Bronchial asthma

1. BRONCHIAL
ASTHMA
MD RUHI TABASSUM
1st yr PG, NRI INSTITUTE OF MEDICAL
SCIENCES

2. INTRODUCTION
• Asthma is a heterogenous disease characterised by airway
inflammation and hyperresponsiveness.
• It is defined by history of dyspnoea, cough, wheeze and chest
tightness which vary over time and in intensity.

3. RISK FACTORS AND TRIGGERS
ENDOGENOUS FACTORS
Atopy Genetic
predisposition
Gender Obesity Infections
• Major risk factor
• Genetic
predisposition to
develop allergic
reactions.
Ex: Allergic rhinitis,
allergic dermatitis.
• Seen with
polymorphism of
genes on ch 5q
• Epigenetic
mechanism like
DNA methylation
and histone
modification in
fetus.
• Two times more
common in males
than females till
childhood
* Due to increased
proinflammatory
adipokines
• Rhinovirus
• RSV
• Coronavirus
• Mycoplasma

4. RISK FACTORS AND TRIGGERS
ENVIRONMENTAL FACTORS
Indoor allergens Outdoor allergens Occupational
sensitizers
Ventilation Smoking
• Most common –
dermatophagoides
-house dust mite
• Domestic pets
• NO2 from
cooking stoves
• NO2
• SO2
• Diesel
particulates
• Pollen, fungal
spores
• Animal allergens
in lab workers
• Chemicals
• Aerosols
• Dampness and
poor ventilation
• Active and passive
smoking

5. • Exercise causes increase osmolality of airway lining which
stimulates the mast cells
• Cold air
• Drugs – Beta blockers, Aspirin and rarely ACE inhibitors
• Stress
• Food – Shell fish, meta bisulphite, tartrazine
• GERD
RISK FACTORS AND TRIGGERS
TRIGGERS

6. PHENOTYPES OF ASTHMA
Intrinsic / Idiosyncratic asthma Extrinsic asthma
Triggered by viral or bacterial infection Atopy related.
Ex: Dermatophagoides
S.IgE normal S.IgE elevated
Skin test negative Skin test positive

7. • Type 2 inflammation is associated with eosinophilia and increased
FeNO. It is seen in 50% bronchial asthmatics with severe asthma.
Cytokines involved are IL4, IL5, IL13. This responds to corticosteroids.
• Non Type 2 inflammation is associated with neutrophilia. It doesn’t
respond to corticosteroids
• Brittle asthma
- Type 1 is associated with frequent fluctuations in lung function with
exacerbation. It’s treated with high dose ICS, LABA, oral steroids.
- Type 2 is associated with near normal lung function followed by
sudden decline and death of the patient due to airway anaphylaxis. It’s
treated with inj adrenaline.

8. PATHOPHYSIOLOGY
Fig 1: Pathophysiology
of asthma
Histamine
prostaglandin D2
and leukotrienes,
cytokines
Major APCs

9. • Cytokines: Th2 cell produce IL4, IL5, IL9, IL13 which mediate the
allergic reaction. Proinflammatory cytokine TNF alpha and IL-1 beta
amplify the response. TSLP(Thymus Stimulated Lymphopoietin) is
released from epithelial cell and increases release of chemokines from
dendritic cell.
• Chemokines: Eotaxin (CCL11) attracts eosinophils via CCR3 whereas
CCL17 and CCL22 attract Th2 cells via CCR4.
• Airway Remodelling: It refers to characteristic structural changes
in bronchial asthma. Epithelial damage results in loss of barrier
function and allows penetration of allergens and exposure of the sensory
nerves which may lead to reflex neural affects on the airway.

10. • Basement membrane is thickened due to sub-epithelial fibrosis with the
deposition of Type 3 and 5 collagen. There is also hypertrophy and
hyperplasia of the smooth muscle due to PDGF. Angiogenesis is seen
due to VEGF. Microvascular leakage from post capillary venules results
in airway edema. Increased mucous secretion due to hyperplasia of
goblet cells and submucosal glands occurs.

