Surviving Pediatric Allergies

Dr. Keya Lahiri

Professor & head, Department of Pediatrics,In-charge Pediatric Chest Clinic,

Seth G.S.M.C. & KEM Hospital, Mumbai-12

What is in the genes cannot be undone but one can definitely prevent and blunt the

manifestations by defining a at risk child by simple parameters and more so by an explicit history

taking. There is a window of opportunity for early diagnosis and intervention in infantile,

preschool and school wheezers.

Allergic Rhinobronchitis was the first definition used to identify the co-morbidity between

asthma and rhinitis. United Airways Disease, One Airway, One Disease or Combined Allergic

Rhinitis and Asthma syndrome (CARAS) have been subsequently proposed and all mean the

same. The issue has been structured as far as the diagnosis, mechanisms, links and differences

and finally ARIA – Allergic Rhinitis and its Impact on Asthma was conceived (an official

document endorsed by WHO). This document was produced through an evidence based

methodology (1).

The important recommendations of ARIA are:-

Patient with persistent rhinitis should be investigated for asthma.

Patient with asthma should be investigated for rhinitis.

A combined strategy for treatment should be carefully designed (1).

The idea that Allergic Rhinitis (AR) and Asthma are not mere co-morbidities but are rather twin

expressions of the same underlying pathology and is supported by the following evidence:

Epidemiological: Nearby 60-80% of asthma patients also suffer from AR.

Anatomical: Columnar epithelium lines the nasal as well as the bronchial mucosa.

Physiological: The nasal and bronchial mucosa are exposed to the same inhaled air, although in

the latter case, the air has been humidified and warmed by the nasal ‘air conditioner’.

Pathological: Most cells, lymphocytes and eosinophils are the inflammatory cells in asthma and

AR.

Therapeutic: Children with nasal polyposis and rhinosinusitis definitely improve on their asthma

scores after sinus surgery. Asthma may appear to be worse because a significant proportion of

cough caused by past nasal drip is misattributed to asthma (2).

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The Concept of Allergic March :

The first atopic manifestation occurs in most cases during early infancy. Atopic Dermatitis (AD)

manifests in the first 3-6 months of life and persists in the majority of cases for several months to

years before the severity abates. Immune deviation towards atopy may be already induced during

the prenatal period but atopic sensitization is not detectable at birth but develop during the first

year of life (3).

Early sensitization to food proteins as well as inhalant allergen is facilitated by allergen exposure

in a dose dependent fashion. IgE responses to food viz. cow’s milk, egg, peanuts, strawberries,

chocolates and shellfish have been described as first immunological markers for atopy, specially

cow’s milk and egg. IgE antibodies to indoor/outdoor allergens are observed several years later.

However strong tobacco smoke exposure during pregnancy and the first year of life can be

considered as an adjuvant for atopic sensitization during infancy. Hay fever does not manifest

before the third pollen season. Allergic Rhinitis is followed by asthma in the allergic march.

Hence atopic dermatitis (AD) with a positive family history of allergy should be considered as a

strong risk factor for subsequent manifestation of asthma and high IgE responses to hen’s egg

have been shown as risk factor for subsequent sensitization to inhalant allergens. These early

markers of atopy during infancy may help in identifying subgroups of children at risk, who would

be suitable candidates for early invention and preventative therapies to reduce the morbidities,

thereby lung damage and significantly improve the quality of life on a daily basis, be it at home,

school or workplace(3).

Thus logically the next approach would be to identify and define a AT RISK child and initiate

appropriate interventions and therapies.

The Roots in Infancy

There have been evidences that the cell priming is initiated in foetal life with a domination of Th-

2 cytokines but the difficulty in defining a child at risk for asthma at birth does not allow any kind

of intervention in pre or post natal period. However, cessation of maternal smoking alongwith

inhalation of external smoking is the prenatal intervention most likely to be effective in reducing

asthma risk in children. It would also be advisable to give mother hypoallergenic diet and avoid

indoor & outdoor allergens. Cord blood IgE could be estimated (4, 5).

Child born in an atopic family should be closely monitored in the well baby clinic with special or

different colour card for easy identification. The Asthma predictive index should be applied as

detailed below.

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Major risk Factors:

a) History of Asthma/Allergy in the parents

b) Eczema

c) Inhalant allergen sensitization

Minor risk Factors:

a) Allergic Rhinitis

b) Wheezing Apart from colds

c) Eosinophilia (>4%)

d) Food allergen sensitization

“1 MAJOR OR 2 MINOR” would diagnose a potential asthmatic child (4).

The at risk baby attending the well baby clinic should be closely examined and monitored for

atopic dermatitis, food allergies, specially cow’s milk, hen’s egg, shell fish, peanuts, chocolates

and strawberries. They may also manifest as recurrent episodes of bronchiolitis and/or recurrent

respiratory infections. It is however essential to rule out congenital anomalies and vegetative

foreign body in such cases with chest CT scans.

Beyond infancy, one encounters persistent preschool wheezers, allergic rhinitis and asthma.

Lower respiratory tract infections are associated with wheezing in 50% of the cases by 6 years of

age.

The 3 phenotypes identified are:-

Transient Wheezers : They manifest in the first three years and are gone by age three

Persistent Wheezers: They manifest in the first three years and still present beyond age

three.

Late onset Wheezers: Symptoms begin between 3 and 6 years of age (5).

Current research in this area is evaluating effects of early intervention with inhaled

corticosteroids, antihistamines and immunotherapy for preventing loss of lung function in the first

six years of life(6). It is well known that early intervention with second generation antihistamines

delayed the onset of asthma and the present EPAAC (Early Prevention of Asthma in Atopic

Children) study anticipates the risk reduction by 50% after administering levocetirizine for 18

months and a follow up period for 18 months. These children are cases of moderate infantile

eczema with a positive family history and specific IgE for dust mite(7).

In an interesting Melbourne Atopy Cohort Study (MACS) 620 children were selected from atopic

families, mothers were interviewed and babies examined. Atopic dermatitis was observed in

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28.9% and food allergy in 58.7% amongst the AD cases. There was increased sensitization to

mite, cat, and egg.

Early Intervention:

Theories have been developed that the early intervention with inhaled glucocorticoid therapy can

be effective in preventing the progression of the disease and the irreversible changes in the

airways that could result in progression of symptoms. Thus there appears to be “Window of

opportunity that is critical for intervention”. Treatment should be adjusted to maintain optimum

control and indirect parameters, viz. symptoms and pulmonary functions must be used to define

it. Once control is established, maintenance medication can be adjusted to the lowest daily

inhaled corticosteroid dose that stabilizes symptoms.

These children are usually required to be treated for a period of 1 to 2 years & adverse effects

such as impaired growth velocities have not been found.

A brief outline of an approach to a child with recurrent wheezing is given as follows:

An infant or preschool child with recurrent wheezing

Major risk factors: Parental Asthma, Eczema, Inhalant allergen sensitization

Minor risk factors: Allergic Rhinitis, Wheezing apart from colds, Eosinophilia (>4%),

Food allergen sensitization

(1 major or 2 minor criteria)

Initiate early intervention

Other interventions: Environmental tobacco smoke avoidance (Prenatal & post natal)

o Allergen avoidance for sensitized children

o Treatment of co-morbid conditions

o Breastfeeding for more than 4 months

o Active life style and healthy diet

Pharmacological therapy:

o Daily controller medication

o As needed quick reliever medication

o Prompt management of exacerbation

Duration of therapy: Usually transient episode in an infant or

up to 1-2 years in a preschool child.

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Goals:

Day time or exertional asthma symptoms < or = 3 times per

week

Night time asthma symptoms < or = 2 times per month.

Rescue bronchodilator use < or = 3 times per week.

Fewer and less severe exacerbation

Potential benefits:

Decreased asthma severity

Prevent or arrest airway remodeling

Fewer patients with persistent asthma

Improvement of health related quality of living (HRQoL)

Predicting persistent asthma in early childhood

NAEPP guidelines define a frequent wheezer as:

> 3 episodes of wheezing in last year

Wheezing > 2 days per week

Wheezing > 2 nights per month

Severe exacerbations within 6 weeks

Major risk factors:

Parental Asthma

Eczema

Inhalant allergen sensitization

Minor risk factors:

Allergic Rhinitis

Wheezing apart from colds

Eosinophilia (>4%)

Food allergen sensitization

As per the Tucson Childrens’ Respiratory Study, Asthma Predictive Index (during first 3 years of

life), one major or two minor criteria are suggestive of positive predictive value for asthma of

48% and for persistent wheezing of 67% and negative predictive value for asthma of 92% and for

persistent wheezing of 77%. With one of the above predictive criteria, a good follow-up will be

needed to pick up a potential asthmatic.

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Preventing asthma:

The major atopic diseases (Atopic eczema, food allergy, allergic rhinitis and asthma) can develop

in sequence or simultaneously in the same child. Atopic eczema may occur in early childhood

followed by food allergy, allergic rhinitis and or bronchial asthma. The concept of “One airway –

one disease” is supported by the common epidemiological, pathological and physiological

characteristic. The family history of atopic diseases is recognized as a major risk factor.

In any wheezer, management is simple & is easily done with newer inhalation therapies having

rapid action with minimal adverse effects. Hence timely management can be very rewarding. As

a general approach, one should identify the potential asthmatics versus non-asthmatics amongst

the wheezers using the NAEPP criteria & follow up over a period of time. Early onset wheezing

such as Bronchiolitis does not need initiation of long term therapy apart from treatment for relief

of the transient wheeze. Among the pre-school children, the natural history of disease by this

time usually establishes the “type” of disease. This entails that a persistent chronic airway

inflammation may potentially predispose to future asthma. Therefore treatment of such children

with steroids for a period of 1-2 years has proven benefits. In addition, prevention of triggers and

control of co-morbidities with proper follow up for development of disease has a “steroid

sparing” effect.

Understanding the Phathophysiology

The immune system protects us from harmful external aggressors. An allergic reaction is an

inappropriate immune response because it is mounted against agents that are not harmful for the

body, these are the allergens. The cells involved in the allergic response at the mucosal surface

have well defined roles.

Epithelial cells create a barrier to the outside world.

The mucous gland and goblet cells secrete mucus and either form a thick or a thin layer above the

epithelium.

The Dendritic cells act as immigration officers so as to stall the proteins, bacteria or parasites.

T Lymphocytes: Function as the “BRAINS” deciding the action to be taken against the protein.

