§ Introduction

§ Epidemiology
§ Aetiology
§ Pathophysiology
§ Clinical Manifestation
 Definition:
Ø Asthma is a chronic inflammatory disease of airways
Ø Asthma is a Condition of Tracheobronchial hyperactivity to various
stimuli leading to episodic bronchospasm and reversible airway
obstruction.
Ø Common symptoms are caused by hyper responsive airways and include
coughing, wheezing, chest tightness and shortness of breath,
Ø The word asthma is of Greek origin and means “panting.”
 Classification of asthma
Ø Atopic/early onset/Extrinsic Asthma:
Ø This is triggered by allergens. Hence, it is also termed as allergic asthma.
Extrinsic asthma is commonly seen in children. About ninety percent of childhood asthma cases are
due to allergens. Individuals with a family history of allergens are at more risk for extrinsic asthma.
Ø Non-atopic/late onset/Intrinsic asthma
Ø It is very hard to treat intrinsic asthma as the causative agent is unknown. It is generally caused by
extremes of emotional feelings like laughing, crying, or contact with chemicals like cigarette smoke,
aspirin, cleaning agents or chest infection or exercises. These agents act by stimulating the response of
the nerves in the air passage.
Ø Exercise induced asthma is a subtype of intrinsic asthma. It is generally seen immediately after
exercising.
Ø A subtype of asthma called the nocturnal asthma is observed in the early hours of the night in
between 2 to 4. It is common with both extrinsic and intrinsic asthma patients. It is essential to treat
this type of asthma to prevent deaths due to asthma in sleep.
 EPIDEMIOLOGY
Ø Bronchial asthma occurs at all ages but predominantly in early life.

Ø 5 % of adults and 7-10 % of children suffer from asthma.

Ø About one-half of cases develop before age 10, and another third occur
before age 40. In childhood, there is 2:1 male/female preponderance.

Ø Up to age 30, asthma is more prevelanent in males; after age of 30, men
and women are equally affected.

Ø Up to 50 % cases of childhood asthma resolve by adulthood.

 AETIOLOGY
1. Precipitating factors of acute asthma attack include:
Ø Allergens
Air bone pollens (grass, trees, weeds), house-dust mites, animal danders, cockroaches,
fungal spores
Ø Respiratory infection
Respiratory syncytial virus (RSV), rhinovirus, influenza, parainfluenza, Mycoplasma
Pneumonia
Ø Exercise
Particularly in cold, dry climate
Ø Environmental exposure
Cold air, fog, sulfur dioxide, nitrogen dioxide, tobacco smoke, wood smoke
Ø Emotions
Anxiety, stress, laughter
Ø Occupational stimuli
Bakers (flour dust); farmers (hay mold); chemical workers (azo dyes, anthraquinone)
plastics, rubber, and wood workers (formaldehyde)
Ø Drugs/preservatives: Two different mechanism can trigger drug induced asthma
 Hypersensitivity reaction due to drugs (e.g Aspirin, ibuprofen, pencillin, products
containing tartrazine) with release of broncho active mediators.
 Extension of pharmacologic effect (β-blockers and bethanechol)
Ø Foods
 A rare case but examples include nut, fish, seafood, dairy products, food colouring especially
tartrazine, benzoic acid, and sodium meta bisulphite
2. Atopy
Ø The body’s predisposition to develop an antibody called immunoglobulin E (IgE) in
response to exposure to environmental allergens
Ø Can be measured in the blood
Ø Includes allergic rhinitis, asthma, hay fever, and eczema
3. Idiosyncratic/non-atopic/late onset asthma
Ø No allergic diseases,(-)skin tests, normal IgE, symptoms
 Some allergens which may cause asthma
Spittle, excrements,
House-dust mites which live in hair and fur
carpets, mattresses and of domestic
upholstered furniture animals

