on mite IgE ab. *Sears et al., Clin. Exp. All. 1989: 19:419; *Peat, Li & Woolcock, JACI 1999: 103:1; $Erwin, Crane, Wickens, Barry et al., JACI ’05: 115:74 .


Specific IgE Antibody Titers in New Zealand

(n=112)

children with wheezing (%)

25

ryegrass cat dog Aspergillus D.pteronyssinus

20

15

10

5

(n=112)

children without wheezing (%)

0

0.35-

0.7-

3.5-

17.5-

50-

>100

15

Erwin, Crane Wickens et al JACI 119;359 â&#x20AC;&#x2DC;07.

10

5

0

0.35-

0.7-

3.5-

17.5-

50-

Range of IgE ab response (IU/ ml)

>100


Ghana: Addo Yobo EO et al, Thorax 1997.

Gabon: Van den Biggelaar A et al, Lancet 2000.

South Africa: Weinberg E, JACI 2000.

Ethiopia: Yemaneberhan H et al, Lancet 1997 and 2001.

Kenya: Perzanowski M, Ng’ang’a L, Odhiambo J et al, J Peds 2002.


Hygiene in action: IgE antibodies to dust mite in sera from wheezing (â&#x2014;&#x2039;) and non-wheezing (â&#x2014;?) children attending two schools one mile apart in the city of Kumasi, Ghana

Ghana

Both the prevalence and titer of IgE antibodies to mite were strongly associated with asthma in the affluent school, but not in the poor school.

Addo-Yobo, Stevens James, Platts-Mills, and Custovic. Clin Exp Allergy; 2011.


San Jose, Costa Rica: Manuel Soto-Quiros, Lydiana Avila, and Peter Heymann

Esmeraldas, Ecuador: Phil Cooper

Soto-Quiros et al. JACI june 2012 Cooper et al. Clin Exp All in press 2012


San Jose, Costa Rica:

*Values <3.5 IU/ml classified as negative #Histories of wheezing Esmeraldas, Risk Factors for Wheezing in Esmeraldas Province, Ecuador (n=290)

Ecuador: Phil Cooper IgE Positive

IgE Negative

Specificity of IgE

Odds Ratios Wheeze/No Wheeze#

Mite > 0.35 IU/ml

52/41

89/108

1.5 (0.9-2.5)

Mite â&#x2030;Ľ 3.5 IU/ml*

20/4

121/145

6.0 (2.0-18.0)**

Alpha-Gal > 0.35 IU/ml

55/55

89/96

1.1 (0.7-1.7)

Ascaris > 0.35 IU/ml

121/101

22/50

2.7 (1.5-4.8)**


High Titers of IgE Ab to Dust Mite Allergen and the Risk for Wheezing Among Asthmatic Children, in San Jose, Infected with Rhinovirus*

Odds ratio for wheezing based on positive tests for RV and titers of IgE ab(IU/ml) to mite. <0.35 IU/ml

Titer of IgE ab to mite:

≥ 17.5 IU/ml

0.35-17.4 IU/ml PCR +

n

PCR neg

95

5

4

[2/2]

8

Stable asthma

63

12

2 [0/1]

12

5 [1/2]

31

1 [0/1]

Control

123

60

13 [6/4]

31

2 [1/1]

14

2 [1/1]

186

73

15 [6/5]

43

7

45

3

Current Wheeze

Non-wheezing children Odds Ratio

PCR + [A/C]

3.89, p=0.07

PCR neg

[A/C]

16

[3/10]

[2/3]

12.3, p<0.001

PCR neg

20

PCR + [A/C]

42

[8/30]

[1/2]

31.5, p<0.001

Non-wheezing children, n=186, includes 63 with stable asthma ands 123 children entering the ER without any history of asthma *Soto-Quirós M, Avila L, Platts-Mills T, Hunt J, Erdman D, … and Heymann PW.

J Allergy Clin Immunol. June 2012


% Children with Positive PCR for RV, HEV, or RSV

Percent of children by current wheeze status with positive PCR for rhinovirus (RV), enterovirus (HEV), or RSV in San Jose, Costa Rica

100% p<0.001

80%

80%

February (dry): RV p<0.001

October (rainy): RV

73%

October (rainy): HEV 60%

October (rainy): RSV 40%

20%

14%

14% 10%

9%

0%

Current Wheeze N=

44

51

Stable Asthma 35

29

Control 57

69


Probability of Current Wheeze

A

Rhinovirus negative RV Negative

1.0

1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0.0

0.0 1

10

100

IgE to Mite (IU/ml)

Rhinovirus RV Positivepositive

B

1000

1

10

100

IgE to Mite (IU/ml)

Soto-QuirĂłs, Avila, â&#x20AC;Ś..and Heymann. JACI June 2012.