B Lymphocytes: Produces antibodies which are needed to aim a mast cell for activation.

Mast cells: Lie first beneath the epithelium but they begin to migrate up between the epithelial

cells during an allergic attack. These are the primary attack cell containing histamine and other

chemicals. They can also signal eosinophils to come and help.

Eosinophils: Contain basic proteins toxic to parasites. They accumulate below the epithelium in

season attracted by signals transmitted by Mast cells and T Lymphocytes.

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Neutrophils is the primary emergency cell arriving first on the scene to restrict the damage and

seen in acute exacerbations (8).

To be able to mount an allergic response, one has to become sensitized to an allergen, a process

which educates the immune system to respond to an allergen. The dentritic cell detects the

foreign protein and breaks them down to small epitopes and pass them to the T Lymphocytes.

The T Lymphocyte being the orchestrator pass chosen episodes to B Lymphocytes with

instructions in the form of interleukins 4 and 13 to make anti bodies. These anti bodies are called

immunoglobulin E or IgE.

IgE binds to specific receptors on the mast cell surface and once armed it is ready to respond

when it encounters an allergen. Although each IgE Molecule is specific to one allergen, mast cell

bind very large number of IgE molecules and will thus respond to a wide variety of allergens.

Exposure to the specific allergen results in mast cell/activation and release of mainly histamine

into the surrounding environment termed as MAST CELL DEGRANULATION. The histamine

thus released leads to symptoms in allergic rhinitis viz. itching, sneezing, running and blocked

nose. Mast cell activation also causes release of other substances which attract eosinophils from

the blood stream and causes allergic inflammation.

Eosinophils form an important limb in the allergic defence. They contain highly toxic granules

such as major basic protein (MBP), Eosinophil cationic protein (ECP), eosinophil derived

neurotoxin (EDP) and eosinophil peroxidase (EPO). Eosinophils are responsible for aggravation

of symptoms eg nasal blockage. They also attack the epithelium and sensory nerves causing

them to be hyperresponsive to non-allergic stimuli eg nasal stuffiness to smoke & cold air. This

hyperresponsiveness is only relieved with anti-inflammatory.

The histamine and proinflammatory proteins cause the endothelial cells to express sequentially

the adhesion proteins E-Selectin, ICAM-1, VCAM-1. The release of inflammatory proteins from

the mast cells and T Lymphocytes including IL-5 and eotoxin in the blood stream makes the

eosinophil express complementary adhesion molecules which allow them to adhere to the

endothelial cells. Thus the eosinophil sticks to the blood vessel wall and thereby squeeze their

way through the wall to migrate to the appropriate allergen site(8).

The transcription factor involved in inflammation is nuclear factor - kB (NF-kB). When NF-kB is

activated by histamine or other inflammatory substances, it stimulates the production of many

adhesion proteins viz. E selectin, ICAM-1 and VCAM-1.

The events happening in asthma and hay fever are the same though there are similarities and

differences. The allergic response in the host is initiated by mast cells and histamine plays an

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important role in its manifestations. The nose and airways become hyperactive to non

immunological stimuli particularly cold air and exercise.

The allergic response in asthma is also initiated by mast cells but histamine does not have such an

important role because the smooth muscle responsible for reversible bronchospasm is much more

sensitive to leukotrienes (mediators from mast cell and eosinophils). There is also deposition of a

thick band of collagen (types 3 & 5) to replace basement membrane damaged by eosinophils and

an increase in the amount of smooth muscle in the bronchi. The main symptom of Asthma is

breathing difficulties which is due to direct consequence of smooth muscle contraction further

aggravated by mucosal swelling and mucus secretion.

Whereas in atopic dermatitis and urticaria very large amounts of histamine is released in the area

of the wheal which means large doses of potent antihistamines are required for effective relief of

symptoms. Release of histamine causes local vasodilatation and increased vascular permeability

and activation of sensory nerves. The effects are a flare and itching. Urticarias are all caused by

mast cell activation(8). Atopic dermatitis is caused by milk proteins which are absorbed through

the intestine into the blood stream and therapy get deposited in the skin. Infantile dermatitis is

seen as a typical exfoliating eczema with severe itching.

Food allergens can cause acute griping pain, nausea and diarrhoea. Anaphylaxis caused by

allergen causes proteins absorbed into the blood stream to release rapid & large amounts of

histamine from basophiles & mast cells. The resultant fall in blood pressure can prove fatal.

Antihistamines may also have antiinflammatory properties and long term use of anti histamines

ameliorates symptoms of allergic rhinitis. They activate MF-kB. The effect stimulated by NF-

kB activation include the expression on blood vessel endothelial cells of adhesion proteins

ICAM -1 and VCAM- 1 which are critically involved in eosinophil accumulation(8).

Corticosteroids act by preventing the transcription of proinflammatory proteins.

‘Minimal persistent inflammation’ is a relatively new and important concept in understanding the

link between AR and asthma. In patients with persistent AR, allergen exposure varies throughout

the year and there are periods in which there is little exposure. Even though symptom free, these

patients still present with inflammation of the nose on microscopic examination.

The transformation of acute AR into sub acute and chronic AR could lead to spread to the lower

respiratory passages because of ‘migration’ of Th2 memory cells.

The question being raised by many clinicians is that “does the treatment of AR influence the

allergic march”? The issue is highly controversial and it is still being debated whether an

appropriate control of AR would prevent the development of bronchial asthma.

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Clinical experience suggests that some patients with both diseases have a better control of asthma

when their rhinitis is adequately treated but more controlled studies are needed to confirm this

observation.

Even though we should await conclusive evidence that appropriate treatment of AR may prevent

associated diseases, it will probably help to control sinusitis and bronchial asthma and will

certainly provide a better quality of life to these patients.

A logical approach would be:

a) A careful history and physical examination

b) Family history of atopy.

c) Trigger factors

d) Drugs and food

Symptoms

The key to accurate and timely diagnosis of AR is heightened awareness of the condition and its

potential co-morbidities. One may pursue specific diagnostic testing and often administer

therapeutic trials of ant-inflammatory medications. However a good history and pertinent

examination are the most effective diagnostic manoeuvers for the identification of AR in

children.

Typical symptoms:

a) Sneezing

b) Itching

c) Rhinorrhoea

d) Congestion (nasal block)

Children either sniff, snort, clear their throats or blow their noses frequently. They also have

red, itchy eyes, ears and throat. Nasal pruritis stimulates grim acing, twitching and picking of

the nose which may lead to epistaxis.

Clear nasal secretions leads to rhinorrhoea. Nasal congestion may be bilateral or unilateral,

may alternate from side to side or more pronounced at night(9).

Associated Symptoms:

Facial pain

Anemia, disturbed taste

Post-natal drip

Disturbed sleep

Snoring

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Malaise, weakness, fatigue

Signs:

Many children develop bluish black discoloration under the lower eyelids termed as

“ALLERGIC SHINERS”. These discolorations are caused by venous stasis in the areolar

tissue of the lower orbitopalpebral grooves from pressure on veins by edematous allergic

mucous membranes of the nasal and paranasal cavities(9).

External Nasal Examination

A horizontal crease over the lower third of the nose is called “DARRIER’S LINE”. This is

caused by rubbing the nose from below upwards with palm of the hand. This action is called

the “ALLERGIC SALUTE” and is done to relieve itching and free edematous turbinates

from the septum.

The child may exhibit grimaces such as nose & mouth wrinkling which relieves the nasal

itching. Picking of the nose may result in epistaxis.

Internal Nasal Examination:

a) Deviated nasal septum

b) Expansion of the nasal bones because of nasal polyps

c) Narrowing of the nasal valve

d) Inferior turbinate hypertrophy: tender, pale purple / pink

e) Nasal polyps: Non-tender, grayish

The entire nasal mucosa takes on a grayish blue hue in allergic rhinitis.

- Abnormalities of facial development

- Dental malocclusion

- Open mouth

- Gaping habitus

In severe cases, during pollen season, mucous membranes of the eyes, eustachian tube,

middle ear and paranasal sinusus may be involved. There is conjunctival irritation (itchy,

watery eyes), redness and tearing, ear fullness & popping, itchy throat and pressure over the

cheeks and forehead. The coincidence of atopic eczema or asthma with a positive family

history of atopy point towards an allergic pathology(9).

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TREAT IN A STEPWISE APPROACH Diagnosis of allergic rhinitis(9)

(history ± skin prick tests or serum specific IgE)

|

Allergen avoidance

Intermittent symptoms Persistent symptoms

______|___________________ ________|_____________ | | | |

Mild

Not in preferred order Oral H1-

blocker Intranasal H1-

blocker And/or

decongestant

Moderate mildSevere |____________|

Not in preferred order Oral H1-blocker Intranasal H1-blocker And/or decongestant Intranasal CS (chromone)

In persistent rhinitis review the patient after 2-4 weeks

If failure step-upif improved continue

for 1 month

ModerateSevere

Intranasal CS

Review the patient after2-4 weeks

______________|_______

Improved Failure

Step down Review diagnosis and continue review compliance Treatment for query infections or1 month other causes | Increase rhinorrhea blockage Intranasal add add CS and ipratropium decongestant or oral dose Itch/sneeze CS Add H1 blocker (short Term) | Failure ====== Surgical referral

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Figure 1: Classification of allergic rhinitis(9)

IntermittentSymptoms

<4 days per week

or <4 weeks

PersistentSymptoms

>4 days / week

and >4 weeks

Mild

normal sleep

normal daily activities, sport,

leisure

normal work and school

no troublesome symptoms

Moderate-Severe

One or more items

abnormal sleep

impairment of daily activities, sport,

leisure

problems caused at work or school

troublesome symptoms

FUTURE ASPECTS OF THERAPEUTIC STRATEGIES

Most therapies are based on improvements in existing therapies or on a better understanding of

the cellular and molecular aspects in atopic diseases. Many new therapies in development are

aimed at inhibiting components of the allergic inflammatory response but there are possibilities of

preventative and curative treatment.

Bronchodilators

This class is used for symptom relief but have no effect on underlying inflammatory process.

Inhaled ß2 agonists are safe and effective and there is no parallel to this drug. They relex smooth

muscle by increasing the concentration of cyclic AMIP and by opening up potassium channels.