Plant pollen

Dust of Food components

Pharmacological
book (stabilizers, genetically
agents (enzymes,
depo- modified products)
sitories antibiotics, vaccines,
serums)
 PATHOPHYSIOLOGY
The major characteristics of asthma include a variable degree of:
Ø Airflow obstruction (related to bronchospasm, edema, and hypersecretion)
Ø Bronchial hyper responsiveness
Ø Airway inflammation.
A. Early phase Allergic reaction
There is immediate response to an antigen.
peak effect 10-30 mins; duration:1.5 to 3.0 hours
Inhaled allergens cause an early-phase allergic reaction .
The allergen reacts with immunoglobulin E (IgE) antibodies. There is rapid activation of
airway mast cells and macrophages, which release pro-inflammatory mediators such as
histamine and leukotrienes that induce contraction of airway smooth muscle, mucus
secretion, vasodilation, and exudation of plasma in the airways. Plasma protein leakage
induces a thickened, engorged, edematous airway wall and a narrowing of the airway
lumen with reduced mucus clearance.
 Late phase inflammatory reaction
The late-phase inflammatory reaction occurs 6 to 9 hours after allergen provocation.
Cells involved in chronic allergic inflammation
1. Eosinophils
2. T-lymphocytes
3. Mast cells
4. Alveolar macrophages
5. Neutrophils

 Eosinophils migrate to the airways and release inflammatory mediators (leukotrienes and
granule proteins), cytotoxic mediators, and cytokines. Leukotrienes C4, D4, and E4 are
released during inflammatory processes in the lung and produce bronchospasm, mucus
secretion,

 T-lymphocyte activation leads to release of cytokines from type 2 T-helper (TH2) cells that
mediate allergic inflammation (interleukin [IL]-4, IL-5, and IL-13). Conversely, type 1 T-
helper (TH1) cells produce IL-2 and interferon-γ that are essential for cellular defense
mechanisms. Allergic asthmatic inflammation may result from an imbalance between TH1
and TH2 cells.
ØMast cell degranulation in response to allergens results in release of mediators
such as histamine; eosinophil, and neutrophil chemotactic factors leukotrienes
C4, D4, and E4; prostaglandins; and platelet-activating factor (PAF). Histamine
is capable of inducing smooth muscle constriction and bronchospasm and may
play a role in mucosal edema and mucus secretion.

Alveolar macrophages release a number of inflammatory mediators, including

PAF and leukotrienes B4, C4, and D4. Production of neutrophil chemotactic
factor and eosinophil chemotactic factor furthers the inflammatory process.

Neutrophils are also a source of mediators (PAFs, prostaglandins,

thromboxanes, and leukotrienes) that contribute to BHR and airway
inflammation.
Failure to adequately minimize severe and long term air way inflammation in
asthma may result in airway remodellung in some patients
Inflammation in Asthma
Asthma: Pathological changes
C L I N I C A L PRESENTATION OFCHRONIC
AMBULATORY ASTHMA
GENERAL

Asthma is a disease of exacerbation and remission, so the patient may not have

any signs or symptoms at the time of exam.

SYMPTOMS

Dyspnea

chest tightness

coughing (particularly at night)