1000


Cat extract (and IgE assays) can be made from dander and/or epithelium, which contain many different proteins. Dander Fel d 1 18 kDa (uteroglobin)

Epithelium Fel d 2 69 kDa (cat albumin)

Tick Bites** Alpha-gal on a a protein (e.g., cat IgA*) 200kDa

69 kDa

Cross reacts Pork-albumin

Cross reacts with Lions!

Cross reacts with all Non-primate mammals

*Gronlund H, et al. The carbohydrate galactose-Îą-1,3-galactose is a major IgE-binding epitope on cat IgA. JACI. 2009; 123:1189. **Commins et al JACI 2011

Cat IgA is Fel d 5. See www.allergen.org.


H h

• Patients presenting with anaphylaxis, or recurrent urticaria who have IgE specific for alpha-gal have normal lung function no increase in asthma symptoms and normal FeNO. • This ectoparasite induced IgE response cross reacts with cat, can make major contributions to total IgE, and appears to be a model for IgE responses to parasites that do not create or increase the risk for asthma. • The results explain previous enigmatic IgE antibodies to cat in a Kenyan village and in the ED in Virginia. Commins et al AJRCCM 185:723. 2012


Commins et al. AJRCCM. 2012;185:723.


Data on serum from 400 seven-year-old children in the Project Viva (Boston), who were randomly selected at birth. • Principal investigator: Matthew Gillman • Co-principal investigator Emily Oken • Co-investigators related to asthma and allergy: Supinda Bunyavanich, Augusto Litonjua, and Diane Gold (Harvard) • Serum assayed at UVA: Lisa Workman

Fairy circle, Charlottesville October 2011


140

Positive high titer IgE antibodies specific to indoor, outdoor, or food allergens among 616 seven year olds from the Viva cohort

30% 120

number of children

100

IgE IU/ml >50

20%

IgE IU/ml 17.5 - 50

80

60

40

IgE IU/ml 3.5 â&#x20AC;&#x201C; 17.5

% values are the total number of sera with IgE antibody >0.35 IU/ml

19% 14% 13% 11%

20

8%

5%

13%

9%

8% 16%

0

Indoor

Outdoor

Foods


Conclusions and Questions • In Africa and South America there are children living in “prehygiene” environments with high prevalence of enteric and helminth infections. • These children may have positive IgE antibodies for mite but the titer is generally low (<3.5 IU/ml) and total IgE is high. • The “post-hygiene” condition is characterized by low average total IgE ,high specific IgE which correlates with asthma. • Changes typical of “post-hygiene” occurred in London ,NYC and Berlin in 1920, so what happened in 1960? • Are we still getting cleaner and is allergy still increasing particularly peanut?


Colleagues: 2006-2012 University of Virginia Scott Commins Libby Kelly Peter Heymann Anubha Tripathi Jake Hosen Sharma Satinover Hayley James Lisa Workman Josh Kennedy

Elizabeth Erwin/Ohio Matt Perzanowski/Columbia Gus Litonjua, Harvard Diane Gold, Harvard

Africa and Europe Eva Ronmark, Sweden Bo Lundback, Sweden Lucy Nâ&#x20AC;&#x2122;Ganga, Kenya Joseph Odiambo, Kenya Adnan Custovic, Manchester Alpha-Gal Research Christine Chung, Nashville Beloo Mirakhur, BMS Qinwei Zhou; ImClone Tina Hatley, Bentonville Phil Cooper Ecuador & Liverpool Manuel Soto-Quiros Costa Rica.

And the many colleagues who have enrolled or referred adult and pediatric cases with the alpha-gal syndrome.


Have specific IgE antibodies continued to increase either in prevalence or titer? • Indoor allergens since 1960? • Peanut in the last ten years? …and if so, why? If oral route is tolerogenic and sensitization occurs through the skin#, then delaying oral exposure to age 2 years may increase sensitization. Has skin changed (i.e., become more permeable) because of daily baths with detergents or antibiotic* soaps for infants? # Lack G, et al. NEJM 2003;348:977. Du Toit G, et al. JACI 2008;122:984. Savage J et al. JACI 2012;130:453. *Triclosan

Arachis hypogaea

Ara h 2


Changes in IgE ab to Alpha-gal (IU/ml) and in Total IgE (IU/ml) after multiple bites from larval ticks.