Asthma treatment can be classified into two broad categories:

1. Inhibit smooth muscle contraction and lead to bronchodilatation (RELIEVERS)

2. Anti-inflammatory (CONTROLLERS).

Levosalbutamol [(R) albuterol] for the treatment Pediatric Asthma

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Short acting, ß2 agonists are the main reliever drugs. They are synthetic analogs of epinephrine

and act as bronchodilators by relaxing bronchial smooth muscles. Levosalbutamol [ albuterol],

FDA approved and launched in 1999, is a single isomer ß2 agonists that is purified,

therapeutically active isomer, known as ‘R’ salbutamol(albuterol). Racemic albuterol is

composed of R, and S albuterol in equal proportion (i.e. 50:50 mix) e.g. 2.5 mgm of nebuliser

solution contains 1.25 mgm R albuterol & 1.25 mgm of S albuterol. These isomers are non

superimposable mirror images, known as sterioisomers. These isomers act in pharmacologic

opposition to one another. Therefore the scientific rationale of potential advantages of levo

albuterol over recemic albuterol in treatment of asthma and other airway diseases(10).

Racemic albuterol is metabolized through sulfation in human tissues, R albuterol is sulfated

eightfold faster leading to longer t12 and accumulation of S albuterol in tissues.

(R) albuterolSelective and high binding to ß2 receptor

Airway smooth muscle intracellular

Ca++ Or no change for 1L-2, 1L-4, 1L-8, 1L-13,

MCP-1Airway tissue spasmogens

eosinophil aclivation; superoxide

formation. Easy to metabolise.Natural R-epinephrine analogNo accumulation

(S) albuterolBinds with low affinity to ß2 receptor

Airway smooth muscle intracellular

Calcium1L-2, 1L-4, 1L-8, 1L-13, MCP-1

Airway tissue spasmogens

eosinophil aclivation; superoxide

formation.

Difficult to metabolize.Un-natural moleculeHigh pulmonary tissue level with regular dosing

Corticosteroids

Steroids provide the standard against which new therapies are judged, however, high doses of

oral steroids would lead to systemic side effects. Inhaled steroids have revolutionized the

treatment of asthma, nasal steroids for the management of allergic rhinitis and topical steroids for

atopic dermatitis but dermal atrophy has restricted its use.

New generation steroids viz. budesonide fluticasone propionate and momentasone furoate have

minimal side effects as the swallowed fraction of the drug is removed by hepatic metabolism.

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However, these drugs are absorbed from the lung or nasal mucosa and may have side effects at

high doses; hence the need for steroids that are metabolized locally viz “Soft Steroids” i.e.

Ciclesonide seems promising as they have less side effects. Steroids inactivated in the plasma are

now in development.

Ciclesonide has potent anti-inflammatory activity and improves pulmonary function and asthma

control in patients. The agent is administered in the form of an inactive prodrug and is well

tolerated, with minimal local side effects and minimal local or no systemic side effects. Thus, it

offers some safety advantages over currently available ICS formulations. Ciclesonide also

provides the convenience of once daily dosing, which may encourage and improve patient

adherence. Finally, the advantages of ciclesonide have been demonstrated for a wide range of

asthma severity, making the drug a reasonable therapy for patients requiring an ICS as the

foundation of their asthma care(11).

Mediator Antagonists

Antihistamines

Older antihistamines caused sedation whereas the new generation fexofenadine Levocetirizine

and desloratidine cause no sedation and improves health related quality of life. They are of

immense benefit in allergic rhinitis, and atopic dermatitis(3).

Antileukotrienes

5. LO inhibitor i.e. Zileuton and cysteinyl-leukotriene receptor (cyst-LT1) antagonists

(pranlucast, zafirlukast, and montelucast) have been developed as an adjuvant. They improve

symptoms, exercise induced asthma, lung function and reduce the need for rescue bronchodilator

and useful in aspirin sensitive asthma. They are effective orally and ho no specific side effects.

They have no benefit over nasal corticosteroids in allergic rhinitis.

Selective inhibitors of inducible No synthetic (iNOS) are now in development. Tryptase

inhibitors (APC 366) is poorly effective in asthmatic patients. More potent trypase inhibitors and

PAR-2 antigonists are now in development

Cytokine Modulators

Anti IL-5

Interleukin (IL-5) is crucial in orchestrating the eosinophilic inflammation of asthma. Humanized

monoclonal antibodies to IL-5 can be used as a single injection reducing blood eosinophils for

several weeks.

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Anti IL-4

IL-4 is critical for synthesis of IgE by ß lymphocyte and also eosinophil recruitment to the

airways. Inhibition of IL-4 may be effective and soluble IL-4 receptors are in clinical

development.

Anti IL-13

IL-13 causes AHR and mucous hypersecretion and may be an important target for the

development of new therapies.

Anti-TNF

Tumor necrosis factor (TNF) amplifies asthmatic inflammation; hence soluble TNF receptors are

a logical approach to asthma therapy.

Chemokine Inhibitors

Chemokines are rantes, MCP-3, MC-4 and eotoxin; may be crucial in the recruitment of

eosinophils in atopics.

Anti-Inflammatory Cytokines

They have anti-inflammatory activity in atopic inflammation. IL-10 inhibits synthesis of

proteins. IFN alpha inhibits Th2 cells, thereby reducing inflammation. IL-12 determines the

balance between Th1 and Th2.

New Anti – Inflammatory Drugs

These are PDES, transcriptor inhibitors, MAP kinase inhibitors, tyrosine kinase inhibitors,

immunosuppressants and cell adhesion blockers

Specific Anti-allergy Drugs

Cromones

Cromones (cromoglycate sodium and nedocromil sodium) are the most specific anti-allergy

drugs. Topical application is effective in asthma, rhinitis and conjunctivitis, but effects are less

marked and effective only a mild disease.

Th2 Cell Inhibitors

Cycloporin A and tacrolimus are relatively less effective CD4+ (Keliximab) which reduces

circulating CD4+, seems to have some effect on asthma.

Preventive Strategies

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Atopy seems to be due to deviation from Th1 to Th2 cells which may arise because of failure to

inhibit the normal Th2 preponderance at birth which in turn may result from environmental

factors such as Th1 response to infectious agent.

Immunotherapy: Specific allergen vaccine.

Peptide immunotherapy: Peptide fragment block T-cell responses.

Vaccination: Induces protective Th1 responses to prevent sensitization and thus prevent atopy.

BCG vaccination has been associated with a reduction in atopic diseases in Japan, but this has not

been confirmed in Swedish population.

Gene Therapy

Atopy being polygenic, there is no role of gene therapy in long term treatment. One needs to

target genes in IL-4 and IL-5 cluster.

Advances in therapy would be facilitated throughout development of more specific anti-allergy

drugs that lack side effects. If it can be taken orally, it would treat asthma, rhinitis and eczema

which often coincide.

The possibility of developing a cure is remote but strategies to inhibit the development of

sensitization in early childhood offer such as prospect in future.

10 Relevant questions to be enquired when dealing with a patient with allergic

manifestations.

1. What is the main problem frequency and severity of your symptoms?

2. Do you have any other allergic disease

Ear, eye, sinus, nose, chest, skin, food

3. Triggers for the same

4. Symptoms seasonal, all year, festivals

5. Occupation and hobbies

6. Allergens at home, dust mite, pets, fungus, insect

7. Allergies to food & drugs

8. Family history of asthma, rhinitis, eczema

9. Disease affect lifestyle, work, school, leisure time, sleep

10. Rx previous, side effect, at Rx even when well

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References:

1. Rogkakou A., Massacane P., Compalate E., Fumagalli., Guerra L., Zanella C., Canonica G.W. One Airway

One Disease Concept. Abstracts 9th ARSR and 10th Biennial Congress of the TPAIS Nov.2004; 24

2. Lahiri Keya. Allergic Rhinitis in Children: Is there a sneeze beyond that wheeze ? 2003:5-6

3. Wahn Ulrich. The allergic March. Abstracts 9th APSEAR and 10th Biennial Congress of the TPAIS.

November 2004; 33

4. Castro – Rodriguez J.A., Holberg C.J., et al. A clinical index to define risk of asthma in young children with

recurrent Wheezing. Am J. Respt. Crit Care Med. 2000; 162:1403-1406.

5. Rusconi F, Galassi C, Corbo G.M., For – as tiere F, Biggeri A, Ciccone G., Renzoni E., and the SIDRIA

Collaborative Group. Risk factors for early, persistent and late-onset wheezing in young children. Am J.

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6. Calpin C., Macarthur C. Stephen D., Feldman W., Parkin P.C., J. Allergy Clin Immunol.1997;100 No.4:452-

456.

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8. Church Martin K., Arion Diana S. Simply Allergy CB Publishing 2004; 13-25

9. Management of Allergic Rhinitis and its Impact on Asthma. Based on the ARIA Workshop report. In

collaboration with the WHO. Jean Bourguet (chair) & Paul van Cauwenberge (Co-chair) and members of

expert Panel 2001;5,18

10. D. Burke & Henderson D.J. British Jr. of Anaesth 2002; 88(4):563-76.

11. O’Connor B. J. Sips P, Engelstatter R Steinjans VW Biberger C, Warst W. Management of moderate to

severe bronchial asthma by ciclesonide: a 12-week trial. Eur Respit J. 2002; 20 (538). Abstract 2579

17

Atopic Dermatitis (AD)- Skin speaksDr Vidya Kharkar

Associate ProfessorDept of Dermatology, KEM Hospital; Mumbai

Atopic dermatitis is a complex disease characterized by genetically determined increased

cutaneous reactivity to a number of allergens. AD manifest as a part of atopic march (In more

than 90% of cases), where patient presents with characteristic dermatitis very early in there life

and later develops asthma or allergic rhinitis. The triggering factors include dry skin, infections,

extreme of temperature, allergies and sensitivities, rough or woolen clothes and stress.

AD is the first manifestation of the atopic triad (AD, asthma and hay fever). It occurs in 60% of

the patients in first year of life, in 38% of the patients it starts around 3 months of age and 70-

95% by 5 years of age. There are three phases of AD in which the site and morphology of lesions

change with age. The infantile phase occurs upto 2 years of age, the childhood phase from age 2

to puberty and the adult phase thereafter. AD is an “itch that rashes” as opposed to a rash that

itches.

In infants less than 2 weeks of age dermatitis affects scalp and face and is difficult to differentiate

from seborrheic dermatitis (AD in infant less than 2 weeks was previously known as Seboatopic

dermatitis).

In infantile phase AD manifests as generalized dryness of skin with dermatitis involving

extensors of lower limbs, creases, scalp and cheeks. Diaper area is often spared. The lesions are

usually symmetric scaly erythematous patches with or without secondary bacterial infection.

