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Epidemiology of allergic

bronchopulmonary
aspergillosis (ABPA)
Dr Ritesh Agarwal MD, DM
FACP, FCCP, FAPSR, FRCP(Glasg)
Associate Professor
Dept. of Pulmonary Medicine
Postgraduate Institute of Medical Education and Research
Chandigarh, India

Chandigarh

Agenda
Epidemiology of ABPA (in asthma)
Community prevalence of ABPA
Prevalence in secondary care cohorts
Prevalence in tertiary care cohorts
Global (and Indian) burden of ABPA
Peculiarities in the Indian ABPA cohort

ABPA
Hypersensitivity pulmonary disorder caused by immune
responses against Aspergillus fumigatus colonizing the
tracheobronchial tree of patients with asthma (and cystic
fibrosis)
little or no tissue invasion by the organism

Agarwal R, et al. Future Microbiol

First description
UK - Hinson KFW et al- [Thorax 1952; 7: 317-33]
US - Patterson R et al- [Univ Mich Med Cent J 1968; 34: 8-11]
India - Shah JR et al- [J Assoc Physicians India 1971; 19: 835-41]

Why so much interest?


The fact that the condition responds remarkably to
glucocorticoid or azole therapy
Early detection and treatment may eliminate the risk of
progression to end-stage fibrotic lung disease

Hogan C, et al. Semin Respir Crit Care Med

New criteria

Agarwal R, et al. Clin Exp Allergy 2013;43:850-

New diagnostic criteria for


ABPA
Predisposing conditions
Bronchial asthma, cystic fibrosis

Obligatory criteria (both should be present)


Type I Af skin test positive or elevated Af IgE (>0.35 kUA/L)
Elevated total IgE levels (>1000 IU/mL)
Other criteria (at least two of three)
Presence of Af precipitating (or IgG) antibodies in serum
Radiographic pulmonary opacities consistent with ABPA
Eosinophil count >500 cells/L in steroid nave patients (may be
historical)

Agarwal R, et al. Clin Exp Allergy 2013;43:850-

Terminology
Aspergillus sensitization

Type 1 positive Aspergillus skin test or


A.fumigatus IgE >0.35 kUA/L

Serologic ABPA (ABPA-S)

Meets the diagnostic criteria for ABPA but no


abnormalities related to ABPA on CT chest

ABPA with bronchiectasis


(ABPA-B)

Meets the diagnostic criteria for ABPA with


presence of bronchiectasis on CT chest

Severe asthma with fungal


sensitization (SAFS)

Severe asthma, fungal sensitization, IgE <1000


IU/mL

Increase in the number of


cases of ABPA
An increasing number of cases of ABPA have been
reported in the last two decades
Heightened physician awareness
Widespread availability of commercial immunological
assays for the diagnosis of ABPA
Initially, the disorder was thought to be rare in North
America, but subsequent reports disproved this myth
ABPA truly has a global presence

Slavin RG, et al. Am J Med 1969;47:306Hoehne JH, et al. Chest 1973;63:177-

Clinical presentation
Although most patients with ABPA are diagnosed in the
third or fourth decade of life, there is no specific age or
gender predilection for its occurrence
Even children and the elderly may be afflicted
Familial occurrence has been documented in up to 5% of
cases

Agarwal R, et al. PLoS One 2013; 8:e61105


Shah A, et al. Ann Allergy Asthma Immunol

Community prevalence
Remains unknown because of lack of population-based
studies
The only population based data available is for
Aspergillus sensitization (NHANES, United States)
Prevalence of Aspergillus sensitization was found to be
6.4% using A.fumigatus specific IgE levels
This data is for the general population, however we want
similar data for asthmatic patients in the general
population

Gerjen PJ, et al. J Allergy Clin Immunol 2009;124:

Primary care cohort


Currently no data is available

Secondary care sequential


cohort
Author

Year

Place

Benatar et al.

1980

Cape Town, S Africa

Donnelly et al.

1991

Dublin, Ireland

Eaton et al.