*

10/26/06 5/21/07 10/9/07 11/6/07 IgE to Alpha-gal 0.49 16.9 48.3 130 Total IgE# 127 199 350 532

2/9/09 33 360

→ Several bites from adult ticks May ‘07 → Multiple bites (~200) from seed ticks August ’07 Serum IgE ab assays 5/14/08: Cat 38, Dog 44, Beef 39, Pork 37.5; Chicken, Turkey, Cod, Dust Mite, Roach and Ragweed all <0.35 IU/ml #Total

IgE of this subject had been consistently less than 200 IU/ml since 1980.

Odocoileus virginianus

A.americanum

T P-M Aug 7th 2007


Stockholm, Sweden: Marianne van Hage

Borstel, Germany: Uta Jappe

Nancy, France: Anne Moneret-Vautrin, Sandrine Jacquenet

Berlin, Germany: Jorg Kleine-Tebbe


A Reactions to Cetuximab

B

Rocky mountain spotted fever

Incidence rates (per 1,000,000 persons) 0 0.1-0.9 1.0-9.9 10.0-14.9 15.0+

C

D

Delayed anaphylaxis to beef

Spread of the lone star tick


Crude Infectious Disease Mortality Rate in the United States from 1900 - 1996

Flu

Water Chlorination Salk Vaccine.

HIV Penicillin

Armstrong, G. L. et al. JAMA 1999;281:61-66.


“ The Asthma Epidemic” Australia, NZ, UK. ….>20% (and Harlem NYC)

Germany, Sweden, Spain… …<10% Prevalence of Asthma: from Eder, Ege and Von Mutius: ..N E J Med 355;21 2006


School children age 10-11 in Kenya (Kabati and Thika), or Atlanta, Georgia.

Height (cm) Total IgE (IU/mL)

FEV1 liters FEV1/FVC % IgE to Ascaris IgE to Cat %Body fat..

GM

Kabati (rural) n=131

Thika n=126

Atlanta n=50

137

135

150

1,055*

106

94

1.66

1.60

2.1*

95%

95%

89%*

74%*

36% 30% 17.4

8% 10% 19.8

70%* 15.5

Perzanowski ; Ng’ang’a; Carter, Odhiambo et al. J Pediatr 2002;140:582. Carter, Perzanowski, A Raymond, et al. JACI 2001; 108:732.


Natural course of house dust mite allergy

• Why is the dust mite “the best allergen in the world?” • Sensitivity to mite in the developing world is not related to asthma, but serum IgE antibody is low titer • A major effect of “hygiene” (clean water, antihelminthic drugs, and “homes”) is the development of high titer IgE antibodies • High titer IgE antibodies to mite establish the risk for asthma and dramatically increase the risk for acute episodes associated with rhinovirus infections


Rural / Urban Comparisons in Ethiopia First Study: Skin tests only related to asthma in the Urban area. Positive skin tests n â&#x20AC;&#x153;Asthmaâ&#x20AC;? n Odds ratio for asthma Urban 2,372 98 (4.1%) 88 11 (6.4-18.9) Rural 990 12 (1.2%) 111** ** None of the skin test positive individuals reported symptoms. Second Study:# Worm load for hookworm but not Ascaris was inversely related to the risk of asthma: O.R. 0.48 (C.I. 0.3-0.8). Conclusions: In the rural area the parasite load may interfere with the relationship between allergy & asthma. In Jimma mite sensitization and exposure strongly related to asthma, i.e. Western model. Yemaneberhan, et al, Lancet 1997, 350:85;

#

Scrivener et al, Lancet 2001, 358.


Natural course of house dust mite allergy

• Why is the dust mite “the best allergen in the world?” • Sensitivity to mite in the developing world is not related to asthma, but serum IgE antibody is low titer • A major effect of “hygiene” (clean water, antihelminthic drugs, and “homes”) is the development of high titer IgE antibodies • High titer IgE Ab to mite establish the risk for asthma and dramatically increase the risk for acute episodes associated with rhinovirus infections


Should physical activity and full expansion of the lungs be an objective of treatment or a normal part of the treatment for asthma?


Cat extract (and IgE assays) can be made from dander and/or epithelium, which contain many different proteins. Dander Fel d 1 (uteroglobin)

18 kDa

Epithelium Fel d 2 (cat albumin)

Alpha-gal attached to a protein (e.g., cat IgA*)

69 kDa

>200 kDa *Gronlund H, et al. The carbohydrate galactose-Îą-1,3-galactose is a major IgE-binding epitope on cat IgA. J Allergy Clin Immunol. 2009; 123:1189-91.

n.b. Cat IgA is Fel d 5w. See www.allergen.org.