Other features include generalized xerosis, dry hair and scalp.

In childhood phase flexural areas and creases of buttocks and thigh are the sites of predilection.

Childhood phase presents as erythematous scaly patches with, nummular exudative lesions with

lichenification along with shiny nails. People with dark skin manifests papular follicular lesion.

After puberty the lesions get localized to the face, neck and body but are more diffuse with

erythema, scaling and less of exudation. Xerosis and lichenification persist. Brown macular

discoloration occurs around the neck in patients with chronic AD - “Dirty neck sign”. Hand and

forefoot eczemas are other common findings.

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Other associated features like Dennie-Morgan fold, hyper linearity of palms, ichthyosis vulgaris,

keratosis pilaris, retroauricular fissures etc. gives a clue to the physician. Ocular involvement

occurs in 30% of the patients.

Criteria to diagnose atopic dermatitis:

1) Seymour and Hanifin diagnostic criteria (1987) for assessing AD in infancy

Major features:

Family history of atopic dermatitis

Evidence of pruritic dermatitis

Typical facial or extensor eczematous or lichenified dermatitis

Minor features:

Xerosis/ichthyosis/hyperlinear palms

Perifollicular accentuation

Chronic scalp scaling

Periauricular fissures

2) Japanese Dermatological Association (1997)

An atopic diathesis:

Personal and/or family history of atopic diseases and have the predisposition to

overproduction of IgE antibodies

Must have three clinical criteria:

pruritus

typical morphology and distribution

chronic and chronically relapsing course

3) Hanifin’s clinical criteria for the atopic dermatitis complex (2001)

1. Essential features

(A) Pruritus

(B) Eczematous changes

i. Typical and age specific patterns

ii. Chronic or relapsing course

These features must be present and, if complete, are sufficient for diagnosis.

2. Important features (seen in most cases)

(A) Early age of onset

(B) Atopy ( IgE reactivity)

(C) Xerosis

These features, seen in most cases, add support to the diagnosis.

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3. Associated features ( clinical associations)

(A) Keratosis pilaris/ichthyosis/palmar hyperlinearity

(B) Atypical vascular responses

(C) Perifollicular changes

(D) Ocular/Periorbital changes

(E) Perioral/Periauricular changes

These features help in suggesting the diagnosis of AD but are too non specific to

be used for defining or detecting AD for research and epidemiological studies.

4. Exclusions

It should be noted that firm diagnosis of AD depends upon excluding

conditions such as scabies, allergic contact dermatitis, seborrheic dermatitis,

cutaneous lymphoma, ichthyoses, psoriasis, and other primary disease

entities

To assess the measurement of severity of AD the SCORAD system is used, which represents an

evaluation encompassing the extent of the disease and patient symptomatology. It uses body

diagrams to record extent and area of involvement and records the intensity of six signs

(erythema, oedema/papulation, oozing/crust, excoriations, lichenification and dryness).

Subjective assessment includes pruritus, sleep loss and “overall skin condition”

There is no laboratory gold standard investigation for diagnosis of AD. Peripheral blood

eosoinophilia and serum total and specific IgE support diagnosis of AD, if found raised. Negative

results of in vivo tests like prick test and patch tests are more useful than positive test. Very strong

positive results of patch testing indicate sensitivity to the positive tested antigen / allergen.

Diagnosis of AD is largely based on physician’s global assessment of the patient’s condition.

Steroids are the cornerstone of treatment of atopic dermatitis. Emollients are essential and should

be applied regularly, even in disease free periods. Topical calcineurin derivatives like tacrolimus,

pimecrolimus provide a promising alternative in mild to moderate disease. Antibiotics for

controlling secondary infection. Sedative antihistaminics to control itch. Oral steroids,

phototherapy and other immuno-suppressants are indicated in very severe disease. Last but not

least, to avoid triggering factors. Latest additions to the treatment are biological modifiers like

Interferon- gamma and thymopentin.

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AD is a disease of exacerbations and remissions. Unfavorable factors prognostically are early

onset (severe disease within first 6 months of life), being the eldest or the only child, association

with a respiratory disease and a very high serum IgE levels. Most patients improve by puberty.

::::::::::::::::::::::::::::::::::::::::

Allergic Rhinitis and Rational Approach to Antihistaminics

Dr Kondekar SV

Lecturer, Dept of pediatrics; GSMC KEMH; Mumbai

The first recorded case of AR (catarrhus aestivus) was described in 1819 by Sir John Bostock, who presented himself as a case report to the Medical and Surgical Society of London. At the dawn of the 20th century, there were only several thousand members of the US Ragweed Association (now defunct). One hundred years later, AR has become the most common allergic/immunologic disorder in the US population

Allergic rhinitis involves inflammatory reaction in the nasal mucosa from repeated allergen exposures that causes hypersensitivity. These reactions may be seasonal or perennial.

Prevalence• 10% to 20% of entire US population : 20 to 40 million individuals• 10% to 30% of adults; Up to 40% of childrenMost common chronic diseaseDevelops before age 20 in 80% of cases• 100% increase in prevalence in each of last 3 decades in developed countries

Epidemiologic studies have consistently demonstrated that AR and asthma commonly coexist.

AR is frequently associated with asthma and is a risk factor for developing asthma; in addition,

many patients with AR demonstrate increased bronchial hyperresponsiveness to inhalation challenge with histamine or methacholine.

ETIOLOGY

IgE-mediated condition resulting from antigen antibody reaction results in release of histamine and other inflammatory mediators in the nasal mucosa

Seasonal - usually reflects sensitivity to air-borne pollens (e.g. ragweed - fall and/or trees/grasses - spring)

Perennial - relatively constant so house dusts, molds, or animal dander are primary sensitizing agents.

Mixed:? Many patients with seasonal allergic symptoms also have a component of perennial allergic rhinitis.

Genetic tendency

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Individuals who have inherited the potential to develop IgE-mediated, or "allergic," responses to otherwise innocuous inhalant allergens, with sufficient exposure will generate allergen-specific IgE after T-cell release of interleukins 4 and 13, and B-cell "switching" to produce IgE antibody-thereby becoming "sensitized."

Seasonal RhinitisCommon allergens:

Grass pollens Tree pollens Weed pollens Mold spores

Predictable sequence of pollination is observed each year:

trees predominate in the spring, grasses in the summer, and weeds in the late summer and early fall.

Symptoms: Watery nasal

drainage Nasal congestion Repetitive sneezing

Itchy eyes, nose, ears, and throat

Nose rubbing Allergic salute

Perennial Allergic Rhinitis Show little or no seasonal variation Symptoms are intermittent or continuous throughout the

year Watery nasal drainage and sneezing are less prominent than

seasonal allergic rhinitis Nasal congestion is often the primary symptom

Allergic triggers I• Dust mites : Carpeting, upholstered

furniture• Animals : Furry or feathered• Pollens

Allergic Triggers II• Cockroaches

Molds: Water damage, leaking roofs, poorly maintained heating/cooling systems

– Can be encountered outdoors as well as indoors

• Foods: Uncommon for chronic symptoms

Environmental Triggers at SchoolIndoors: Chalk dust Dust/dust mites

Insufficient airflow Cockroaches Second hand smoke Paints Magic markers Glue/paste Pets Cleaning agents

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Molds New furnishings or equipment

Outdoors: Pollens (grass, trees, weeds), Molds, Pesticides PATHOPHYSIOLOGY

1. Sensitization2. Early (acute) phase reaction3. Late phase reaction4. Chronic disease

The early phase occurs promptly, and lasts approximately 1 hour. The late phase typically begins in 3 to 6 hours, peaks at 6 to 8 hours, and subsides in 12 to 24 hours. 1. SENSITIZATION

• Previous exposure produces IgE antibodies• IgE antibodies attach to mast cells in

tissues - Eye, nose, lung, skin, GIT

Allergen ↓

AP cells ← processed allergen↓CD4 T cells↓

B cells→ Plasma cells↓

IgE antibodies --------sensitises mast cells

2. EARLY PHASE REACTIONAllergen attaches to IgE on mast cell

↓ Release of mediators Histamine, LT, PAF, PG

↓Act on nerves, blood vessels

Production of mediators continues actions on blood vessels, nerves

↓Recruit inflammatory cells eosinophils and basophils IL5 IL4

↓ EBP PAF,Sneeze, itch, runny nose, stuffy nose

3. LATE PHASE REACTION• 2-8 hours after initial reaction• Same symptoms as early reaction• Release of mediators from recruited cells• Related to severity of early reaction

The late phase is promoted by factors generated in the early phase that encourage release of inflammatory mediators chemokines, and cytokines and the activation and recruitment of cells to the nasal

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mucosa such as eosinophils and basophils. .

Allergen↓

Dendritic cells↓ MHC III – T cell RrTh2 cells↓---------------------------------------------------------------------------↓ ↓

↓B cells Eosinophils

Mast cells↓ ↓

↓IgE→Mast cells Basic proteins, Histamine,

Leukotrieneslipids, cytokines

Platelet activating F

IL5 IL4

Neurotropins ↓Chronic Allergic ReactionFurther sneezing, Nose block , Eczema

CHRONIC DISEASE

Hyper responsiveness

Late Phase

Reaction

Priming

Mast cell Cellular

infiltrationE B Mo Ly

Blood vesselsnerves

Resolution

Complication

Irreversible disease

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Priming = Need less allergen to trigger symptoms Hyperreactivity = Symptoms from exposure to strong or

irritating fumes or odors Inflammation = Ongoing symptoms, more of stuffiness

Allergic rhinoconjunctivitis four major symptoms of AR: sneezing, pruritus,

congestion, and drainage Patients with AR commonly experience concomitant ocular

symptoms, so much so that the term "allergic rhinoconjunctivitis“ is frequently used as an alternative to AR

Of the four major symptoms, pruritus and sneezing are more specific for AR than for other conditions in the differential diagnosis of chronic rhinitis

Additional (ocular) Symptoms Associated with Allergic RhinitisEye: Symptoms

Itching redness TearingPuffiness

Others:PNDripSore throat coughThroat clearing and hoarsenessDecreased sense of taste

SIGNSLacrimationHyperemiaEyelid edemaAllergic “shiner”

Mucus in oropharynxCobblestone pharynxMouth breathing

Chronic nasal congestion may produce• Dry irritated

or sore throat

• Snoring• Pain around

eyes• Mouth

breathing• Orthodontic

disturbances

• Frontal headaches/sinusitis

• Chronic cough

• Otitis media/possible hearing loss

• Altered smell and/or taste

• Sleep disturbance, with or without daytime fatigue

• Asthma exacerbation

Systemic Symptoms of Allergic RhinintisSome patients with allergic rhinitis experience:

• Weakness• Discomfort or

uneasiness• Irritability

• Fatigue• Difficulty

concentrating• Decreased appetite

Pediatric AR and its comorbid disorders• Conjunctivitis • Pharyngitis

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• Sinusitis• Asthma• Eczema• Otitis media• Lymphoid hypertrophy/

obstructive sleep apnea• Speech impairment• Failure to thrive• Reduced quality of life

PATIENT ASSESSMENTPatient History: Key Findings:

o Provocation Allergen exposure

o Quality "Watery" nasal discharge

"Frequent Sneezing“

"Itchy eyes“

o Region Eyes, Nose, Throat, Sinuses Severity

o Temporal relationship September - October April – May

associated pruritus of other facial structures (eg, throat, ears, palate) Past Medical History: Adults

BPH Narrow angle

glaucoma Cardiac

patients Family history

of allergic disease

Medication Hx: R/O drug-induced causes

Physical Examo No fever, no

lymphadenopathy

o Pale boggy turbinate

o infraorbital congestion ("allergic shiners")

o subtotal or complete nasal obstruction may be present, along with suffusion

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of conjunctivae.