2000

Al-Mobeireek et al.
Ma et al.
Total*

Total
No. with
asthmatics ABPA(M)
500

13 (2.6%)

1390

14 (1.0%)

Auckland, N Zealand

255

13 (5.1%)

2001

Riyadh, Saudi Arabia

264

07 (2.7%)

2011

Beijing, China

200

05 (2.5%)

2609

52 (2.6%)

*random effects
model

Benatar SR, et al. Clin Allergy 1980;10:28


Donnelly SC, et al. Ir J Med Sci 1991;160:28
Eaton T, et al. Chest 2000;118:6
Al-Mobeireek AF, et al. Respir Med 2001;95:3
Ma YL, et al. Zhonghua Jie He He Hu Xi Za Zhi 2011;34:90

Secondary care cohorts

Less than 2%
2-5%
>5%

Tertiary care
Study

Country

Type of study

Prevalence of ABPA in
asthma (n/N)
88/273

Campbell et al. (1964)

UK

Retrospective

Agbayani et al. (1967)

US

Prospective

1/53

Henderson et al. (1968)

UK

Prospective

5/46

Khan et al. (1976)

India

Retrospective

17/367

Sobti et al. (1978)

India

Prospective

18/200

Basich et al. (1981)

US

Prospective

12/42

Attapattu et al. (1991)

SL

Prospective

8/134

Eaton et al. (2000)

NZ

Prospective

9/35

Kumar et al. (2000)

India

Prospective

32/200

Maurya et al (2005)

India

Prospective

8/105

Agarwal et al. (2007)

India

Prospective

155/755

Prasad et al. (2008)

India

Prospective

18/244
Agarwal R, et al. Int J Tuberc Lung Dis

Tertiary care
Prevalence of ABPA in asthma

12 studies (2,454 asthma patients)


Agarwal R, et al. Int J Tuberc Lung Dis

Our experience
Active screening of asthmatics
997 asthmatics screened with Aspergillus skin test
Aspergillus sensitization - 378 (38%) patients
ABPA - 209 patients (21%)
ABPA without bronchiectasis (serologic ABPA) - 47
(22.5%) patients
ABPA with bronchiectasis - 162 (77.5%) patients

Agarwal R, et al. Chest 2006; 130:


442-8
Agarwal R, et al. Chest 2007; 132:

Burden of the disease


Scoping review
193 million adults with asthma worldwide using Global Initiative
Against Asthma (GINA) calculations

Assuming overall prevalence of ABPA as 2.5% (secondary care


cohort prevalence), the global burden of ABPA was 4.8 million
(range,1.4-6.8 million)

Denning DW, et al. Med Mycol 2013; 51:361-370

Burden of SAFS

The global burden of SAFS is about 6.8 million

Studies in this millennium

Prevalence is higher in the Indian population compared to other populations


292/1855 [15.7%] vs. 24/707 [3.3%]; p <0.00001
Agarwal R, et al. Clin Exp Allergy 2013;

Burden in India
Total population (2011 Indian census)

1,210,569,573

Adult Indian population (>=15y)

838,218,964

Asthma prevalence adults >=15y

27,661,226

ABPA prevalence
0.70%

193,629

2.50%

691,531

5%

1,383,061

SAFS: 968,143

In Peer Review

Prevalence in severe asthma


Even higher prevalence in severe acute asthma
In a study of 57 consecutive patients with severe acute
asthma
Prevalence of Aspergillus sensitization and ABPA: 51%
and 39%, respectively
Significantly higher than our outpatient asthma group:
AS- 38% and ABPA- 21%

Agarwal R, et al. Mycoses 2010; 53: 138-1

Epidemiologic
peculiarities in the
Indian ABPA cohort

High-attenuation mucus
(HAM)
Pathognomonic finding of
ABPA

Uncommonly described
from other centers - Seen in
almost 20% of our patients
Could be recognition bias or
could really represent a
different spectrum of ABPA
Patients with HAM have
severer immunological
findings compared to other
patients and are prone for
relapses

Agarwal R, et al. Am J Roentgenol 2006; 186:


904
Agarwal R,et al. Chest 2007; 132:1183-1190

ABPA in COPD
In India, ABPA has been identified in conditions other
than asthma and cystic fibrosis

ABPA in COPD
In a study of 200 consecutive COPD patients (and 100
healthy controls)
Aspergillus sensitization was found in 17 (8.5%) patients
with COPD
Two (1.0%) COPD patients fulfilled the criteria for
diagnosis of ABPA

