1. Mannitol Challenge Test New method of asthma diagnosis
경희대학교 동서신의학병원 호흡기내과
최 천 웅

2. Asthma “ chronic inflammatory disorder of the airways in which many
cells and cellular elements play a role. The chronic inflammation
is associated with airway hyperresponsiveness that leads to
recurrent episodes of wheezing, breathlessness, chest tightness,
and coughing, particularly at night or in the early morning. These
episodes are usually associated with widespread, but variable,
airflow obstruction within the lung that is often reversible
either spontaneously or with treatment ”
GINA

3. The asthma diagnosis
“ Measurements of lung function (spirometry or peak
expiratory flow) provide an assessment of the severity
of airflow limitation, its reversibility, and its variability,
and provide confirmation of the diagnosis of asthma “
GINA

4. Diagnostic validity of spirometry, PEF and reversibility
Sensitivity
Specificity
Positive predictive value
Negative predictive value
Beta-2-reversibility
49%
70%
85%
29%
Peak flow variability
43%
75%
86%
28%
Steroid reversibility
12%
100%
66%
Smith, AJRCCM 2004
Hunter, Chest 2002

5. The asthma diagnosis
“ For patients with symptoms consistent with asthma,
but normal lung function, measurements of airway
responsiveness to methacholine, histamine, mannitol,
or exercise challenge may help establish a diagnosis
of asthma ”
GINA

6. Inflammation
Responsive airway
smooth muscle
Symptoms + =

7. What is a Bronchial Challenge Test (BCT)?
Laboratory based test designed to
mimic variable airways obstruction using
inhaled bronchoconstrictive stimuli,
during which an exaggerated response
(airway hyperresponsiveness) to a particular bronchoconstrictor agent can be measured

8. When might you use a BCT? As diagnosis confirmation
As a follow-up test to monitor treatment
To document severity of BHR
To exclude asthma in patients with chronic cough
To assess suitability to scuba dive or undertake a particular occupation
As part of clinical research studies

9. Subject Selection - Contraindications
Absolute
Hypersensitivity to mannitol
Severe airways obstruction at baseline
(FEV1 < 1.2L in adults)
Recent MI (< 3 months)
Recent CVA (< 3 months)
Known arterial aneurysm
Inability to understand the procedures and implications of a challenge test
Relative
Spirometry-induced airways obstruction
Moderate to severe airways obstruction
Recent URTI (< 2 weeks)
During exacerbation of asthma
Hypertension
Pregnancy
Epilepsy requiring drug treatment

10. Performing a Challenge Test - Terminology
FEV1 (Forced Expiratory Volume in one second)
FVC (Forced Vital Capacity)
Pre-challenge/baseline and 0mg readings
Diluent
Cumulative dose
PD15 / PC15 (Provocative dose/concentration)
PD20 / PC20
Recovery test

11. Lung Function Measurements
FEV1 is measurement of choice
Well standardized
Reproducible during serial measurement
FVC measurements are exhausting when performed repetitively

12. Classes of Challenge Tests
Direct
agonist or mediator (usually histamine or methacholine) is administered and acts on a specific receptor on bronchial smooth muscle causing it to contract. Identifies responsiveness to the administered substance.
Indirect
agonists or mediators (histamine, leukotrienes, prostaglandins) are released from inflammatory cells (mast cells, eosinophils)
in response to the stimulus, e.g. allergen, dry air, osmotic change. Identifies responsiveness to endogenously released mediators of inflammation.

13. Histamine, methacholine Exercise, EHV, NaCl, mannitol
Mechanisms of AHR
Direct stimuli:
Indirect stimuli:
Histamine, methacholine
Exercise, EHV, NaCl, mannitol
Increased osmolarity
Inflammatory cell
Histamine, prostaglandins,
Leukotriens..