wheezing, or a whistling sound when breathing, these often occur in association

with exercise, but also occur spontaneously or in association with known

allergens.
SIGNS
Expiratory wheezing on auscultation, dry hacking cough, or
signs of atopy (allergic rhinitis and/or eczema) may occur.
INVESTIGATIONS /LABORATORY TESTS
Ø Spirometry demonstrates obstruction (FEV1/FVC less than 80%) with reversibility following
inhaled β2-agonist administration (at least a 12% improvement in FEV1).
OTHER DIAGNOSTIC TESTS
Ø A fall in FEV1 of at least 20% following 6 minutes of near maximal exercise
Ø Blood count: Slightly elevated white blood cell , eosinophil count and lgE concentration in
blood during an acute attack.
Ø Elevated FeNO (greater than 12ppb)
Ø Positive methacholine challenge (PC20 FEV1 less than 12.5 mg/mL
SEVERE ACUTE ASTHMA
Ø Uncontrolled asthma, with its inherent variability, can progress to an
acute state where inflammation, airways
edema, excessive accumulation of mucus, and severe
bronchospasm result in a profound airways narrowing
that is poorly responsive to usual bronchodilator therapy
C L I N I C A L PRESENTATION SE V E R E
ACUTE ASTHMA
GENERAL
An episode can progress over several days or hours (usual scenario) or
progresses rapidly over 1 to 2 hours.
SYMPTOMS
Ø Severe dyspnea
Ø Shortness of breath, chest tightness, or burning.
Ø The patient is only able to say a few words with each breath.
Ø Symptoms are unresponsive to usual measures (inhaled β2- agonist
administration.
SIGNS
Ø Expiratory and inspiratory wheezing on auscultation(breath sounds may
be diminished with very severe obstruction)
Ø Dry hacking cough
Ø Tachypnea
Ø Tachycardia
Ø Pale or cyanotic skin
Ø Hyperinflated chest with intercostal and supraclavicular retractions,
hypoxic seizures if very severe
Ø Normal or slightly elevated temperature.
Investigations/ Laboratory Test
Ø Pulmonary function Test : PEF and/or FEV1 less than
50% of normal predicted values.
Ø Arterial blood gas measurement: Decreased arterial
oxygen (PaO2), andO2 saturations by pulse oximetry (SaO2
less than 90% on room air is moderate to severe).
Ø Decreased arterial or capillary CO2 if mild, but in the
normal range or increased in moderate to severe
obstruction
 OTHER DIAGNOSTIC TESTS
Ø Blood gases to assess metabolic acidosis (lactic acidosis) in severe
obstruction.
Ø Complete blood count if there are signs of infection (fever and
purulent sputum).
Ø Serum electrolytes as therapy with β2-agonist and corticosteroids can
lower serum potassium and magnesium and increase glucose.
Ø Chest radiograph if signs of consolidation on auscultation.
Ø Electrocardiogram (ECG) may show sinus tachycardia
Ø Skin prick test may identify allergens than trigger asthma
Ø Oseophagal Scopy
 Stages of Severity of an acute asthma attack
Symptoms FEV1 or FVC Arterial PaO2 PaCo2
pH

I: Mild Mild dyspnea and wheezing 50- 80 % of normal Normal or Normal or Normal or
increase decrease decrease

II: Moderate Respiratory distress at rest 50 % of normal Increase Decrease Decrease

and marked wheezing

III :Severe Marked respiratory distress, <50 % of normal Normal or Decrease Normal or
loud wheezing, coughing, decrease increase
difficult speaking, accessory
chest muscle use and chest
hyperinflation

IV: Respiratory Severe respiratory distress, <25% of normal Markedly Decrease Markedly
failure Confusion, lethargy, decrease increase
cyanosis, disappearance of
breath sound, and pulsus
paradoxus >12 mmHg
 Treatment Objective
Ø Relieve symptoms and thus enable the patients to carry on normal daily activities

Ø Improve pulmonary functions

Ø Control life threatening disease exacerbations

Ø Prevent complications

Ø Identify and eliminate causative agents, thus reducing the incidence of acute asthma attacks

Ø Treat any chronic symptoms

Ø Prevent or manage disease complications

Ø Teach the patients about the disease state , proper use of medication, and possible side effects,

thereby improving compliance and promoting preventive measures

 Drug therapy
The pharmacological agents used to treat asthma are divided
into two board categories
Relievers and controllers
Relievers
- These drugs are used to treat an acute attack (Rescue medications)
- Quick relief of symptoms
- Action lasts 4-6 hrs
e.g: Bronchodilator (beta2 agonist)
Preventers
- Prevent future attacks
- Long term control of asthma
- Prevent airway remodelling
 PREVENTERS
Corticosteroids Anti-leukotrienes
Prednisolone, Betamethasone Montelukast, Zafirlukast
Beclomethasone, Budesonide
Fluticasone Xanthines
Theophylline

Long acting 2 agonists Mast cell stabilisers

Bambuterol, Salmeterol Sodium cromoglycate
Formoterol

COMBINATIONS
Salmeterol/Fluticasone
Formoterol/Budesonide
Salbutamol/Beclomethasone
Therapy
Management of acute asthma
A. β-adrenergic drugs: e.g. Isoproterenol, epinephrine, metaproterenol,
terbutaline
ᵝ-adrenergic receptor agonist

Selective Non selective (adrenaline, Isoprenaline)

