By Dr Ashok Kumar

Asthma

is a syndrome characterized by airflow obstruction that varies markedly, both spontaneously and with treatment.
is a heterogeneous inflammatory disease of the airways. that makes them more responsive than non-asthmatics to a wide range of triggers, leading to excessive narrowing with reduced airflow, symptomatic wheezing and dyspnea.

Asthma

 Asthma

is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors and triggers have been identified. Upper respiratory tract virus infections such as rhinovirus, respiratory syncytial virus, and coronavirus are the most common triggers of acute severe exacerbations.

 There

is chronic inflammation in the respiratory mucosa from the trachea to terminal bronchioles. The airway mucosa is infiltrated with activated eosinophils and T lymphocytes, and there is activation of mucosal mast cells. Airway Remodeling with increased airway smooth muscle, fibrosis, angiogenesis, and mucus gland hyperplasia. The airway inflammation in asthma is associated with airway hyper-responsiveness.

 The

diagnosis of asthma is usually apparent from the symptoms of wheezing, dyspnea, and coughing. Variable and intermittent airways obstruction, and airway hyperresponsiveness are diagnostic. Confirmed by objective measurements of lung function.

 Simple

spirometry confirms airflow limitation with a reduced FEV1, FEV1/FVC ratio, and Peek Expiratory Flow. Reversibility is demonstrated by a >12% and 200-mL increase in FEV1 15 minutes after an inhaled short-acting B2-agonist or in some patients by a 2 to 4 week trial of oral corticosteroids.

 The

increased airway response is normally measured by methacholine or histamine challenge with calculation of concentration that reduces FEV1 by 20%. This is rarely useful in clinical practice.

Non-Pharmacological
Treatment

begins with the identification and elimination of possible environmental inhalant allergens that can trigger symptoms. Substantially reducing exposure to these allergens significantly reduces lung inflammation, improves clinical symptoms, and decreases the need for medications. Allergen Immunotherapy is another option that has been shown to provide similar effects.

 1. 2. 3.

Numerous agents are used, including Inhaled corticosteroids (ICSs) 2 agonists (short and long acting) Leukotriene antagonists, Cromones, Monoclonal antibodies. Of these, ICSs remain the mainstay of treatment for persistent asthma according to various guidelines.

4.
5.

 ICS

decrease airway inflammation and remodeling, hyper-responsiveness, improve asthma symptoms and decrease morbidity.

These

are now considered first-line therapy in the management of persistent asthma. ICS therapy has been shown to have long-term efficacy in adults as well as children.

There are currently 6 ICSs approved by the US FDA

1.
2. 3. 4. 5. 6.

Beclomethasone dipropionate (BDP) Budesonide (BUD), Triamcinolone acetonide (TA) Flunisolide, Fluticasone propionate (FP), and Mometasone furoate (MF). All of these ICSs are effective and safe, although therapeutic profiles differ slightly among ICSs.

 Local :
oral

candidiasis, dysphonia, and cough.

Systemic :
Skin

thinning and bruising. Bone mineral density can be reduced with long-term, high-dose therapy. Risk of cataracts and glaucoma may be increased. In children, growth suppression and adrenal suppression are seen with high doses.

Step 5 Step 4 Step 3 Step 2 Step 1

Class ICS

Examples Ciclesonide

Dissociated steroids

Soft steroids IgE and Mast Cell Targets Omalizumab

Mechanism of action Local activation, depot formation, rapid metabolism. Transrepression without Transactivation. Drug inactivated when not in lungs Anti-IgE therapy Anti-CD23 antibody

Lumiliximab

Spleen tyrosine kinase Inhibits Mast cell (Syk) inhibitors signaling.

Novel AntiInflammatory Agents Cytokine Inhibitors

Roflumilast

PDE4 inhibitor

Soluble IL-4 receptor

Mepoluzimab Suplatast tosilate Daclizumab Etanercept

IL-4 antagonist
IL-5 antagonist Suppresses IL-4 and IL-5 IL-2 receptor antagonist TNF- antagonist

Vaccines

AIC vaccine (DNA vaccine)

Toll-like receptor 9 agonists

 The

anti-inflammatory action of Corticosteroids are mediated by inhibition of transcription (transrepression), whereas associated side effects are mediated by transactivation of gene expression. Dissociated steroids have only transrepression activity without transactivation

Soft steroids :
These

unique steroids are pharmacologically active at the desired site, but their distribution away from the site results in rapid metabolic deactivation that prevents toxicity.