DIFFERENTIAL DIAGNOSIS Vasomotor/Irritant

Rhinitis Chronic Sinusitis Nonallergic rhinitis

with eosinophilia Gustatory rhinitis Atrophic Rhinitis Rhinitis

Medicamentosa Rhinitis associated

with Drugs (eg, antihypertensive agents, oral contraceptives)

Rhinitis associated with systemic disease(eg, Hypothyroidism, Wegener's Granulomatosis, Sjögren's Syndrome)

Structural Factors (Septal Deviation, Nasal Polyposus,Nasopharyngeal Carcinoma)

DifferentialInfectious bacterial sinusitis

viral infection (common cold)

Rhinitis medicamentosa

Non-allergic (NARES)Vasomotor

Other -

Key FindingPurulent discharge, fever, lymph-adenopathy, no itching

Negative allergy history.

Medication hx of excessive use of nasal decongestant inhalers, clonidine, or reserpine tx.

Lab dxNo itching or conjunctivitis

Congenital or acquired mechanical obstruction.

AR: hallmarks seasonality / trigger related symptoms occurrence of symptoms with certain exposures or

situations (eg, walking into a pet store), improvement of symptoms during spring, summer, or fall

seasons when in air-conditioned environments (buildings or automobiles),

and the experience of prominent itching of nose, eyes, ears, throat, or palate.

The diagnosis of AR requires(1) positive history,

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(2) demonstration of IgE-mediated potential to inhalant allergens by cutaneous (or in vitro) testing, and (3) correlation between history and cutaneous (or in vitro) test findings.

Immediate hypersensitivity skin testing is recommended as the preferred diagnostic study, as it is associated with reduced cost, is more sensitive, and entails no delay in obtaining results.

Individuals with skin disorders or who are unable to suspend antihistamine medications such that skin testing would be uninterpretable, are candidates for in vitro testing to detect elevated levels of specific IgE to inhalant allergens.

Allergic rhinitis and its Impact on Asthma ARIA classification (WHO)

Intermittent Symptoms 4 days/wk Or symptoms 4 weeks

Persistant Symptoms > 4 days per week Or > than 4 weeks

Mild Normal sleep No impairment of daily activities,

sports, leisure Normal work and school No troublesome symptoms

Moderate-severe One or more items Abnormal sleep Impairment of activities, sports, leisure Abnormal work and school Troublesome symptoms

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[Type text]

Managing Patients with ARFour general principles ( Ameircan Academy of Allergy Asthma and Immunology)

1. Education and monitoring 3. Pharmacotherapy2. Avoidance of allergen / triggers 4. Immunotherapy

1. Education and monitoring Understanding pathophysiology Understanding and monitoring seasonal mold and spore pattern Understanding the need to be in pollen, pet and dust free environment as much possible.

2. Avoidance1. Avoidance of clinically relevant allergens = reduction of symptoms and medication

reliance = the most important aspect 2. allergic to outdoor pollens, => air conditioning can lead to dramatic symptom relief.

By reducing indoor relative humidity, it also significantly reduces mold spore and dust mite.

3. reduce exposure to dust mites by encasement of the mattress, box spring, and pillow in impermeable covers, reducing indoor relative humidity, washing bedding weekly in a hot cycle (>130° F) and, if possible, removal of carpets in favor of tiled or hardwood flooring.

4. For individuals allergic to cat or dog dander best is elimination of the pet from the home

5. second-best measures include restricting the pet from the allergic person's bedroom, use of high-efficiency particulate or electrostatic air cleaners, and removal of carpets and other upholstered items that otherwise serve as reservoirs for allergens.

3. PharmacotherapyBecause avoidance measures will likely be incomplete and patients with AR will continue to be exposed to clinically relevant levels of aeroallergens, virtually all patients with AR will benefit from medication.

Therapeutic OptionsAntihistaminics: Oral / Intranasal Decongestants: Oral / TopicalAnticholinergics: Oral / Intranasal

Combinations: AH + Decongestants

Cromolyn sodium, Leukotriene antagonista, and immunotherapy

4. Immunotherapy Allergen immunotherapy entails the incremental administration of inhalant allergens to

induce immune system changes in host response to natural exposure to these allergens. Numerous randomized, double-blinded, placebo-controlled trials have shown that

allergen immunotherapy can reduce levels of symptoms and medication reliance. A 3-year trial of allergen immunotherapy in which 37 of 44 patients were randomized to

injections of timothy grass pollen or placebo found a significant reduction in symptoms and medication use for rhinitis and asthma with allergen immunotherapy.( Allergen immunotherapy: a practice parameter. American Academy of Allergy, Asthma and Immunology. American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 2003;90(suppl 1):1-40.

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[Type text]

Management of AR: ARIA stepwise approach: Rationalising AR therapy

Mild persistant

Moderate severe

PersistantMild intermittent Moderate severe

intermittentIntranasal corticosteroids,Sodium Cromolyn

Patient Education and allergen avoidanceIntranasal decongestant (<10 days) or oral decongestant +/-Oral or local nonsedating antihistamine

Immunotherapy if other therapies failModify doses and agents depending on symptoms: STEP DOWN !Detection and treatment of comorbid conditions

Rationalising AR therapy What to use? Why to use? When to use? How to use?

As per ARIA guidelines Non sedating

antihistamines are main stay of therapy round the year and episodic.

Add on steroids for moderate and severe cases.

Inhaled/intranasal medicines to be preferred over oral medicines.

Cromolyn and immunotherapy as additional in refractory cases.

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ADJUNCTIVE TREATMENT Ocular Symptoms:Antihistamine-Decongestant Combination Nasal Congestion - avoid topical nasal decongestants Cromolyn sodium - antihistamine intolerant or anticholinergic effects must be avoided

(costly and frequent administration). Saline irrigation - use liberally

COMPARISON with Rx ANTIHISTAMINES Chlorpheniramine = Cromolyn Astemizole (Rx) > Chlorpheniramine Cetrizine (Zyrtec) LCTZ Fexofenadine (Allegra) ≥ LCTZ > DLR Loratadine (Claritin) Drug of Choice = Inhaled Nasal SteroidIntranasal ICS The therapeutic effects of ICs include vasoconstriction and reduction of mucosal edema,

inhibition of mediator release, suppression of cytokine production, and inhibition of inflammatory cell infiltration.

ICs are effective for reducing nasal congestion, rhinorrhea, and sneezing, and also may relieve ocular symptoms.

Systemic effects are minimal at recommended doses. The major adverse effect of ICs is local irritation or epistaxis; patients should be

instructed to suspend IC use at the first sign of bleeding or irritation, and to direct the nasal spray laterally, away from the nasal septum.

Medications for AR Symptoms, Ocular Symptoms, NNT, and NNH

Medication Sneezing Rhinorrhea Congestion Pruritus Ocular

Symptoms

NNT NNH

Antihistamine,oral

++ ++ + +++ ++ 15.2 51

Antihistamine,intranasal

++ ++ + ++ 0 5 22

Intranasalsteroid

+++ +++ +++ ++ ++ 4.4 48

Intranasalcromolyn

+ + + + 0      

Decongestant,oral

0 0 + 0 0      

Decongestant,intranasal

0 0 ++++ 0 0      

Anticholinergic,intranasal

0 ++ 0 0 0      

Antileukotriene 0 + ++ 0 ++ 14.3 167  number needed to treat (NNT) and number needed to harm (NNH) Effects of H1 antihistaminics:

H1 receptor: Decreased allergic inflammation and symptoms, itching sneezing, rhinorhea and whealing

Nuclear Factor αβ: decreased antigen presentation, expression of CAM, chemotaxis and proinflamatory cytokinesCalcium Ion chanels: decreased mediator release

Class 1st Gen 2nd Gen 3rd Gen??

Ethanolamines Clemastine fumarateCLASSIFICATION OF ANTIHISTAMINICSDiphenhydramine HCl

Alkylamines Triprolidine

Chlorpheniramine maleate

Acrivastine  

Pheniramine maleate

Phenothiazine Promethazine HCl

Piperazines Hydroxyzine HCl Cetirizine HCl Levocetirizine

Piperidines Astemizole Tecastemizole

Terfenadine Fexofenadine

Cyprohepatadine Loratadine DesloratadineAntihistaminics: a Re- View

Many new are chemically related to older medications in the class. acrivastine is related to triprolidine, cetirizine is a metabolite of hydroxyzine, levocetirizine is an enantiomer of cetirizine, desloratadine is a metabolite of loratadine, and fexofenadine is a metabolite of

terfenadine.Antihistamines potential Adverse effects:

Most are with first generation AH1. Cardiac Chanels: Prolonged QT interval, Sometimes ventricular arrhythmias,

independently of the H1-receptor. Astemizole and terfenadine which are no longer used, block the rapid component of delayed rectifier potassium current (IKr). As a result, these two agents potentially prolong the monophasic cardiac action potential and QT interval, induce the development of early after-depolarizations and dispersion (slowing) of repolarization, and thereby may cause torsades de pointes. New second-generation H1-antihistamines such as cetirizine, desloratadine, fexofenadine, and loratadine have 50 percent inhibitory concentrations in the micromolar range and have a thousandth of the potency in blocking the IKr current.