11. ASPIRIN INDUCED ASTHMA
• Seen only in 1-5 % of asthmatics. It is preceded by perennial rhinitis and
nasal polyps. Aspirin intake causes rhinorrhoea, conjunctival injection,
facial flushing and wheezing
LOX pathway
COX pathway
Leukotrienes
Prostaglandins
Aspirin
Archidonic Acid

12. • It is due to the increase in the leukotrienes LT C4, LT D4, LT E4
• Treatment : Inhalational corticosteroids, SABA, Antileukotrienes.
ASPIRIN INDUCED ASTHMA

13. CLINICAL FEATURES
SYMPTOMS
• Wheeze, dyspnoea, cough, chest tightness.
• Nocturnal worsening and typical awakening in early morning hours.
• Prodromal symptoms like itching under the skin, discomfort
between the scapulae, inexplicable fear(impending doom) may be
seen.
• Seasonal variation, symptoms more common during winters

14. • Expiratory wheeze, rhonchi throughout the chest.
• Hyper inflation
• Children may present with non productive cough(cough variant asthma)
INVESTIGATIONS
• Chest X-ray: It shows hyper inflated lungs.
• Spirometry is considered to be the gold standard for diagnosis of asthma
CLINICAL FEATURES
SIGNS

15. SPIROMETRY: FEV1/FVC RATIO <0.7 indicates obstructive pattern
POSITIVE BRONCHODILATOR REVERSIBILITY
IS DIAGNOSTIC OF ASTHMA
Administraton of 400mcg Salbutamol ,increases
FEV1>12% OR >200ML,after 15 min duration
POSITIVE BRONCHIAL PROVOCATION TEST:
Useful in patient with no symptoms
Methacholine inhalation causes more than or equal to 20%
fall in FEV1
DIURNAL VARIABILITY >20% Variability of PEFR
POSITIVE EXERCISE CHALLENGE TEST >20% Fall in FEV1
FeNO-Fractional Concentration of Exhaled Nitric Oxide Increased in bronchial asthma with eosinophilia
May not increase in neutrophilic asthma
False positive in atopy,eczema
Skin test Used to identify the allergen.
DIAGNOSIS

16. Fig 2: Spirometry and flow-volume loop in asthmatic compared to normal subject. There is a reduction in
forced expiratory volume in 1 second (FEV1) but less reduction in forced vital capacity (FVC), giving a
reduced FEV1/FVC ratio (<70%).

17. Fig 3: Approach to
asthma

18. TREATMENT OF BRONCHIAL ASTHMA
• The main drugs for asthma can be divided into bronchodilators, which
give rapid relief of symptoms mainly through relaxation of airway
smooth muscle, and controllers, which inhibit the underlying
inflammatory process.
BRONCHODILATOR THERAPIES
• There are three classes of bronchodilator in current use: β2-adrenergic
agonists, anticholinergics, and theophylline; of these, β2-agonists are
by far the most effective.

19. • β2-agonists :
Mechanism of action: β2-Receptors are coupled through a stimulatory G
protein to adenylyl cyclase, resulting in increased intracellular cyclic
adenosine monophosphate (AMP), which relaxes smooth muscle cells and
inhibits certain inflammatory cells, particularly mast cells.
• Short acting beta agonists: SABA-Albuterol and terbutaline, have a
duration of action of 3–6 h. They have a rapid onset of
bronchodilatation and are, therefore, used as needed for symptom relief
(relievers). Increased use of SABA indicates that asthma is not
controlled. They are also useful in preventing EIA if taken prior to
exercise. SABA are used in high doses by nebulizer or via a metered-dose
inhaler (MDI) with a spacer.

20. • Long-acting β2-agonists (LABA) include salmeterol and formoterol, both of
which have a duration of action over 12 h and are given twice daily by
inhalation
• Ultra Long acting: Indacaterol, olodaterol, and vilanterol, given once daily.
LABA have replaced the regular use of SABA, but LABA should not be given
in the absence of ICS therapy as they do not control the underlying
inflammation. This has led to the widespread use of fixed combination
inhalers that contain a corticosteroid and a LABA, which have proved to be
highly effective in the control of asthma and prevention of exacerbations.
• Example :FORACORT is combination of Formeterol and Budesonide.