14. Bronchial Provocation Stimuli- examples
Direct
Histamine
Methacholine
Indirect
Exercise
Eucapnic Voluntary Hyperpnoea (EVH)
4.5% Hyperosmolar (hypertonic) saline
Dry powder mannitol
Adenosine monophosphate (AMP)

15. Delivery of Challenge Agents
Jet /ultrasonic nebuliser using tidal breathing
Dosimeter allowing delivery during inspiration only
Bicycle ergometer or motor-driven treadmill
Specially developed particle generator

16. Methacholine Methacholine is administered via a nebuliser
Number of techniques
Tidal breathing
Dosimeter
FEV1 measured 1-2 minutes after each dose
Accumulating dose to see a 20% reduction in FEV1
Result expressed as PC20 or PD20

17. AHR to methacholine
20%

19. Advantages of Methacholine
Widely used / market has experience with these agents
High sensitivity in patients referred to the lab with respiratory symptoms
(sensitivity is much lower in a random population)
High negative predictive value for current disease
(good at excluding current disease, rather than
confirming its presence)
Dose-response curve

20. AHR to methacholine in healthy subjects – random sample population
12 asthmatics (4.1%)
279 non-asthmatics
+ AHR 21% (58)
- AHR 79% (221)
Porsbjerg, Chest 2006

21. AHR to methacholine High sensitivity, but low specifity
FP tests in rhinitis, COPD and in healthy subjects
Correlation with airway inflammation moderate
Need for more specific BCT

22. Disadvantages of Methacholine
Low specificity for identifying active asthma.
High rates of false positive results
A positive response can occur in healthy people
i.e. smokers, recent URTI or COPD etc.
Direct challenge tests correlate less well with airway inflammation than indirect challenges
Do not exclude EIA (exercise-induced asthma)
Ineffective for assessing response to treatment
Potential operator exposure to stimulus
Practical disadvantages (nebuliser, equipment, patient acceptability)

23. Disadvantages of Methacholine

24. Indirect BCT act via airway inflammation
Direct challenge tests
(methacholine, histamine)
Responsive airway
smooth muscle =
Symptoms
Inflammation +
Indirect challenge tests
(exercise, hypertonic saline, mannitol)

25. Indirect challenge tests
Exercise in the laboratory
Exercise in the field
Eucapnic voluntary hyperpnea
Indirect challenge tests
4.5% saline
4.5% saline *
dry powder mannitol

26. Hypertonic Saline 4.5% saline administered via an ultrasonic nebuliser
FEV1 measured 60 seconds after each exposure
Response expressed as a PD15

27. Advantages of Hypertonic Saline
High specificity for active asthma/airway inflammation
Predicts exercise-induced asthma
Dose-response curve
More than one mediator involved
Can use in to monitor response to therapy
Useful in the assessment of patients with a past history of asthma who wish to SCUBA dive
More acceptable to parents of children undergoing testing because saline is not seen as a chemical

28. Disadvantages of Hypertonic Saline
Cough during challenge
Salivation during challenge
Patient is attached to a nebuliser continuously for
several minutes
Unpleasant salty taste
Clean up time & weighing delivered dose

29. Exercise
Exercising at the highest intensity sustainable for minutes.
Can be performed in the field, or in the laboratory.
FEV1 measured 5,10 & 15 minutes after exercise
Positive test: >10% drop in FEV1

30. Eucapnic Voluntary Hyperventilation (EVH)
Voluntary hyperventilation of dry air containing 5% CO2
Hyperventilation at 30 x FEV1 for 6 mins
FEV1 measured 3, 5, 10, 15 & 30 mins post EVH
Positive test: >10% drop in FEV1

31. Advantages of Exercise and Hyperventilation
Specificity and Sensitivity data are similar to those of
hypertonic saline
Biologically relevant stimulus, > 1 mediator involved
Common trigger of asthma
Negative test indicates good control or mild asthma
Accepted by the IOC, to determine effectiveness/optimal dose of medication used to prevent EIB
Useful in evaluating the ability to perform demanding work in subjects with a history of asthma (defence forces, SCUBA)
Better in children than direct challenges for distinguishing asthma from other diseases