Have specific IgE antibodies continued to increase either in prevalence or titer? • Indoor allergens since 1960? • Peanut in the last ten years? …and if so, why? 1. If oral route is tolerogenic and sensitization occurs through the skin#, then delaying oral exposure to age 2 years may increase sensitization. 2. Has skin changed (i.e., become more permeable) because of daily showers and daily baths for infants? # Lack G, et al. NEJM 2003;348:977. Du Toit G, et al. JACI 2008;122:984.

Arachis hypogaea

Ara h 2


Colleagues: 2006-2011 • • • • • • • • • • • • • •

Scott Commins; UVA. Jake Hosen; UVA. Sharma Satinover; UVA. Christine Chung;. Beloo Mirakhur; BMS. Qinwei Zhou; Imclone. Eva Ronmark. Sweden. Judith Woodfolk; UVA. Diane Gold, Boston. Tina Hatley; Arkansas. Lucy N’Ganga,Kenya Joseph Odiambo,Kenya Elazabeth Erwin, Ohio Matt Perzanowski,NYC

We are grateful for support from NIH grants AI-20565. U19-070364; DE017982 and to Bristol-Myers Squibb (BMS), ImClone Systems and Phadia..

Daisy Platts-Mills MD 1868-1954


San Jose , Costa Rica, 2009-2012 Manuel Soto Quiros, Lydiana Avila, & Peter Heymann


The Central Problem with hygiene as an explanation for the rise of asthma. =Clean water, universal wearing of shoes, helminth eradication, and separation from farm animals occurred in New York, Boston, Munich and London by 1920. =Rise in asthma didnâ&#x20AC;&#x2122;t start until 1960, although the rise in hay fever had started much earlier! Thus rise in allergic disease might well reflect changes in hygiene early in the 20th century but the rise in asthma requires a different explanation. Are changes still occurring today, ie is hygiene still getting better (ie worse) and if so how?


Matt Perzanowski and friends in Thika, North of Nairobi, Kenya

What is the essence of hygiene?â&#x20AC;ŚClean water, control of helminth infection and shoes.


Clemens von Pirquet used the word allergen in 1906 to describe all foreign antigens, but to include those substances that “induce supersensitivity without immunity.” • What did he mean by “without immunity?” • Absence of: i. Delayed hypersensitivity skin tests ii. Serum precipitins iii. Complement fixation

See Introduction to Prausnitz and Küstner, 1921.


Three major assumptions about food allergy will have to change : i) Onset of allergy to red meat is rare in adults. ii) IgE mediated reactions to food occur within one hour. iii) IgE antibodies to oligosaccharide epitopes are not relevant.


• Living on a farm in the first year of life decreases the risk of asthma and atopy • Diversity of microbial exposure† was inversely related to risk of asthma: – PARSIFAL study: odds ratio 0.62 (95% CI 0.44-0.89) – GABRIELA study: odds ratio 0.86 (95% CI 0.75-0.99)

• Certain organisms were more significant, including Listeria, Bacillus sp., Corynebacterium, and also the fungal taxon Eurotium (odds ratio 0.37, 95% CI 0.18-0.76) †Mattress

dust was screened for DNA to of environmental bacteria, many of which are not identified by culture


Modifiable Risk Factors for Asthma Admission in Children Manchester, UK. Asthma Admission [AA] (n=82)

Stable Asthma [SA] (n=82)

Inpatient Control [IC] (n=82)

Cat Owner

30% 18%

35% 25%

9% 25%

0.5 1.0

0.04 0.42

Total IgE (IU/mL)

439

183

56

0.1

<0.001

IgE to Mite IgE to Cat

20.3 1.6

5.2 1.0

0.8 0.39

0.1 0.4

<0.001 0.02

Mite IgE + Exposure

57%

43%

24%

0.1

<0.001

Cat IgE Exposure

11%

11%

0%

1.0

---

Any Allergen + HRV

29%

2.4%

1.2%

0.002

0.002

Hay Fever

* Conditional logistic regression p-values.

AA vs. SA* AA vs. IC*

Murray et al. Thorax 2006. 61:376.