2. H1 Rr: decreased neurotransmission in CNS, increased sedation, decreased cognitive and psychomotor performance, increased appetite. Second-generation H1-antihistamines least or no central nervous system S/E, (lipophobicity and affinity for P-glycoprotein that is expressed on vascular endothelial cells in the central nervous system).CNS penetration : none for fexofenadine to 30 percent for cetirizine.

3. First generation antihistamines being lipophilic liberally penetrate CNS causing drowsiness and sedation

4. Serotonin Rr : increased appetite5. Alfa adrenergic Rr: hypotension, dizziness, reflex tachycardia6. Muscarinic Rr: increased dry mouth, urine retention, sinus tachycardia

Drug Sedation Anticholinergic side effects

Antiemetic effects

Chlorpheniramine maleate

+ ++ -

Diphenhydramine HCl +++ +++ ++/+++Clemastine ++ +++ ++/+++

Promethazine HCl +++ +++ ++++

Hydroxyzine HCl +++ ++ +++

Cetirizine HCl + - -

Loratadine + -/+ -

Levocetirizine -/+ - -Desloratadine -/+ -/+ -Fexofenadine - - -

Various OTHER potential side effects of first generation are:Depression, suicidal tendencies, potential for abuse, Impaired driving performanceloss of productivity by workers, injuries, and deaths in aviation and traffic accidentshangover i.e., impaired cognitive and psychomotor performance with or without (perceptible sedation)

In rare cases, both first- and second-generation H1-antihistamines are reported to cause adverse effects, the mechanisms for which are incompletely understood These effects include fixed-drug eruption, photosensitivity, urticaria, fever, elevation of liver enzymes and hepatitis, and agranulocytosis.

AH Dosages in children

1st Generation AntihistaminesDrug Dosage Age

groupPromethazine (5mg/5ml)

5 - 15 mg/day 2 – 5 yrs10 - 25 mg/day 5 – 10 yrs10 mg bid – 20 mg tds > 10 yrs

Hydroxyzine (10 mg/ 5 ml)

1 - 2.5 mg/kg/day in divided dosage (3 - 4 times)

1- 6 yrs

1 - 2 mg/kg/day in divided dosage (3-4 times)

> 6 yrs

Diphenhydramine (7mg/5ml)

5 ml QID 1 – 5 Yrs

  10 ml QID 6 – 12 Yrs

Clemastine (0.5 mg/5ml)

1 tsf bd - 3 tsf bd 6 – 12 Yrs

Methdilazine 4 mg every 6 - 12 hrs 3 – 12 Yrs

NEWER ANTIHISTAMINESDosage Age group

Cetirizine (5 mg / 5ml) 2.5 mg bd or 5 mg od

2 – 5 yrs

5 mg bd or 10 mg od

6 – 11 yrs

Levocetirizine (2.5 mg/ 5 ml)(Not available in developed markets)

5 mg od 6 – 12 yrs

Loratadine (5mg/5ml) 1 tsf daily 2 – 6 yrs2 tsf daily > 6 yrs

Desloratadine (2.5 mg / 5 ml) 2.5 ml od 1 – 5 yrs5 ml od 6 - 11 yrs

Fexofenadine# (30 mg / 5 ml) 30 mg bd 2-11 yrs (AR & CIU)# Recently approved by USFDA in children less than 6 years. However, in india, 30 mg bd approved in 6 – 11 yrs

15 mg bd 6 Months – 2 Years(CIU)

Adult doses : Azelastine (Astelin) 2 sprays in each nostril BIDCetirizine (Zyrtec) 5 or 10 mg daily; Fexofenadine (Allegra) 180 mg daily or 60 mg BID; Loratidine (Claritin) 10 mg daily; Desloratidine (Clarinex) 5 mg daily

Monotherapy with oral antihistamines provides greater symptom relief and a better

quality of life than a combination of antihistamine and nasal steroid, according to a meta-analysis of more than 40,000 patients.(Juliane Köberlein, PhD, epidemiologist, Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany)

Many first-generation H1-antihistamines have never been adequately studied All first-generation H1-antihistamines, and some second-generation H1-antihistamines

such as desloratadine and loratadine are metabolized by the hepatic cytochrome P450 (CYP450) system.

Cetirizine is excreted largely unchanged in the urine, and fexofenadine is excreted largely unchanged in the feces. second-generation H1-antihistamines, which have a wider therapeutic index After a single oral dose, the onset of action occurs within one to three hours. The duration

of action for many oral H1-antihistamines is at least 24 hours, facilitating once-daily dosing.

Although topical intranasal and ophthalmic H1-antihistamines differ in their pharmacokinetics, most of them need to be administered twice daily because of washout from the nasal mucosa or conjunctivae. Dose adjustment is not required in special populations.

( Multiple RCTs to prove efficacy of second generation AH: fexofenadine and loratadine improved quality of life and rhinitis symptoms compared with placebo. Astemizole improved rhinitis symptoms compared with placebo, but astemizole has been associated with prolongation of the QTc interval, and may induce ventricular arrhythmias. conflicting results about the effectiveness of terfenadine compared with placebo on rhinitis symptoms. Terfenadine is associated with the risk of fatal cardiac toxicity if used with macrolide antibiotics, oral antifungal agents, or grapefruit juice.

RCTs found that other oral antihistamines (acrivastine, azatadine, brompheniramine, cetirizine, desloratidine, ebastine, levocetirizine, mizolastine, and rupatadine) improved rhinitis symptoms compared with placebo. Drowsiness, sedation, and somnolence were the most commonly reported adverse effects of oral antihistamines.RCTs found that pseudoephedrine plus oral antihistamines (fexofenadine, acrivastine, cetirizine, terfenadine, triprolidine, loratadine, or azatadine) improved overall symptoms of seasonal allergic rhinitis compared with pseudoephedrine, oral antihistamine, or placebo alone. The most common adverse effects reported with combination treatment were headache and insomnia.)But not a single RCT for first generation sedative anti H1

Conclusion

H1-antihistamines are best taken on a regular basis, rather than as needed, in order to reduce allergic inflammation and prevent symptoms.

Tolerance to doses that achieve clinical efficacy does not develop. The dose–response curve for efficacy is flat as compared with that for adverse effects, especially with the use of first-generation H1-antihistamines.

The relief from symptoms may be incomplete, however, because leukotrienes and other mediators also play a role in allergic inflammation

First generation Anti H1 has least role in management of AR fexofenadine, cetirizine, desloratadine, azelastine should be a preferable monotherapy

therapy in that order. Inhaled antihistamines should be prefered over oral antihistamines.=========================================================

SpirometryDr J M Joshi

Professor and HeadDepartment of Respiratory Medicine

TN Medical College and BYL Nair Hospital Mumbai Email: drjoshijm@email.com

Spirometry is the measure of airflow during inspiration and expiration. It can easily be

performed in the physician’s consulting room, with simple and affordable equipments called

spirometers. The test is performed in the sitting position (by convention) and airflow is recorded

as forced and sustained expiration followed by forced and sustained inspiration. 3 efforts, which

have less than 5% variability between each other, are selected and the best effort is used for

interpretation. Routinely, only expiratory flow may be recorded before and after administration of

bronchodilators i.e. 200 mcg salbutamol. However, both expiratory and inspiratory recordings are

required for evaluation of upper airway obstruction.

Uses Of Spirometry:

Evaluation of cases with respiratory symptoms

Assessment of severity of respiratory disorders

Assessment of response to therapy

Pre operative pulmonary evaluation

Detection of pulmonary functional abnormality in predisposed individuals e.g. occupational

exposures, neuromuscular, chest wall, or upper airway disorders

Spirometric Equipment

Several spirometers are available commercially. Selection depends on the cost and individual

requirement. American thoracic society (ATS) recommends that the equipment

should record 7 litres volume and 12 L/second flow rate

should be calibrated with a 3 L syringe

should record minimum FVC and FEV1 and

should record flow volume curve or flow volume loop or both.

American Thoracic Society (Ats) Recommendations For Performing Spirometry

* Effort: Maximal, smooth, and cough free

* Position: Sitting

* Exhalation time: 6 seconds

* End of test: 2 second volume plateau

* Reproducibility: FVC within 5% in 3 acceptable tests

Spirometric Measurements

The spirometric recording is represented in 2 forms, graphic (Figure 1) and absolute values

(Figure 2).

Interpretation Of Spirometric Data: (Figure3)

Diagnosis & Fallacies

Spirometry is only a diagnostic aid and should be interpreted only with clinical and radiological

correlation. Values recorded on different equipment and by different technicians may vary

considerably. The same degree of functional abnormality on spirometry may result in different

degrees of disability in different patients. Two basic types of pulmonary function abnormalities

are described using the basic spirometric parameters, obstructive and restrictive.

Obstructive Abnormalities:

Airway disorders such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis,

etc. show as obstructive abnormality on spirometry.

FEV1% = FEV1 (observed) / FEV1 (predicted)<80%

FEV1/ FVC % = FEV1 (observed) / FVC (observed) < 75%

When clinical evaluation suggests airway obstruction low FEV1% predicted suggests an

obstructive abnormality. Severity can be graded as 60%-80% mild, 40%-60% as moderate and

less than 40% as severe. Good bronchodilator reversibility (BDR) is considered when

improvement in FEV1 by 200ml and >12%, both occur after a dose of bronchodilator.

FEV1/FVC on the other hand does require predicted values as both FEV1 and FVC are patient’s

recorded values. This ratio is an accurate diagnostic parameter for obstructive abnormalities.

However false normalization of FEV1/FVC may occur in moderate to severe airway obstruction

caused by marked fall in FVC due to air trapping. Also low FEV1/FVC may occur due to

reduction in forced expiratory volume alone in the earlier stages of neuromuscular disorders and

may be misdiagnosed as airway obstruction.

Peak Expiratory Flow Rate (PEFR)

The various flow rates like MMFR, PEFR are reduced to less than 75% of their predicted values

in obstructive disorders. PEFR recording can be done on peak flow meters, which are cheap,

portable and easy to use.

All the child needs to do is to blow out as quickly and forcefully as possible (keeping the lips

sealed over the mouth piece) after a complete inspiration to total lung capacity (TLC). The

highest of three readings is recorded.