32. Disadvantages of Exercise and Hyperventilation
Expensive equipment
No dose-response curve
Risk of steep fall in lung function post test (exercise)
Protocol governing test (Criteria for elderly subjects, number of supervising personnel etc)
Exercise testing is not reliable in elite athletes

33. Mannitol (Aridol) Challenge

34. Mode of Action

35. Mannitol (Aridol) Challenge
Administration via a small hand held dry powder inhaler
Mannitol given in doses of ;
0,5,10,20,40, 80(2x40),160(4x40),160(4x40),160(4x40) mg
FEV1 measured between each dose
Positive response defined as a ≥ 15% fall in FEV1 from baseline or ≥10% fall in FEV1 between consecutive doses
Response expressed as PD15

37. Advantages of Aridol (mannitol)
High specificity for active asthma
Strong correlation with active airway inflammation
Identifies EIA (Exercise Induced Asthma)
Useful in monitoring response to therapy
Standardised/reproducible;
Reduction in variability in preparation, delivery with a standardised
test kit
Practical benefits;
No nebuliser required/ no sterilisation of equipment
Good patient acceptability
Limits exposure risk for asthmatic technicians performing the test
Approved by regulatory authorities

38. Aridol: Dose Response Curve

39. Aridol - useful in monitoring response to Tx
No PD15
recorded in
7/18 after
635mg of
mannitol
1000
Change in response to mannitol after
6 - 9 wks
mg budesonide
to Mannitol (mg)
100 15 PD
p < 0.001 10
Pre R
During R x x
J Brannan 2002 Respirology
Gmean PD15 (95%CI) : 78 mg (51, 117) 289 mg (202, 414) n = 18

40. Disadvantages of Aridol
Some cough during challenge
Cost (depends on cost of competitors)
Test is new/unknown/unfamiliar

41. Mannitol and inflammation

42. Mannitol and methacholine vs airway inflammation
Correlation coefficients
Mannitol
Methacholine
PD15
PD20
Sputum eosinophils(%)
-0.52*
-0.28
Exhaled NO (ppb)
-0.63**
-0.43*
*:p < 0.05, **:p< 0.001
Porsbjerg, CEA 2008

43. Mannitol and methacholine vs eNO in a random population sample
Porsbjerg, ERS 2009

44. Mannitol and inflammation - summary
AHR to mannitol is more closely associated with
airway inflammation than AHR to methacholine
A response to mannitol will indicate inflammation
that causes AHR in a real life situation

45. AHR to mannitol = Symptoms + Sputum eosinophils Exhaled NO AHR to
methacholine
Responsive airway
smooth muscle =
Symptoms
Inflammation +
AHR to mannitol

46. Mannitol for diagnosing asthma

47. Mannitol for diagnosing asthma
Sensitivity
Specificity
Positive predictive value
Negative predictive value
Brannan 2005
(n=502)
(6-83 y)
60%
95% _
Sverrild 2009
(n=238)
(15-25 y)
59%
98%
91%
90%

48. Mannitol vs methacholine for diagnosing asthma
Sensitivity
Specificity
Positive predictive
value
Negative predictive
Mannitol
Methacholine
59%
68%
98%
80%
91%
49%
90%
Anderson 2009
(n=509 )(6-50)
56%
51%
73%
75%
79%
78%
48%
46%
Sverrild 2009
(n=238)(15-25 y)

49. Mannitol for diagnosing asthma- Summary
Moderate sensitivity
– NB: subjects with normal lung function!
High specificity – high positive predictive value

50. Mannitol and asthma treatment

51. AHR to mannitol and effect of inhaled steroids
Increase in PD15 after 6-9 weeks of treatment with
inhaled budesonide μg/d: 78 mg to 289 mg
Brannan Respirology 2003

52. Downtitration of steroids
Survival curve using AHR to mannitol measured at the visit prior to an ICS reduction
Dashed line: norm-responsive
Continuous line: hyperresponsive subjects
Leuppi AJRCCM 2001

53. mannitol and asthma treatment-Summary
AHR to mannitol improves with ICS treatment
AHR to mannitol predicts asthma deterioration
during ICS down-titration

54. “Who to test – how to interpret?”
“What can we use it for..?”
“Who to test – how to interpret?”