Long acting: salmetrol, formetrol
Short acting: salbutamol; Isoetharine
These drugs
Relaxes smooth muscle present of airways; Enhances mucociliary clearance from the
respiratory tract; Inhibit mediator release from the mast cell and basophil and
cytokine from the inflammatory cells in the airways.
Therapeutic effects: relieve bronchoconstriction
Administration and dosage:
These drugs are given to asthmatics via a nebulizer or
metered dose inhaler (MDI) because of longer duration and
fewer side effects when compared to other dosage forms
Precautions and Monitoring Effects:
Drugs should be used cautiously in patients with a history of
 arrhythmias,
 coronary artery disease,
 hypertension or diabetes.
Ø Nervous system effects : Tremor, nervousness, headache, dizziness,
weakness and insomnia
Ø Palpitations and tachycardia occur. Pulse rate should be monitored
closely in patients receiving any of β – Adrenergic agents.
Ø Epinephrine and isoproterenol in repeated dose may cause
myocardial ischemia and arrhythmias.
Theophylline compounds :
These spasmolytic agents can be administered if β – Adrenergic agents fail to
control an acute asthma attack.
Therapeutics effect: relax bronchial smooth muscle, reduce mucus secretion,
enhance mucociliary transport
Administration and dosage :
Intravenous therapy: Theophylline and Aminophylline
Theophylline: The usual loading dose for adults and children is 5-6 mg/kg based
On lean body weight, administered over 30 minutes. Loading dose for obese
patients (i.e weight greater than 20 % standard weight) should be based on total
body weight. Aminophylline contains 80 % theophylline. Dosage for aminophylline
is approximately 1.2 times that of theophylline
Ø Maintenance dose is administered by continuous infusion and is adjusted by
monitoring theophylline Serum levels. Maintenance dose for obese patients should be
based on lean body weight.
Precautions and monitoring effects: These drugs are contraindicated in
Ø patients with Hypersensitivity to xanthin compound & with a history of arrhythmias
Caution use is indicated in patients with
Ø Peptic ulcer disease, Gout, Coronary artery disease & Diabetics Mellitus
Adverse effect
CNS effect: dizziness, restlessness, insomnia, convulsions
Ø Palpitations and tachycardia
Ø Gastrointestinal effects: nausea, vomiting, anorexia
Corticosteroids
Corticosteroids (e.g., beclomethasone, betamethasone, hydrocortisone ,
Prednisone)
Therapeutic effects: suppress the inflammatory response.
Mechanism of action:
Ø Decrease inflammatory cell activation, recruitment, and infiltration
Ø Decrease mucus production
Ø Decreased metabolites of Arachidonic acid (prostaglandins, leukotrienes)
Administration and dosage
Ø Intravenous corticosteroids are administered when the patient cannot use
the oral route during acute asthma attack. The duration of therapy is short
but may be continued as oral therapy if symptoms persist; the dose is then
rapidly tapered. Hydrocortisone and Methylprednisolone are the most
commonly used agents.
Ø Beclomethasone, dexamethasone, flunisolide, budesonide are available in
aerosol form, which is preferred because of lower incidence of adverse
effect.
Ø Prednisone and prednisolone are the preferred oral agents
Precaution and monitoring effects
 Corticosteroids should be used cautiously in elderly and paediatric
patients and in those with Diabetes mellitus, hypothyroidism,
peptic ulcers or other gastrointestinal diseases, chronic infections,
cushing’s syndrome, myasthenia gravis, and psychotic tendencies.
 Inhaled steroids may cause local effect such as dry mouth, fungal
infection of mouth and throat (spacer device reduces these adverse
effect)
Other drugs
Anticholinergic Drugs may cause bronchodilation by inhibiting acetylcholine
stimulation of efferent vagal pathways , reducing intrinsic vagal tone to bronchial
smooth muscle.
During an acute attack, anticholinergic may be synergistic when combined with β
adrenergic agonists and should be used only as second line therapy in selected
Patients.
a) Aerosolized atropine usage decreased due to high incidence of adverse effects
b) Ipatropium bromide can be given to patients with acute and chronic asthma
poorly controlled by β-adrenergic alone. The nebulized form is more effective in
acute attacks. The Dose for maintenance therapy is two to four inhalations every
6 hours.
AntiHistamines Terfenadine and astemizole
Help to prevent the histamine mediated responses that influenzes asthma.
These agents are useful for patients with allergic rhinitis.
Antibiotics are administered if the patient has a known or suspected
bacterial infection as suggested by yellow, green, or brown sputum
Non pharmacological treatment
Humidified oxygen is administered to all patients with severe acute asthma
to reverse hypoxemia.
Intravenous fluids and electrolytes may be required if the patient is
dehydrated.
Chronic asthma
Goal of therapy: To decrease morbidity and mortality of asthma by early
treatment.
Chronic asthma occurs when symptoms are most frequent and require
long term prophylactic therapy.
Ø β- adrenergic agonists by inhalation are used alone for mild-
moderate episodes and also for chronic prophylaxis in patients with
frequent symptoms.
Ø Proper use of MDI with or without a spacing device increase the
efficacy of these agents.
Ø Corticosteroids are used in combination with other agents for the
treatment of moderate to severe chronic asthma.
Ø Inhaled corticosteroids are used for moderate episodes or as chronic
prophylaxis
Ø Short course oral therapy are used when the intermittent episodes are
severe. Prednisone is given high dose (40-80 mg/day in adults )for upto
5-10 days, then rapidly tapered
Cromolyn sodium
 To treat mild, moderate, or severe chronic asthma; it sometimes helps to reduce
the amount of corticosteroid needed.
 Prophylactic treatment for exercise induced asthma and seasonal asthma.
 This drug has no value of an acute asthma attack
Therapeutic effect: Suppress allergan induced bronchospasm.
Mechanism o f Action: Cromolyn acts locally on the lung mucosa, inhibiting the
degranulation of sensitized mast cells . It suppress the release of histamine and
other mediators from mast cells, thereby Decreasing the stimulus for bronchospasm.
Administration and dosage: Cromolyn is available as 20 mg capsule whose
contents are inhaled via special turbo inhaler, as a nebulizer solution (20 mg/2 mL),
and as a MDI, providing 0.8 mg per inhalation.
Theophylline
Ø Added to regimen when therapy other inhaled agents has been
maximized. This agent is most beneficial in patients with early morning
symptoms. Serum monitoring level, adverse drug reaction and
concomitant drug use is essential for long term therapy.
Anticholinergic agents
Especially ipatropium bromide are effective bronchodialators may be
added instead of theophylline or when theophylline therapy has failed
Antileukotrienes
 Cysteinyl-leukotrienes are potent bronchoconstrictors,
cause microvascular leakage, and increase eosinophilic
inflammation through the activation of cys-LT1-receptors.
These inf lammatory mediators are produced
predominantly by mast cells and, to a lesser extent,
eosinophils in asthma.
 Antileukotrienes, such as montelukast and zafirlukast,
block cys-LT1-receptors and provide modest clinical benefit
in asthma. genomic differences in the leukotriene pathway.
ASTHMA - Using Inhalation Therapy