21. • SIDE EFFECTS
The most common side effects are muscle tremor and palpitations, which
are seen more commonly in elderly patients. There is a small fall in plasma
potassium due to increased uptake by skeletal muscle cells, but this effect
does not usually cause any clinical problem.
ANTICHOLINERGICS
Mechanism of action:
They prevent cholinergic nerve-induced bronchoconstriction and mucus
secretion. They are less effective than β2-agonists in asthma therapy as
they inhibit only the cholinergic reflex component of bronchoconstriction,
whereas β2-agonists prevent all bronchoconstrictor mechanisms.

22. Short acting muscarinic antagonist(SAMA):Ipratropium Bromide
Long-acting muscarinic antagonists (LAMA): including tiotropium
bromide or glycopyrronium bromide, may be used as an additional
bronchodilator in patients with asthma that is not controlled by maximal
doses of ICS-LABA combinations.High doses of SAMA can
be given by nebulizer in treating acute severe asthma but should only be
given following β2-agonists, as they have a slower onset of
bronchodilation.
Side effects :
The most common side effect is dry mouth; in elderly patients, urinary
retention and glaucoma may also be observed

23. • Theophylline Theophylline use has now fallen out of favor as side effects
are common.
• Mechanism of action:The bronchodilator effect is due to inhibition of
phosphodiesterases in airway smooth-muscle cells, which increases cyclic
AMP. Theophylline activates the key nuclear enzyme histone deacetylase-2
(HDAC2), which is a critical mechanism for switching off activated
inflammatory genes and therefore reduces corticosteroid insensitivity in
severe asthma.
• . It may be used as an additional bronchodilator in severe asthma. Low
doses of theophylline, giving plasma concentrations of 5–10 mg/L, have
additive effects to ICS and are useful in patients with severe asthma. At low
doses, the drug is well tolerated.

24. • IV aminophylline (a soluble salt of theophylline) was used for the treatment of
severe asthma but has now been largely replaced by high doses of inhaled SABA,
which are more effective and have fewer side effects. Aminophylline is occasionally
used (via slow IV infusion) in patients with severe exacerbations that are refractory
to SABA.
• Side Effects. The most common side effects are nausea, vomiting, and headaches
.Diuresis and palpitations may also occur, and at high concentrations cardiac
arrhythmias, epileptic seizures, and death may occur due to adenosine A1-receptor
antagonism. Theophylline side effects are related to plasma concentration and are
rarely observed at plasma concentrations <10 mg/L. Theophylline is metabolized
by CYP450 (CYP1A2) in the liver, and, thus, plasma concentrations may be
elevated by drugs that block CYP450 such as erythromycin and allopurinol

25. CONTROLLER THERAPIES
• Inhaled Corticosteroids ICS are the most effective controllers for
asthma.
• Mode of Action :ICS reduce inflammatory cells ex:Eosinophils in the
airways and sputum, and numbers of activated T lymphocytes and
surface mast cells in the airway mucosa.
• The major effect of corticosteroids is to switch off the transcription
of multiple activated genes that encode inflammatory proteins such as
cytokines, chemokines, adhesion molecules, and inflammatory
enzymes.

26. • Their main mechanism is recruitment of HDAC2, which reverses the
histone acetylation associated with increased gene transcription.
Corticosteroids also activate anti-inflammatory genes such as mitogen-
activated protein (MAP) kinase phosphatase-1, and increase the
expression of β2-receptors.
• They are effective in preventing EIA and nocturnal exacerbations. ICS
are now given as first-line therapy for patients with persistent asthma,
but if they do not control symptoms at low doses, it is usual to add a
LABA as the next step.

27. • Local side effects include hoarseness (dysphonia) and oral candidiasis,
which may be reduced with the use of a large-volume spacer device.
At high doses, there may be some suppression of plasma and urinary
cortisol concentrations
• Systemic Corticosteroids Corticosteroids are used intravenously
(hydrocortisone or methylprednisolone) for the treatment of acute
severe asthma.Approximately 1% of asthma patients may require
maintenance with OCS.