55. What do we want to use it for ? - Rule out or rule in asthma?
Rule out asthma
Rule in asthma
Test with high sensitivy – specifity
may be less relevant
Test with high specificity - preferably also a high sensitivity
E.g. work-related symptoms
: To rule out occupational asthma
E.g. to make an objective diagnosis of asthma before starting treatment with ICS
Direct test
Indirect test

56. Who to test? Direct test Indirect test
(Rule out asthma)
Indirect test
(Rule in asthma)
Suspicion of occupational asthma
Clinical suspicion of asthma in subjects with normal lung function
Uncharacteristic symptoms
– e.i. low suspicion of asthma
Clinical suspicion of exercise induced
asthma in subjects with normal lung
function
(Elite athletes (IOC criteria))
Elite athletes (IOC criteria)
Military personel, policemen, firemen

57. Interpreting guide - mannitol
Diagnose?
Comments
Test
Result
Ongoing inflammation, start/increase inhaled steroids
Asthma1
Positive
Differential diagnosis:
Some COPD patients may have a positive mannitol test2
Consider: COPD patients with a positive mannitol test may respond to ICS treatment 2
Aridol
Mannitol
Indirect Bronchial
challenge test
Negative predictive value intermediate (50-89%) 5,6: Consider mild asthma with negative test
No asthma
Mild asthma/ ”outside season” with little active inflammation present
Further diagnostic work-up might be needed
Negative
Asthma?
On treatment?
- Wellcontrolled asthma4
”Step down” steroids?
In cooperation with Prof. MD Vibeke Backer and MD PhD Celeste Porsberg, Bispebjerg Hospital, Denmark and Prof. MD Leif Bjermer, University Hospital Lund, Sweden Ref Leuppi et al Pulmonary Pharmacology and Therapeutics 18: Cockcroft et al Current Allergy and Asthma reports 2009, 9: Leuppi et al. Am J Respir Crit Care Med 2001, 163: Sverrild et al J Allergy Clin Immunol Epub ahead of print, 6: Anderson et al Respiratory Research ,23;10:4. copyright Nigaard Pharma AS. 57

58. A new diagnostic algorithm?
Breathlessness
Wheezing
Cough
FEV1 and FVC
PEF monitoring 2 weeks
Variation > 20 %
(D-PEF > 100 l/min) + -
Beta2-reversibility
> 12% and D-FEV1 >200 ml
FEV1 normal?
Steroid reversibility
(fx prednisolon 37,5mg for 10 days
D-FEV1 > 500 ml
Bronchial provocation
Histamine, methacholine:
FEV1 fall > 20 %
Mannitol:
15 % fall in FEV1
D-FEV ml
Asthma possible
FEV1/FVC < 70 %
Further investigations
Patient does not have asthma
ASTHMA
COPD
Ulrik, UfL 2002

59. Always remember - No one simple asthma test
FEV1<80%pred
AHR
eNO>20ppb
Reversibility
>12%
Sputum eosinophils
> 3%
FEV1/FVC<80%pred
ASTHMA

60. Conclusions
AHR to mannitol reflects airway hyper-responsiveness related
to ongoing airway inflammation
The mannitol test has a high PPV, and may be used to confirm a clinical suspicion of asthma in patients with a normal lung
function
A positive mannitol test may also support a decision to
commence ICS treatment
A negative mannitol test should not be used to rule out
a suspicion of asthma