ØInhalation therapy is the most widely used therapies for the

treatment of asthma. Inhalation therapy is the most effective,
safe and cost effective of all therapy.

Ø Specific agents (e.g., cromolyn, nedocromil, formoterol,

salmeterol, and ipratropium) are only effective by inhalation
Why inhalation therapy?
Oral
Inhaled route
Slow onset of action
Rapid onset of action

Large dosage used Less amount of drug

used
Greater side effects Better tolerated
Not useful in acute Treatment of choice
symptoms
in acute symptoms
Aerosol Delivery system
The three principle types of devices widely used are
Ø MDI :Metered dose inhalers
Ø DPI: Dry powder inhalers
Ø Nebulizer

Metered Dose inhaler

Nebulizer mask
Dry Powder
 Metered dose Inhalers

MDI consist of
Ø a pressurized canister with a metering valve
Ø The canister contains active drug, low-vapor-pressure propellants such as
chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA), cosolvents, and/or
surfactants.
Ø Metered dose aerosol inhalers contain a suspension of Active drug, with a
typical particle size 2-5 µm in a liquefied propellant. Operation of the device
releases a metered dose of the drug with a droplet size of 35-45 µm. The
increased droplet size is due to the propallent which evaporates when expelled
from the container.
Metered Dose Inhaler Metering valve
How MDI Technology Works
Spacer
©1998,.