28. • Systemic side effects, including truncal obesity, bruising, osteoporosis,
diabetes, hypertension, gastric ulceration, proximal myopathy,
depression, and cataracts, may be a major problem, and steroid-sparing
therapies may be considered if side effects are a significant problem.
• If patients require maintenance with OCS, it is important to monitor
bone density so that preventive treatment with bisphosphonates or
estrogen in postmenopausal women.

29. Mechanism of action: Cysteinyl-leukotrienes are potent
bronchoconstrictors; they cause microvascular leakage and increase
eosinophilic inflammation
Antileukotrienes, such as montelukast and zafirlukast, block cys-LT1-
receptors and provide modest clinical benefit in asthma.
They are less effective than ICS in controlling asthma but are useful as
an add-on therapy in some patients not controlled with low doses of
ICS, although less effective than a LABA. They are given orally once
or twice daily and are well tolerated.
Antileukotrienes

30. • Cromones Cromolyn sodium and nedocromil sodium are asthma
controller drugs
• Mechanism of action: They inhibit mast cell and effective in blocking
trigger-induced asthma such as EIA and allergen- and sulfur dioxide-
induced symptoms.
• Cromones have relatively little benefit in the long-term control of
asthma due to their short duration of action (at least four times daily
by inhalation

31. • Steroid-Sparing Therapies Methotrexate, cyclosporin A, azathioprine,
gold, and IV gamma globulin have all been used as steroid-sparing
therapies.
• Anti-IgE Omalizumab is a blocking antibody that neutralizes
circulating IgE without binding to cell-bound IgE and, thus, inhibits IgE-
mediated reactions. The treatment is very expensive and is only suitable
for highly selected patients who are not controlled on maximal doses of
inhaler therapy and have a circulating IgE within a specified range.
Omalizumab is usually given as a subcutaneous injection every 2–4 weeks
and appears not to have significant side effects, although anaphylaxis is
very occasionally seen. .

32. NEWER MODALITIES
Anti-IL-5 Antibodies that block IL-5 mepolizumab, reslizumab or its
receptor benralizumab markedly reduce blood and tissue eosinophils and
reduce exacerbations in patients who have persistently increased sputum
eosinophils despite maximal ICS therapy.
Immunotherapy Specific immunotherapy using injected extracts of
pollens or house dust mites has not been very effective in controlling
asthma and may cause anaphylaxis

33. Bronchial Thermoplasty: Bronchial thermoplasty is a bronchoscopic
treatment using thermal energy to ablate airway smooth muscle in
accessible bronchi. It may reduce exacerbations and improve asthma
control in highly selected patients not controlled on maximal inhaler
therapy, particularly when there is no increase in inflammation. .

34. MANAGEMENT OF CHRONIC ASTHMA
• Diagnosis is established by objectively using spirometry or PEF
measurements at home. It is assessed by symptoms, night awakening, need
for reliever inhalers, limitation of activity and lung function.
• There are several validated questionnaires for quantifying asthma control,
such as the Asthma Quality of Life Questionnaire (AQLQ) and Asthma
Control Test (ACT).

35. Fig 4: Asthma control

36. Parameter Intermittent Mild Persistent Moderate
Persistent
Severe
Persistent
Day time
symptoms
<2/wk >2/wk Daily Throughout the
day
Nocturnal
Symptoms
<2/month >2/month >2/wk Daily
Managemen
t
STEP 1 STEP 2 STEP 3 STEP 4
SABA SABA
+
Low Dose ICS
SABA
+
High Dose ICS
+
LABA
SABA
+
LABA
+
Oral
corticosteroids

37. • Stepwise Therapy: For patients with mild, intermittent asthma, a
SABA is all that is required The treatment of choice for all patients is
an ICS given twice daily.
• It is usual to start with an intermediate dose (e.g., 200 [μg] bid of
[beclomethasone dipropionate] BDP) or equivalent and to decrease
the dose if symptoms are controlled after three months. If symptoms
are not controlled, a LABA should be added, which is most
conveniently given by switching to a combination inhaler.