Agarwal R, et al. Med Mycol 2010;48:988-9

ABPA in pulmonary tuberculosisrelated fibrocavitary disease

Dhooria S, et al. Int J Tuberc Lung Dis 2014: In P

ABPA in pulmonary tuberculosisrelated fibrocavitary disease


Case-control study
50 consecutive symptomatic new referrals with PTBrelated fibrocavitary disease (and 50 controls)
AS was present in 16 (32%) cases
Five (10%) patients met the criteria for diagnosis of ABPA

Dhooria S, et al. Int J Tuberc Lung Dis 2014: In P

Environmental factors in ABPA


Prospective case-control questionnaire based study
Living conditions (home environment, presence of
moisture in the walls, details of house type, presence of
separate kitchen), use of water coolers, type of fuel,
contact with farm, cattle and pets
202 subjects of asthma (103 and 99 Aspergillus
unsensitized and sensitized asthma respectively) and 101
ABPA

Agarwal R, et al. Lung India 2014; In Pre

Environmental factors in ABPA


Rural residence
Number of people residing in home,
median (interquartile range)
Non-cemented house
Presence of moisture in walls
Use of water-based air cooler
History of farming
Presence of window in the kitchen
Presence of exhaust in the kitchen
Contact with pets
Contact with cattle
Exacerbation of symptoms with
organic matter

Aspergillus
unsensitized
asthma (n=103)
50 (48.5)
05 (4-7)

Aspergillus
sensitized
asthma (n=99)
45 (45.5)
05 (5.7)

ABPA
(n=101)

P
value

66 (66)*
06 (5-7)

0.007
0.48

17 (16.5)
22 (21.4)
43 (41.7)
20 (19.4)
94 (91.3)
49 (47.6)
16 (15.5)
30 (29.2)
10 (9.7)

09 (9.2)
25 (25.8)
65 (65.7)*
18 (18.2)
88 (88.9)
48 (48.5)
08 (8.1)
25 (25.3)
09 (9.1)

09 (8.9)
29 (28.7)
54 (53.5)
28 (27.7)
95 (94.1)
58 (57.4)
13 (12.9)
34 (33.7)
19 (18.8)

0.32
0.48
0.003
0.20
0.43
0.3
0.56
0.43
0.07

Agarwal R, et al. Lung India 2014; In Pre

Genetic predisposition
Innate immunity
Surfactant protein A2 gene
polymorphisms
Mannose-binding lectin gene
polymorphisms
Toll-like receptor 9 gene
polymorphisms
Adaptive immunity

Interleukin 10 promoter
polymorphisms
Interleukin 15 polymorphisms
Tumor necrosis factor-
polymorphisms
Transforming growth factor-
polymorphisms

HLA associations

Others

Interleukin 4 receptor alpha


polymorphisms
Interleukin 13 polymorphisms

CFTR gene mutation


CHIT1 gene mutations

Agarwal R, et al. Clin Exp Allergy 2013;43:850-

Genetic predisposition
Innate immunity
Surfactant protein A2 gene
polymorphisms
Mannose-binding lectin gene
polymorphisms
Toll-like receptor 9 gene
polymorphisms
Adaptive immunity

Interleukin 10 promoter
polymorphisms
Interleukin 15 polymorphisms

Not studied well in the Indian


Population
Tumor necrosis factor-
polymorphisms

Transforming growth factor-


polymorphisms

HLA associations

Others

Interleukin 4 receptor alpha


polymorphisms
Interleukin 13 polymorphisms

CFTR gene mutation


CHIT1 gene mutations

Agarwal R, et al. Clin Exp Allergy 2013;43:850-

Summary
ABPA has a global presence, significant burden and is far
more common than previously thought
The community prevalence is not known but the
prevalence is secondary care is about 2.5%
Need for community data, which is difficult to obtain
Data from primary care cohort should be obtained that
would serve as a surrogate for community prevalence

Thank you

Working group on ABPA


Join the ISHAM ABPA
working group
Contact us at:
agarwal.ritesh@pgimer.edu.in
arunaloke@hotmail.com
david.denning@manchester.ac.uk