Relationships between IgE Antibodies and Wheezing or Medication Usage Allergen Cat Dander

IgE Titer by Classâ&#x2030;

Odds Ratios*

Negative

I, II

III-VI

Wheezing

78/666

23/66

44/86

3.8 (2.6-5.5)

Medication

73/671

24/65

49/81

4.6 (3.2-6.6)

Wheezing

81/680

22/64

40/71

3.9 (2.6-5.6)

Medication

76/685

27/59

41/70

4.8 (3.3-6.9)

Wheezing

84/689

25/70

36/59

3.9 (2.7-5.7)

Medication

79/694

27/68

41/54

4.9 (3.4-7.1)

Wheezing

97/724

15/60

33/34

3.8 (2.5-5.7)

Medication

96/725

15/60

36/31

4.2 (2.8-6.3)

Wheezing

72/644

22/71

51/103

3.8 (2.6-5.4)

Medication

66/650

25/68

56/98

4.8 (3.3-6.9)

Wheezing

52/525

19/89

74/204

3.2 (2.2-4.6)

Medication

47/530

16/92

84/194

3.9 (2.7-5.7)

Fel d 1

Dog

Horse

Any Mammal

Any Allergen

Titer of IgE antibody was significantly associated with both wheezing and medication use.


High Titers of IgE Antibody to Dust Mite Allergen and the Risk for Wheezing Among Asthmatic Children Infected with Rhinovirus: San Jose, Costa Rica Rhinovirus Negative RV Negative

Probability of Current Wheeze

A 1.0

1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0.0

0.0 -0.5

0.0

0.5

1.0

1.5

2.0

2.5

IgE to Mite [log10(IU/ml)]

Rhinovirus Positive RV Positive

B

3.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

IgE to Mite [log10(IU/ml)]

Soto-Quiros M, Avila L, Erdman D, Carper H, Murphy D, James H, Platts-Mills T, â&#x20AC;Ś, Heymann P. 2012; submitted.


San Jose, Costa Rica: Manuel SotoQuiros, Lydiana Avila, and Peter Heymann

Esmeraldas, Ecuador: Phil Cooper

Risk Factors for Wheezing in Esmeraldas Province, Ecuador (n=290) IgE Positive

IgE Negative

Specificity of IgE

Odds Ratios Wheeze/No Wheeze#

Mite > 0.35 IU/ml

52/41

89/108

1.5 (0.9-2.5)

*

20/4

121/145

6.0 (2.0-18.0)**

Alpha-Gal > 0.35 IU/ml

55/55

89/96

1.1 (0.7-1.7)

Ascaris > 0.35 IU/ml

121/101

22/50

2.7 (1.5-4.8)**

Mite â&#x2030;Ľ 3.5 IU/ml

*Values <3.5 IU/ml classified as negative #Histories of wheezing


Should physical activity and full expansion of the lungs be an objective of treatment or a normal part of the treatment for asthma?


Contrast Between Exposure to Dust Mite or Cat Allergens and the Relevant Immune Responses 40

30

Dust Mite [and cockroach] IgE + IgG Cat IgG

Cat IgG

20

A 10

B Cat IgE 0 0.01

0.1

1

10

Airborne Allergen Exposure ď ­g/day The dashed line indicates the approximate value of 20 ď ­g Fel d 1/g floor dust or the presence of a cat. Editorial Clin Exp All April 2002, Custis et al. Clin Ex All.2003


Mean (GM) total IgE values in sera from 18-year-olds in Norrbotten, Sweden.

IgE antibodies to cat, dog, or horse Positive

Negative

No positive IgE assay

Asthma n =145

209 IU/ml n=72

23.2 IU/ml n=73

17.1 IU/ml n=53

No Asthma n =816

128 IU/ml n=164

24.8 IU/ml n=652

18.1 IU/ml n=522


â&#x20AC;&#x153;Remember when we used to have to fatten the kids up first?â&#x20AC;?


Wheeze

Stable Asthma

Control

42 34 29

40

25

20

18 13

≤0.35 0.36-17.49 ≥17.5

N=

10

23

60

9

≤0.35 0.36-17.49 ≥17.5 ≤0.35 0.36-17.49 ≥17.5 13

18

32

71

31

16

Soto-Quirós, Avila, Platts-Mills, et al. J Allergy Clin Immunol. Revision requested.


In 1979, Jeremy Cogswell in Poole, Dorset started a birth cohort of 85 children to study the role of viral infections in the development or exacerbation of asthma

â&#x20AC;˘ That objective failed completely because the virologists of the time could not grow viruses from the children and they did not have PCR â&#x20AC;˘ We (i.e., Susan Wilkins and I at first, then Richard Sporik and Steve Holgate) co-opted the study and showed: I. Very strong association between sensitization to mite and asthma at age 10 years II. Good evidence that mite allergen in the house early in life increased risk for sensitization and asthma Sporik, et al. NEJMed 1990. Sporik, et al. House dust mite exposure as a cause of asthma. CEA1992.