Uses:

Monitor asthma control by diurnal variability

Early detection of exacerbation

Objective assessment of status and guide to use of asthma action plan

Follow response to therapy

Disadvantages:

Effort dependent

Measures only large airway function

Not a substitute for FEV1

Reference values:

i. PEFR/Height normograms

ii. Personal best readings

iii. Green/yellow/red zones (Asthma action plan)

iv. Diurnal variation<20%

v. Approximate reference: PEFR = 4.9 x ht (cm)- 379Lpm(Weng&Levison)

Example of spirometry demonstrating obstructive abnormality:

Observed Predicted %Pred

FVC 2.63 3.11 84

FEV1 1.58 2.28 69

FEV1/FVC 60 73

Restrictive Abnormalities:

Chest wall, pleural, and lung parenchymal diseases show as restrictive abnormality on

spirometry.

FVC % = FVC (obs)/FVC (pred)<75%

FVC is dependent on the patient's performance; therefore reduced FVC does not diagnose but

only suggests a restrictive abnormality, which should be correlated clinically and radiologically.

Reduction in FVC may occur due to air trapping in moderate to severe airway obstruction.

Measurement of residual volume (RV) and total lung capacity (TLC) using helium dilution

technique or body plethysmography may be used to confirm restrictive abnormalities. However,

in practice interpretation of spirometric data with clinical correlation is usually adequate.

Example of spirometry showing restrictive abnormality:

Observed Predicted %Pred

FVC 0.96 2.75 35

FEV1 0.94 1.90 49

FEV1/FVC 98 69

Figure 1: SPIROMETRIC RECORDINGS

Spirogram: Graphic display of volume versus time:

Volume in liters

Time in Seconds

Flow rate versus volume: Graphic display of flow rate versus volume

Flow volume curve (only expiratory recording)

Flow rate L / Sec

Volume in litres

Flow volume loop when inspiratory flow is also recorded

Flow rates

L / sec

Volume in litres

Normal `Obstructive abnormality Restrictive abnormality

Figure 2: SPIROMETRIC DATA

The minimum parameters required for spirometric interpretation are

FVC : forced vital capacity

FEV1 : forced expiratory volume in 1 second

MMFR (MEFR25-75) : maximal mid-expiratory flow rate

PEFR : peak expiratory flow rate

All the above parameters are read as normal or abnormal when compared to predicted values.

Predicted values vary as per age, sex, height and ethnic groups, are obtained by large-scale

studies in the community and are readily available for use. Value above 75% of predicted are

generally considered as normal.

Figure 3: INTERPRETATION OF SPIROMETRIC DATA

FEV1/ FVC %

Low Normal

FVC% FVC%

Normal Low Low Normal

Obstructive Mixed Defect Restrictive Normal

Repeat test 15-30 min after 200 mcg of SalbutamolIncrease in FEV1 by 12% and 200ml

No YesPoor BDR Good BDR

Abbreviations: FVC- Forced Vital Capacity FEV1- Forced Volume in 1 second BDR- Bronchodilator reversibility

Aerosol Therapy

Dr. C. T. Deshmukh, Professor, Department of Pediatrics, K.E. M. Hospital

Aerosol therapy is the administration of a drug by the inhalation technique. Aerosol is a suspension of fine liquid or solid particles in air and administered by nasal or oral respiratory route. The drugs are administered for their local action on bronchial tree.

The key to respiratory aerosol therapy is the particle size. The optimal size for penetration and

deposition in the alveoli and smaller airways is 1-5m .

An inhalation device should produce majority of the particles in the respirable range, the

inhalation technique should be easy, to avoid impaction and the patient should be able to provide

a breath hold for 5-10 seconds

Inhalation Devices

Understanding of dynamics of inhalation and drug deposition in the lungs had led to

development of very efficient and easy to use devices.

A multitude of inhalation devices are available in the market, but essentially there are

three methods of administering aerosolized drugs :-

i) Metered dose inhaler (MDI)

ii) Nebulisers and

iii) Dry powder inhalers (DPI)

Metered dose Inhalers

Pressurized aerosol forms contain one or more active ingredients, which upon actuation emit a fine dispersion of liquid and / or solid materials in a gaseous medium.

The system consists of :- Plastic casing or the Actuator, Pressurized aluminum (metal) canister, active ingredient (drug), surfactants and the propellant. For an optimal drug delivery, inhalation following actuation should be from functional residual capacity and a 5-10 second breath hold. Patient (including majority of the children) who cannot coordinate actuation and breathing, and who cannot breath hold, may not get effective use of MDIs and spacer devices may be beneficial.

Method of MDI Use

Take the cap off the MDI

Shake the MDI

Hold MDI upright

Breathe out completely

Place mouth piece between teeth (or 4cm from lips)

Head titled slightly back wards

Fire the MDI

Breathe in deeply and slowly

Continue to inhale until lungs are full

Hold breath (count to ten slowly)

Breath out slowly

Wait for a minute and repeat above steps.

Advantages of MDIs

i) Inexpensive and portable

ii) Small, compact, convenient and readiness for use.

iii) Manually operated.

iv) Less chance of Nosocomial infection

v) Accuracy of dose

vi) Mechanical reliability.

Disadvantages of MDIs

i) Difficult to time discharge from MDI and inhalation

ii) Breathholding may not be possible

iii) Inhaled steroids using MDI may cause oral candidiasis and dysphonia.

iv) Potential for patient abuse and delay in medical help.

Nebulizers

Nebulization is the generation of small droplets (Mist) suitable for inhalation from a nebulizing solution containing the drug. The energy for aerosol generation is derived from compressed air or ultrasonic waves i.e. from Jet Nebulizers or Ultrasonic Nebulizers.

Jet Nebulizers

Jet Nebulizers are portable devices producing compressed air. The delivery of the mist

i.e. drug to the patient should be through the mask and preferably through the mouthpiece.

Ultrasonic Nebulizers

High frequency (1-2 mHz) sound waves produced by a vibrating peizo electric crystal,

which when focussed on the surface of liquid creates a fountain of droplets. They are generally

used in intensive care units and are expensive.

Dry Powder Inhalers DPIs

Micronized drug is mixed with a carrier substance (Lactose) and the mixture filled into a gelatin

capsule (Rotacap), which is loaded into the inhaler (Rotahaler) device. The capsule is cut or

sheared in the device by rotating the device and the drug is inhaled by the patient deeply and

slowly from the mouth piece.

Advantages of DPIs

1) Less coordination required than MDI

2) Portable

3) Multidose capabilities

Disadvantages of DPI

1) Cannot be used for children below 3-4 years.

2) May cause reflex cough other local side effects.

3) Capsules may be damaged by humidity and may not be broken.

4) Cannot use in acute attack of asthma.

5) More expensive.

REFERENCES

1) Newhouse MT, Pulmonary Drug Targeting with Aerosols. The American Journal of Asthma

and Allergy for Pediatricians. 1993; 7(1):23-35.

2) Newhouse MT. Asthma therapy with aerosols: Are nebulizers obsolete? A continuing

controversy. J Pediatr 1999; 135: 5-8.

3) Schuh S, Johnson DW, Stephens D, Callahan S, Winders P, Canny G. J. Comparison of

albuteral delivered by a method dose inhaler with spacer versus a nebulizer in children with

mild acute asthma, J Pediatr 1999; 135: 22-7.

4) Leversha AM, Campanella SG, Aickin RP, Asher MI. Costs and effectiveness of spacer

versus nebulizer in young children with moderate and severe acute asthma. J. Pediatr 2000;

136: 497-502.

5) Wildhaber J H, Dore ND, Wilson JM, Devadson SG,, Le Souef PN. Inhalation therapy in

asthma: Nebulization of pressurized metered-dose inhaler with holding chamber? Inviro

comparison of lung deposition in children. J Pediatr 1999; 135: 28-35.

6) Everard ML, Clark AR, Milner AD. Drug Delivery from holding chambers with attached

facemask. Arch Dis child. 1992; 67: 580-85.

7) Miller WL, Mason J W. Small volume nebulizers versus metered dose inhalers. Chest.

1993; 103: 655-5.

Recapitulating Inhalation Devices – Nebulisers

Dr.Rajwanti K Vaswani, Associate Professor ; Dr.Vikas C Bhadoria, House OfficerDepartment of Pediatrics Seth G.S.Medical College &K.E.M Hospital, Mumbai

Key Messages Nebulisation therapy is highly effective in obstructive airflow diseases of children & in

whom coordinated breathing is difficult for hand held devices. For effective nebulisation, it is mandatory to have minimum drug volume of 4-5 ml,

nebulisation time of 10 mins & gas flow of 6-8 liters/min. Dryness should not be considered as an endpoint of nebulisation & needs to be continued

till about a minute after spluttering occurs. Parents need to be given written instructions provided by the British Thoracic Society

(BTS) and all children requiring long term nebulisation should be monitored in Pediatric Chest clinic.

IntroductionNebulisation therapy is widely used throughout the world in pediatric medical practice both for acute emergency and domiciliary long term treatment of respiratory diseases, comprising chiefly of airflow obstruction.

The word “Nebuliser” (from the Latin “nebula”, mist) was first used in 1872 and was defined as breath assisted chambers which convert liquid into a fine spray called “Aerosol” especially for medical purposes.

Compared to systemic medications, aerosols have a faster action as they are directly delivered to their site of action (the bronchial tree) and because of the high topical concentration, smaller doses of the medications are used with the consequent reduction in unwanted side effects. Although aerosol therapy can be delivered through different types of devices , nebulisers remain the most commonly used aerosol delivery devices next to hand held devices.

Nebuliser TherapyAims :

To deliver a large therapeutic dose of the drug as an aerosol in the form of respirable particles (< 5 um), within a fairly short period of time usually 5–10 minutes.

To provide effective aerosol therapy that repeatedly and quickly delivers sufficient drug to the site of action, with minimal wastage, at a low cost.

Indications:Absolute:

Too sick children e.g. small children with severe asthma, infants & in subjects who are incapable of managing hand held inhalers.

Drugs not available in hand held delivery devices Where there is need to target treatment to particular generation of bronchi or alveoli.

Ventilated children, where more efficacious aerosol therapy is required which is usually not achieved by hand held devices as the lung disease is more severe.

Relative: Need for large therapeutic dose. Patient preference. Practical convenience. Minimise side effects.