©1998,
Respironics Inc.
 Spacer Devices
Ø Holding chamber or reservoir
Ø Attachment to a MDI
Ø 2 types
§ Small volume spacer tube-spacer
§ Large volume spacer conical spacer
Advantage:
Ø Increases drug disposition in the lungs
Ø Decrease drug disposition in the mouth
 Drugs available MDI
Ø β agonists
Salbutamol (albuterol), terbutiline, fenoterol, salmetrol, fometerol
Ø Steroids
Budesonide (Pulmicort); Fluticasone(Flovent); Beclomethasone
(Beclovent)
Ø Anticholinergic
Ipatropium bromide (Atrovent), oxitropium bromide
Ø Mast cell stabilizer
Nedocromial sodium
Dry powder inhalers
Ø A Dry powder inhaler (DPI) is a device that delivers medication to the lungs
in the form of a dry powder
Ø This is device used to deliver a measured dose of medicine in a powdered
form. The medicine in powdered form is packed inside a capsule, the
powder inhaler device is used to break open the capsule and inhale its
contents.
Accuhalers
Ø Accuhalers contain medication as a dry powder.
Ø Diskhaler dry powder inhaler. The drug is kept in a series of little
pouches on a disk; the diskhaler punctures the pouch and drug
is inhaled through the mouthpiece
Ø Rotahaler dry powder inhaler used with Rotacaps capsules. Each
capsule contains one dose; the inhaler opens the capsule such
that the powder may be inhaled through the mouthpiece.
 Nebulizer
Ø This device is used to deliver higher dose of medications when the
breathing becomes too difficult
Ø Turns an aqueous solution of drug into fine mist
Ø Drugs will be inhaled with normal respiration
Ø Medication reaches lower airways more effectively
Ø Two types-jet & ultrasonic nebulizer
Jet Nebulizer Ultrasonic nebulizer
Cools during operation Heat up during operation
Less expensive More expensive
Small aerosol particle size Large aerosol particle size
Drugs available for nebulizer
Øβ agonists
Salbutamol, terbutiline, fenoterol
ØAnticholinergics
Ipatropium bromide
ØSteroids
Budesonide
ØSodium cromoglycoate
 Choice of inhalation therapy

Ø Infants Nebulizer
Ø Children
 ˂ 4 years Nebulizer
 4 years DPI/MDI/spacer
 7 years DPI/MDI
Ø Adults DPI/MDI
Ø Acute episodes Nebulizer
 Advantages of Inhalation therapy

 Smaller dose of medication

 Target delivery of medication,
 Quicker action
 Safe
 Three Steps of Asthma Treatment

Step 1 - Control bronchospasm with short- acting b2 agonists or long-acting

salmeterol

Step 2 - Control inflammation with inhaled corticosteroids or leukotriene

antagonist

Step 3 - Control severe exacerbation with oral corticosteroids

The primary therapy of acute exacerbations is pharmacologic, which includes

inhaled short-acting β2-agonists and, depending on the severity, systemic
corticosteroids and O2
 Symptoms/Day PEF or FEV1 Daily Medications
Symptoms/Night PEF variability
STEP 4 Continual ≤ 60% Preferred treatment:
Severe Frequent ˃30% – High-dose inhaled corticosteroids
Persistent AND
– Long-acting inhaled beta 2-agonists
AND, if needed,
– Corticosteroid tablets or syrup long term (2
mg/kg/day, generally do not exceed 60 mg per day).
(Make repeat attempts to reduce systemic
corticosteroids and maintain control with high-dose
inhaled corticosteroid
STEP 3 Daily ˃ 60% – <80% Preferred treatment:
Moderate ˃ 1 night/week – Low-to-medium dose inhaled corticosteroids and
Persistent Long-acting inhaled beta 2-agonists.
• Alternative treatment
– Increase inhaled corticosteroids within medium-dose
range OR
– Low- to medium-dose inhaled corticosteroids and
either leukotriene modifier or theophylline.
 Symptoms/Day PEF or FEV1 Daily Medications
Symptoms/Night

STEP 2 ˃2/week but ≥ 80% • Preferred treatment:

Mild ˂ 1x/day – Low-dose inhaled corticosteroids.
Persistent ˃ 2 nights/month • Alternative treatment : cromolyn,
leukotriene modifier, nedocromil, OR sustained
release theophylline to serum concentration of
5–15 mcg/mL.
STEP 1 ≤ 2days/week ˃ 60% – <80% • No daily medication needed.
Mild ≤ 2 nights/month • Severe exacerbations may occur, separated by
Intermittent long periods of normal lung function and no
symptoms. A course of
systemic corticosteroids is recommended.

Source: Modified from National Asthma Education and Prevention

Program. Stepwise approach for managing asthma in adults and children
older than 5 years of age