Modifiable Risk Factors for Asthma Admission among Children in Manchester, UK. Asthma Admission [AA] (n=82)

Stable Asthma [SA] (n=82)

Inpatient Control [IC] (n=82)

Cat Owner

30% 18%

35% 25%

9% 25%

0.5 1.0

0.04 0.42

Total IgE (IU/mL)

439

183

56

0.1

<0.001

IgE to Mite IgE to Cat

20.3 1.6

5.2 1.0

0.8 0.39

0.1 0.4

<0.001 0.02

Mite IgE + Exposure

57%

43%

24%

0.1

<0.001

Cat IgE Exposure

11%

11%

0%

1.0

---

Allergen + HRV

29%

2.4%

1.2%

0.002

0.002

Hay Fever

* Conditional logistic regression p-values.

AA vs. SA* AA vs. IC*

Murray et al. Thorax 2006. 61:376.


Relevance of Rhinovirus and allergy to acute asthma in US and UK; Duff et al, Pediatrics. 1993 92:535. Rakes et al, AJRCCM. 1999 159:785. Heymann et al. JACI. 2004 114:239. Murray et al. Thorax. 2006 61:376.


Table IV. Odds ratio for wheezing based on positive tests for RV and titers (IU/ml) of IgE antibodies (ab) to dust mite (D. pteronyssinus).

Titers (IU/ml) of IgE ab to mite:

<0.35

≥ 17.5

0.35-17.4

n

PCR -

PCR +

PCR -

PCR +

PCR -

PCR +

Current Wheeze

95

5

4†

8

16

20

42

Stable asthma

63

12

2

12

5

31

1

Control

123

60

13

31

2

14

2

186

73

15

43

7

45

3

Non-wheezing children# Odds Ratio*

3.89 [0.9-16] p=0.07

12.3 [3.8-39] p<0.001

31.5 [8.3-108] p<0.001

*Odds ratio for wheezing among RV (real-time PCR) positive compared to negative subjects Soto-Quirós, Avila, Platts-Mills, Erdman, …, Heymann. High titers of IgE antibody to dust mite allergen and the risk for wheezing among asthmatic children infected with rhinovirus. JACI. June 2012.


Costa Rica: Titers of allergen-specific IgE antibody (wheezing children 7-12 years; n=96)

1000

Titer of IgE (IU/ml)

100

25 12 10

1.8

2.4

1.6

1.4

0.9

1

1.8

1.3

1.4

<0.35

A

16

11 gr ia ah

og

25 D

er gi llu s

ar rn lte A

*GM values (in blue) include only children whose titers were â&#x2030;Ľ 0.35 IU/ml

x 82

x 77

B

12

ia

is ar sc A

x 69

at

4

42

x 81

C

x 88

sp

38 er

.g er m B

ia m

x 53

x 58

53

90 B lo

.p te D

x 44

am

93 r

0.1 % Positive:

x9

P.

x9


Molecules

Proteins: Que a 1

Proteins: Lol p 1

Molecules Glycosylation: Mux f 3 Molecules

Molecules

Proteins: Der p 1, 2,…14

Proteins: Fel d 1, 2,…8

Glycosylation: Alpha-Gal


Molecular structure of proteins in the same family as Der p 1: A) Der p 1 (dust mite cysteine protease), B) human cathepsin K, C) falcipain-2 from Plasmodium falciparum, and D) thiol proteinase from Staph aureus V-8. Images by permission of Maksymilian Chruszcz at the University of Virginia. See Platts-Mills and Woodfolk Immunological Reviews 2011


Allergy Asthma Proc. 2012;33:110.

• Severe allergic reaction occurring within one hour after eating shrimp, bacon, and grits (cornmeal) – initial serum assays negative • Skin test positive to the grits he ate but negative for fresh box! • Microscopy identified extensive contamination with D. farinae; IgE to D. farinae: 92.3 IU/ml April 2012: letter to editor enquired about possibility of tropomyosin cross-reactivity between shrimp and mite in this case • ISAC analysis (Dr. Robert Hamilton, Johns Hopkins) showed Der f 2: 42.9, Der p 2: 27.5, Blo t 5: 0.72, and all tropomyosins negative Conclusion: severe anaphylactic reaction to oral mite allergen in a patient with IgE antibodies to the relatively heat stable group 2 allergens


IgE antibody and group of subjects testing positive for human enterovirus (HEV) or respiratory syncytial virus (RSV) Specific IgE Antibody Titers Virus

HEV*

RSV

Group

Total IgE

FENO (ppb)