38. • The dose of controller should be adjusted accordingly, as judged by the
need for a rescue inhaler. Low doses of theophylline or an antileukotriene
may also be considered as an add-on therapy, but these are less effective
than LABA
• If asthma is not controlled despite the maximal recommended dose of
inhaled therapy, it is important to check adherence and inhaler technique.
In these patients, maintenance treatment with an OCS may be needed and
the lowest dose that maintains control should be used.
• Occasionally omalizumab and anti-IL-5 may be tried in steroid-
dependent asthmatics who are not well controlled. Once asthma is
controlled, it is important to slowly decrease therapy in order to find the
optimal dose to control symptoms.

39. Fig 5: Stepwise approach to asthma therapy according to the severity of asthma and ability to
control symptoms. ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; OCS, oral corticosteroid

40. Case history: A 45 yr old female patient presented to the casualty with
chief complaint of dyspnoea,cough and chest tightness,fear of impending
doom since 3 hours. The patient is unable to speak full sentences, highly
uncomfortable, unable to lie down and using accessory muscles for
respiration.
Vitals: BP – 140/90 mm of Hg, PR: 138/min, RR: 30/min, SpO2: 75%
On examination, there is bilateral expiratory wheeze, diffusely present over
the chest.
Patient is a known asthmatic since 10 yrs,not using medications since few
months.

41. Discussion
Acute severe exacerbation of asthma
Clinical features
1.SOB at rest,
2.use of accessory muscles for respiration,
3.RR>30/min,
4.HR>120/min,
5.B/L wheeze diffusely over lungs
6.Pulsus Paradoxus: Fall in B.P. by 12 mm of Hg on inspiration.
Functional criteria: PEFR <50%; Sp02<90%; paO2 <60mm of Hg

42. SILENT CHEST
• Life threatening sign
• On auscultation there is no wheeze, giving a false impression of patient
recovery.
• No sounds are heard due to complete closure of airways .
• Other signs which help in diagnosis are:
1. Altered sensorium
2. Decreased respiratory effort
3. Decreased sPO2,increased Paco2.

43. Treatment of acute exacerbation of asthma
1. Oxygen support
2. Nebulisation with SABA: Salbutamol 5mg by jet every 20min for 3 doses.
Later 2.5-5mg every 1 hr for 4 hrs; SAMA and Inhalational corticosteroids.
3. Systemic Steroids: Injection Hydrocortisone 100mg IV stat
4. If not improving, a trial of IV MgSO4 2gm infusion over 20min can be
given
5. IV Theophylline is useful in acute exacerbation not responding to ICS.
6. In life threatening asthma, patient might need invasive mechanical
ventilation.

44. Differential diagnosis
• In foreign body obstruction, stridor is present .
• In upper airway obstruction, secondary to tumour, stridor and localized
wheeze is present.
• In LVF, bilateral basal crepts, raised JVP, pedal edema are present.
• COPD : Irreversible damage to the airways occurs.
Persistent cough is present and symptoms show less variability.
No Bronchodilator reversibility is seen.

45. ASTHMA COPD OVERLAP
• Few asthmatics who are smokers show features of COPD
• Similarly some patients with COPD show bronchodilator reversibility
and increased airway and blood eosinophils.
• They may benefit from triple therapy with ICS, LABA and LAMA.

46. Refractory Asthma
• A small proportion of patients (~5%) are difficult to control despite
maximal inhaled therapy. It is important to check adherence to therapy
and inhaler technique. Some of these patients will require maintenance
treatment with OCS.
• There are two major patterns of difficult asthma: some patients have
persistent symptoms and poor lung function, despite appropriate
therapy, whereas others may have normal or near normal lung function
but intermittent, severe (sometimes life-threatening) exacerbations.

47. Corticosteroid-Resistant Asthma
• It is defined by a failure to respond to a high dose of oral
prednisone/prednisolone (40 mg once daily over 2 weeks)
TREATMENT
• Low doses of theophylline
• Maintenance treatment with OCS
• Omalizumab- Allergic asthma
• Anti-IL-5 – Mepolizumab, Reslizumab

48. Technique of using MDI

49. REFERENCES
• Harrisons Principles of Internal Medicine, 20th edition
• Fishman’s Pulmonary Diseases and Disorders

50. THANK YOU