 Ciclesonide

is a prodrug soft steroid that is activated in the lungs to active metabolite des-ciclesonide (des-CIC). Des-CIC has 100 times greater affinity for the GR than CIC. Once in the circulation undergoes extensive first-pass metabolism (>99%) by the liver. Bioavailability of CIC is <1%. Incidence of local side effects (pharyngitis, candidiasis, or dysphonia) similar to or less than placebo.

 Omalizumab

is a recombinant humanized monoclonal anti-IgE antibody approved for clinical use in severe asthma. It binds circulating IgE and thereby prevents it from attaching to mast cells. It does not affect IgE bound to mast cells, it can take weeks to months for IgE bound to mast cells to disappear.

 Lumiliximab

: An anti-CD23 antibody, acts as an immunomodulator, reduces IgE concentrations in patients with mild asthma. Spleen tyrosine kinase (Syk) is involved in the activation of mast cells through IgEdependent pathway. R112 is inhibitor of Syk, has been shown to decrease nasal symptoms in patients with allergic rhinitis. More studies are needed to test its efficacy in asthma.

 Th2

cells produce interleukins IL-4, IL-5, and IL13, all of which are important in asthma and other allergic diseases. Mepolizumab is a monoclonal antibody that targets IL-5, it effectively reduced eosinophil levels in blood and sputum. Pitrakinra is a recombinant IL4 that acts as a competitive antagonist at IL4 and IL13. Nebulized pitrakinra has improved FEV1 and decreased inflamation.

 Etanercept

shown a decrease in bronchial hyperresponsiveness, improved FEV1 and athma related quality of life. Infliximab did not show any improvement in peak expiratory flow rates. Long term treatment with anti-TNF agents can cause reactivation of chronic infections like Tuberculosis.

 Theophylline

was commonly used in the management of asthma in the past. is a nonselective phosphodiesterase (PDE) inhibitor has significant side effects. Roflumilast is a selective PDE4 inhibitor given orally, inhibit both early and late asthmatic responses, effects are comparable to low doses of inhaled steroids. Cilomilast is another PDE4 inhibitor under evaluation

Bronchial Thermoplasty
Smooth

muscle hypertrophy is an important finding in severe athma. smooth muscle mass can be reduced with controlled delivery of thermal energy to bronchial wall during bronchoscopy. Studies have shown that Thermoplasty reduces severe exacerabations and improves quality of life.

Allergen immunotherapy represents the only disease-modifying treatment that can potentially alter the natural course of asthma. A new form of immunotherapy is using oligodeoxynucleotides (short single-stranded synthetic DNA molecules) as conjugates. CpG oligonucleotides (CpG-ODN, resembling bacterial DNA) engage Toll-Like Receptor 9 on Bcells, dendritic cells resulting in induction of Th1-type and T-regulatory-type immune responses.

 There

will be shift of Th2 IgE to Th1 CMI response for the conjugated antigen, after repeated exposure. are potent inhibitors of atopic responses, suppressing Th2 cytokine and, reducing airway eosinophilia, systemic levels of IgE.

CpG-Oligonucleotides

Amb a1 (a ragweed-pollen antigen) Immunostimulatory oligonucleotide Conjugated(AIC) vaccine was shown to offer long-term clinical efficacy in the treatment of ragweed allergic rhinitis. Immunotherapy found to be more effective for allergic rhinitis than for asthma

 It

is estimated that about 40% of cases asthma is based on neutrophilic airway inflammation. Possibly triggered by environmental exposure to bacterial endotoxin, particulate air pollution, and ozone, as well as viral infections. Patients with non-eosinophilic athma have increased neutrophils and IL8 in their airways.

 Cartocosteroids

are of limited efficacy in non-eosinophilic athma. Macrolides like Clarithomycin and Telithromycin are active against Atypical bacteria, which are known to cause acute exacerebations. They also have anti-inflammatory action, have been shown to be effective in acute exacerbations of asthma.

 Magnesium

sulphate is smooth musle

relaxant. Intravenous magnesium sulphate is a safe treatment for acute asthma. Doses of up to 40 mg/kg/day (maximum 2 g) by slow infusion have been used. It can also given by nebulisation.

 Theoretically

furosemide can produce bronchodilation.

failed to show any significant benefit of treatment with nebulised furosemide compared to 2 agonists.

Studies