Asthma

Diagnosis of Asthma

Wrong Dx is often made - 12% ERJ 2003 Robinson et al
Need compatible history (intermittent chest tightness, wheeze, dyspnoea, cough, exposure history) to give the right pre-test probability AND either (1) Bronchodilator reversibility (2) Variability or (3) inducibility
- Bronchodilator reversibility: ATS criterion 12% and 200mL in either of FEV1 or FVC
  - By itself not sufficient to make a Dx - can be seen in COPD (see TORCH study, where patients can move in and out of BR) - See figure below. Incidence of reversibility inversely proportional to COPD severity.
  - Up to 42% of patients with COPD can demonstrate BR http://dx.doi.org/10.1378/chest.10-2974
    - Reversibility status changes in up to 50% of patients with COPD between clinic visit

Inducibility
- This is performed through tests to assess for airway hyper-responsiveness - concept that asthmatics have a more highly responsive airway
- Direct challenge test: histamine or methacholine challenge
- Indirect challenge test: mannitol

Note positive test is not specific (1-7% normal population, up to 25% if smoking) in the wrong group
Methacholine or histamine challenges are "direct" challenges - they directly stimulate airway smooth muscle cells
Manitol, hypertonic saline, exercise challenge tests and eucapnic voluntary hyperventilation are indirect tests, and require presence of mast cells
Negative predictive value is most useful for methacholine test

Variability using peak flow tools
- Very effort dependent, cannot check how good the blow is as you can with spirometry (flow vs time curve)
- Spiro can be grossly abnormal whilst peak flows still within normal range, therefore can cause under-estimation of severity
Use of exhaled nitric oxide
- Not well validated for the diagnosis of asthma - some role in predicting eosinophilic inflammation
- NO has many functions, including vasodilating, bronchodilating, neurotransmission and co-ordination of cilia beat frequency
- NO is produced through Nitric oxide synthase (NOS) of which there are three isoforms - neuronal NOS, inducible NOS and endothelial NOS.
  - nNOS and eNOS are constitutively active, whilst iNOS is induced on endothelial surface by inflammatory cytokines [IL-1, IL4, IL13], reduced by glucocorticoids, bacteria, tobacco smoke
- Ongoing research as to its utility in management
  - Have used FeNO based Rx for severe asthma in pregnancy – fewer exac (NNt = 6), improved qol, better neonatal outcomes

Anne woolcock was one of the first people to measure airway hyper-responsiveness. In her initial experiments, she found that the response to histamine in asthmatic airways was more sensitive and did not have a plateau.
Asthmatic airways are not just hyper-responsive, but they have evidence of remodelling both in large and small airways.

Changes in wall thickness represent changes not just in airway smooth muscle but also extracellular matrix.

In Asthma, the airway lumen is already thickened due to the effects of remodelling and inflammation therefore luminal narrowing is far more pronounced
Airway smooth muscle tends to be both hypertrophied and demonstrate evidence of hyperplasia. Furthermore, they also had more capability of narrowing

Childhood asthmatics have worse attained lung function at the age of 18. See picture.
In patients with persistent asthma, lung function was worse as an infant in the perth cohort.
Development of sensitisation and exposure to RTIs esp those assoc with fever are the most important risk factors for those that will develop asthma when they get older.
With treatment, airway hyper-responsiveness takes longer to stabilise than FEV1. This probably reflects airway remodelling.

It is important to deliver the inhaled medication to its right target. In mild to moderate asthma, ventilation is not greatly affected, however in severe asthma there are many ventilation abnormalities which seem to be fixed, perhaps as a consequence of small airways remodelling.
Large particles tend to be deposited in the mouth and throat due to inertial impaction. Fine particles (<5 um) have the greatest potential for peripheral lung deposition, as can be seen below.
Ideal inhaler therefore should be breath actuated, match flow rate, fine particles and continuous on demand flow

Duration of inhalation should be longer as well - as this promotes greater peripheral lung deposition per unit fine particle fraction - go "long and slow"
Holding chambers are very important to maximise drug delivery to lung.
In vitro evidence shows single puff into spacer is better than multiple.
5 – 10s delay is important if no static electricity (wash with detergent, let air dry don’t wipe down). This study held puff in chamber for 0, 1, 5, 20s.
If static then the particles get held in the chamber walls. Slow inhalational rate of 30L/min is optimal with spacers and give 10s breath hold.

Dysfunctional breathing = 30% in severe asthma cohort, Rx helps
anxiety/ depression = 49%, Rx helps
Allergic rhinitis = 80%, Rx helps
non-allergic rhinitis = 70%, Rx helps
GORD = 60%, but treating doesn't necessarily improve outcome
OSA = 75 - 95%, Rx helps
VCD = 20% all asthmatics, 75% severe asthma
Most of the benefit from treating comorbidities are from observational studies. RCTs exist for rhinitis and obesity only - however quality of evidence was very low (Cochrane review 2012)
There are standard questionnaires that can be used which improve diagnosis because, especially for PMVC & dysfunctional breathing we are useless at diagnosing them on clinical gestalt
With regards to vocal cord dysfunction - one could use mannitol under direct laryngoscopy visualisation to aid diagnosis