Cockroach

Dpt

Df

Bt

Cat Dander

Current Wheeze

<0.35

94.7

53.1

1.20

<0.35

<0.35

591

12

Current Wheeze

<0.35

3.67

2.31

<0.35

<0.35

<0.35

100

31

Stable Asthma

0.64

8.96

4.90

2.98

<0.35

<0.35

273

26

Current Wheeze†

1.77

782

415

558

<0.35

0.93

4712

14

Current Wheeze

<0.35

2.52

19.4

89.3

<0.35

4.11

769

24

Current Wheeze

<0.35

651

362

22.5

17.4

<0.35

1365

62

Current Wheeze

<0.35

2.31

1.32

6.77

<0.35

<0.35

181

22

Control

<0.35

12.5

7.47

3.61

<0.35

0.37

119

31

Current Wheeze

<0.35

<0.35

0.59

0.68

<0.35

<0.35

144

5

Current Wheeze

0.71

77.9

34.0

5.84

<0.35

<0.35

414

29

Current Wheeze

0.54

19.8

7.96

3.82

<0.35

<0.35

890

14

Current Wheeze

<0.35

25.0

6.48

130

10.1

2.99

543

48

Current Wheeze‡

0.47

<0.35

<0.35

<0.35

<0.35

<0.35

54.8

19

Current Wheeze

1.11

1.08

0.72

<0.35

<0.35

<0.35

460

11

Current Wheeze

<0.35

186

75.1

23.9

<0.35

0.61

476

29

Current Wheeze

<0.35

12.3

11.0

30.3

<0.35

<0.35

102

20

Current Wheeze

<0.35

192

78.4

38.8

<0.35

<0.35

638

6

Ascaris

IgE ab results of class 4 or above (≥ 17.5 IU/ml) are shown in red


Allergen Exposure, Sensitization and Asthma among Middle School Children: A Population-based (n= 1,621), Case Control Study Atopic children Asthma among the children Âľg/g specifically sensitized## Sensitized Not Odds ratio ______________________________________________________________________ Mite* < 0.2-0.6 22/56 7/22 8/70 3.6 (0.98-13) (Group 1)

0.62-10.0 10.2-155

Cat* (Fel d 1)

< 0.5-1.9 2.0-23.0

26/54

8/26

8/76

4.0 (1.14-14.2)

19/40

8/69

6.9 (2.4-20)

15/56

8/15

17/92

5.0 (1.4-18)

23/54

8/23

10/74

3.4 (1.01-11.5)

40/54**

23.4-920 11/54ns 6/11 11/88 8.4 (1.8-39) ______________________________________________________________________ * Highest concentration in the house in Âľg/g Group 1 dust mite or Fel d 1. # ns Chi square test for trend on 6 exposure categories. ** p< 0.001 p= 0.3 Data from: Sporik et al. AJRCCM 1995,151:1388; Squillace et al. AJRCCM 1997, 156:1760; Sporik et al., Thorax 1999, 54:675.


Specific IgE Antibody Titers in Sweden

(n=728)

children without wheezing (%)

(n=69)

children with wheezing (%)

25

timothy grass cat dog birch D.pteronyssinus

20

15

10

5

0

0.35-

0.7-

3.5-

17.5-

50-

>100

0.35-

0.7-

3.5-

17.5-

50-

>100

15

10

5

0

Range of IgE ab response (IU/ ml)


Relevance of Immune Responses to Cat Allergens in a MiteFree Area of Northern Sweden: Kiruna, Lulea and Piteรถ Antibodies to Cat, Risk of Asthma and Total IgE

n

โ€ข

Total IgE IU/mL Risk for Asthma

None

514

20.4 (18-23)

1.0

IgG only

100

19 (14.6-26)

0.9 (0.53-1.6)

IgE > 0.35 183

86 (70-106)

4.7 (2.8-7.1)

Perzanowski, Ronmark, Lundback , et al., 2009


Highest IgE Class to Mammalian Allergens (Cat, Dog, or Horse) vs. Medication Use in the Past 12 Months 100%

Kiruna N=961 Age 18 yr

90% 80% 70%

Medications Daily - yellow Every Day Often - blue Often Sometimes - red Sometimes Never Never - grey

60% 50% 40% 30% 20% 10% 0% Negative N = 716

0.35-

0.7-

3.5-

17.5-

50-

100-

30

63

80

41

15

18

IgE antibody (IU/ml)


1000

Alpha-gal specific titers

1000

Alpha-gal specific IgE (IU/mL)

Commins et al AJRCCM 2012

100

100

10

10

1

1

0.35

•x8

Number <0.35 0.1

• x 13

• x 58

• x 55

• x 175

Asthma (N = 68)

Controls (N = 59)

Random controls (N = 217)

0.1

Cat in home No cat in home (N = 96) (N = 112) Anaphylaxis, urticaria, or angioedema subjects

Clinic subjects

Limit of detection


Norrbotten, Sweden 1000

199/219

9/127

r =0.92; p<0.001

100

Fel d 1 (IU/ml)

Fel d 1 (IU/ml)

1000

Kabati, Kenya

10

Chi square for asthma p<0.001

1

0.1

100

10

1

0.1

0.1

1

10

100

0.1

1000

1

100

1000

Cat Epithelium (IU/ml)

Cat Epithelium (IU/ml) 1000

IgE to Alpha-Gal (IU/ml)

1000

1/233 Alpha Gal (IU/ml)

10

100

10

1

0.1

97/127 100

r =0.77; p<0.001

10

No relationship to asthma

1

0.1

0.1

1

10

100

Cat Epithelium (IU/ml)

1000

0.1

1

10

100

Cat Epithelium (IU/ml)

1000


Esmeraldas,Ecuador Phil Cooper

Risk Factors for Wheezing in Esmeraldas Province, Ecuador (n=290) IgE Positive

IgE Negative

Specificity of IgE

Odds Ratios Wheeze/No Wheeze#

Mite > 0.35 IU/ml

52/41

89/108

1.5 (0.9-2.5)

*

20/4

121/145

6.0 (2.0-18.0)**

Alpha-Gal > 0.35 IU/ml

55/55

89/96

1.1 (0.7-1.7)

Ascaris > 0.35 IU/ml

121/101

22/50

2.7 (1.5-4.8)**

Mite â&#x2030;Ľ 3.5 IU/ml

*Values <3.5 IU/ml classified as negative #Histories of wheezing


Positive high titer IgE ab to indoor, outdoor, or food allergens among 400 seven-year-olds from the Viva cohort .

90

31% 80

IgE IU/ml >50 70

Number of children

IgE IU/ml 17.5-50 60

20% IgE IU/ml 3.5-17.5

50

% values are the total number of sera with IgE antibody >0.35 IU/ml

40

30

16%

20

10

13%

8%

15%

13%

0

Indoor

Outdoor

Foods

9%


Sequential class switching is required for the generation of high affinity IgE antibodies. Huizhong Xiong , ..Maria de Lafaille, and Juan Lafaille. Journal of Experimental Medicine: Jan 16th 2012 i) IgE B cells are rare in germinal centers (GC). ii) IgE plasma cells can be derived by direct switch from IgM or via IgG B cells which have undergone maturation in germinal centers . iii) They suggest that only IgE antibodies made via the germinal center route are relevant to allergic disease and even that low affinity antibodies are protective.

NB Deficiency of Bcl6 impairs GC but allows normal IgE in patients with DOCK8 mutations and Immunodeficiency. See Zhang et al NEJMed 2009


IgE antibody responses; an introduction Major targets include helminths, pollens, the constituents of inhaled dust, foods and ecto-parasites. High affinity is an important feature of IgE ab, and of the IgE receptor on mast cells and basophils. Production of IgE is closely controlled and indeed most antibody responses do not include IgE; Thus i) The antibody responses to tetanus, diphtheria, malaria, influenza, TB, etc. do not include IgE ii) Total serum IgE is generally very low; less than one microgram/ml iii) Specific IgE can make a major contribution to total IgE


High Titers of IgE Antibody to Dust Mite Allergen and the Risk for Wheezing Among Asthmatic Children Infected with Rhinovirus*

Odds ratio for wheezing based on positive tests for RV and titers of IgE ab(IU/ml) to mite . <0.35 IU/ml

Titer of IgE ab to mite:

0.35-17.4 IU/ml PCR +

≥ 17.5 IU/ml

n

PCR neg

Current Wheeze

95

5

4

[2/2]

8

Stable asthma

63

12

2 [0/1]

12

5 [1/2]

31

1 [0/1]

Control

123

60

13 [6/4]

31

2 [1/1]

14

2 [1/1]

186

73

15 [6/5]

43

7

45

3

Non-wheezing children Odds Ratio

PCR + [A/C]

3.89, p=0.07

PCR neg

[A/C]

16

[3/10]

[2/3]

12.3, p<0.001

PCR neg

20

PCR + [A/C]

42

[8/30]

[1/2]

31.5, p<0.001

*Soto-Quirós M, Avila L, Platts-Mills T, Hunt J, Erdman D, … and Heymann PW.

J Allergy Clin Immunol. June 2012

Thomas A E Platts-Mills