Nebulisers

Principle: Nebulisers used in aerosol drug delivery produce a polydisperse aerosol where most of the drug released is contained in particles 1–5 um in diameter. Most nebulisers use compressed air for atomization, but some use ultrasonic energy. With the advent of portable, oil free compressors and injection moulding of plastics, a wide variety of disposable nebulisers have become available.

Types :

Jet Nebulisers: Jet nebulisers consist of a nebulising chamber in which an aerosol is generated with a flow of gas provided either by an electrical compressor or compressed gas (air or oxygen).

Ultrasonic Nebulisers: Ultrasonic nebulisers are self-contained electrical devices in which an aerosol is generated by vibrating fluid placed within them. They can nebulise larger volumes of fluid and are quiet.

Jet Nebulisers

Mechanism: In a jet nebuliser the driving gas (usually oxygen/air) passes through a very narrow hole known as venturi from a high pressure system. At the Venturi, the pressure falls and the gas velocity increases greatly producing a cone shaped front. This passes at high velocity over the end of a narrow liquid feed tube or concentric feeding system creating a negative pressure at this point. As a result of this fall in pressure, liquid is sucked up by the Bernoulli Effect and is drawn out into fine ligaments. The ligaments then collapse into droplets under the influence of surface tension. This primary generation (atomization) typically produces droplets 15–500 um in diameter. Coarse droplets impact on baffles while smaller droplets may be inhaled or may land on internal walls returning to the reservoir for renebulisation. Different jet nebulisers have different output characteristics determined by the design of the air jet and capillary tube orifices, their geometric relationship with each other and the internal baffles. For a given design,the major determinant of output is the driving gas flow. For most commercially available jet nebulisers, the optimal operating flow rate appears to be 6 to 8 L/min.

Parts of Jet Nebuliser

Fig 1

Salient Factors affecting drug output from jet nebulisers: Driving gas flow rate: Most jet nebulisers are now designed to work at a flow rate of 6–

10 l/min which would be further governed by nebuliser design dimensions of the connecting tubing and, to a lesser extent, the drug used.

Viscosity, surface tension & temperature of Nebulisation solution: The primary droplet. size is related to surface tension and viscosity, but the baffles in jet nebulisers control the output size. Warming solutions will reduce viscosity and nebulisation time. In ultrasonic nebulisers, it is found that the droplet size is proportional to the viscosity of the Nebuliser fluid, the more viscous fluids having the lowest outputs. Highly viscous solutions like antibiotics require powerful compressors and slowly nebulise.

Residual volume of drug: The term residual volume is often used to infer drug wastage but residual mass of drug is the important factor and may not be directly related to the residual volume of fluid. Nebulisers which leave a low residual mass of drug are preferable. Residual volume may be reduced a little by tapping the nebuliser intermittently during operation.

Breathing pattern and tidal volume: In conventional jet nebulisers, the aerosol is carried in a volume of air which is dependent upon the driving gas flow. If the patient’s inspiratory flow is greater than the driving gas flow, air will be entrained; diluting the

aerosol. The effect of this is that infants and children inhale a much larger dose than adults when computed as dose per kilogram. Once children are over six months of age, the dose inhaled is independent of body size and the per kilogram dose inhaled gradually reduces as they grow.

Method of Inhalation: The patient should be instructed to sit upright in a chair, to take normal steady breaths, not to talk during the nebulisation, and to keep the nebuliser upright.Nebulisers just before meals may spoil an already small appetite, but others who are severely breathless may need the bronchodilatation.

Types of jet Nebulisers: Conventional Nebulisers are the most commonly used type of jet nebuliser which has a constant output of aerosol from the nebuliser during both inspiration and expiration; however a large amount of drug is wasted as it is produced during expiration. To overcome this other types are available like Conventional jet nebuliser with spacer, Manual flow interrupter jet nebuliser,Open vent jet nebulisers,Breath assisted, open vent jet nebulisers ,but there use is still not common and popular in our country.

Ultrasonic NebulisersMechanism: Unlike jet nebulisers, the operation of an ultrasonic nebuliser does not require any external gas source. The ultrasonic nebuliser uses a rapidly vibrating piezoelectric crystal to produce aerosol particles. Ultrasonic vibrations from the crystal are transmitted to the surface of the drug solution where standing waves are formed. Droplets break free from the crests of these waves and are released as aerosol. The size of droplets produced is inversely proportional to two thirds of the power of the acoustic frequency. A more recent design of ultrasonic nebuliser uses the vibration of the piezoelectric crystal to generate an aerosol indirectly. Crystals vibrate around feeding tube, turning it into a peristaltic pump, which forces liquid through a ceramic mesh (pore size 4.6 µm), creating an aerosol. Factors affecting drug output and method of inhalation described in jet nebulisers apply equally to ultrasonic nebulisers.

Commercially Available Ultrasonic Nebuliser

Fig 2

Table 2: Merits and demerits of Jet and Ultrasonic NebulisersJet Nebulisers Ultrasonic NebulisersOperating flow rate of the jet nebuliser can be easily adjusted to produce a wide range of

Oscillation frequency of the ultrasonic nebuliser is not amenable to changes.

respirable particlesLarge size noisy device and its use causes cooling of the inspired gas

Comparatively small sized, Relatively noise free and warm

Requires an external gas flow, and, when used on patients on mechanical ventilation, requires adjustment of the ventilator flow rate to ensure a constant pressure

Doesn’t require external gas flow, hence ventilatory settings remain unaffected.

Comparatively low cost Expensive Device

Table 3: Commonly used Inhaled Drugs for Obstructive DiseaseDrug Dosage

Salbutamol 0.15 mg/kgTerbuatline Sulphate 0.3 mg/kgIpratropium Bromide 250 ug 6 hrlySodium Cromoglycate 20 mgBudesonide 0.5-1 mg twice daily

Practical points to be remembered:

Drug Volume: Most nebulisers work with drug volumes of 2–5 ml. If the system used has a residual volume of more than 1.0 ml (shown on packing) the drug volume should be made up with 0.9%sodium chloride (not water) to a minimum of 4.0 ml.

Nebulising Time:” Dryness” should not be used as an end point. Patients should be advised to nebulise until about a minute after “spluttering” occurs. This should take 5–10 minutes. An upper limit should be specified. Patients should tap the nebuliser cup towards the end of treatment.

Cleaning: Patients using nebulisers regularly should clean them daily, and patients using them intermittently should clean them after each use. The nebuliser and mouthpiece or mask should be disconnected, disassembled , washed in warm water with a little detergent and allowed to air dried overnight. The nebuliser should be for a few seconds with no drugs in it before the next treatment. Nebulisers used in ventilator circuits should not be left permanently in line and should be cleaned and changed between nebulisation.

Maintenance: Disposable components (plastic tubing, .nebuliser cup, mask or mouthpiece) should be frequently changed every three to four months. Compressors need servicing annually by the local nebuliser service manufacturer.

Patient Instruction: Firstly, patients must be shown how to use their nebuliser by an expert in aerosol therapy preferably a pediatric pulmolologist. The first treatment should always be done under supervision. For longer term use patients should have written instructions provided by their local nebuliser service or derived from the BTS guidelines and have to be followed up regularly in pediatric chest clinic.

Safety related to Nebulisation: Although drugs delivered as aerosols have been mostlyfound to be extremely safe, certain clinical situations may require caution on the part of the clinician. High doses of beta-2 agonists administered through the nebuliser have been reported in rare cases to lead to arrhythmias. Inhaled corticosteroids in large doses may lead to suppression of hypothalamus pituitary-adrenal axis and must be used cautiously in growing children. Risk of

cross-infection with use of nebuliser in hospital patients is also well known and various methods for decontamination of nebulisers have been described.

Following points need to be remembered for Nebulisers in a chest clinic. Compressors should conform to BS5724 or IEL 601-1(BTS standards).A compressor

should be matched with a nebuliser to give an adequate rate of output with a high proportion of particles of appropriate size for a therapeutic effect.

The performance of any chosen combination of compressor and nebuliser should be verified for each class of drug used (bronchodilators, steroids, antibiotics) from published data or new laboratory measurements.

A service should provide foot pump, battery, or 12 volt adapted compressors for occasional emergency use in case of power failure.

Nebulisers should be easy for patients to use and clean. Supplies of mouthpieces or face masks should be available for patients on different drug treatments.

All equipment should be checked for electrical safety and performance before use. Compressors should be serviced regularly, at least annually.

If a Nebuliser is not working, the compressor should be checked. Compressors should be available for loan or replacement while servicing or repairs are being carried out.

Two sets of Nebulisers and disposables such as tubing should be provided initially. Standard equipment needs replacing every 3–6 months, although some more durable units may need to be replaced less frequently.

Records of Nebuliser service should be kept on a computerized data base.

Research Advances: At present, it is not possible to predict accurately drug delivery to the lungs from invitro

studies of Nebuliser performance in both ventilated children and those on aerosol therapy on outpatient basis. The relationship between in vitro studies (including the effect of breathing patterns) and pharmokinetic and radioisotope studies (in case of ventilators) of drug delivery to the lungs needs to be more closely examined.

Little is known about how different types & modes of mechanical ventilation, lung disease & abnormal lung function affect an aerosol delivery through nebulisers & needs to be extensively studied.

Conclusions: Nebulisers are highly efficacious in providing immediate relief in acute situations like severe asthma and ventilated children where hand held devices or systemic drugs may be either difficult to administer or delay in action. Selective & larger generation of bronchioles & alveoli are targeted for drug delivery which may not be possible with hand held devices.Using the appropriate device and conditions it is possible to nebulise virtually any drug and in almost any dose. For b2 agonists, where only a small airway dose is required to achieve maximum bronchodilatation, variation in drug delivery between devices may be less critical. Nebulisers vary greatly in the size of droplet they produce, their nebulisation time, and drug output which may have a marked effect on the therapeutic response.

References:

1. British Thoracic Society. Guidelines on the management of asthma. Thorax 1993; 48:S1–24.

2. Dennis JH, Hendrick DJ. Design characteristics for drug Nebulisers. J Med Eng Techno 1992; 16:63–8.

3. 2 O’Driscoll BR, Cochrane GM. Emergency use of nebulised bronchodilator drugs in British hospitals. Thorax 1987; 42 : 491–3.

4. Kendrick A, Smith EC, Denyer J. Nebulisers: fill volume, residual volume and matching Nebuliser to compressor.Respir Med 1994; 89 : 157–9.

5. Kradjan WA, Lakshminarayan S. Efficiency of air compressor driven Nebulisers. Chest 1985; 87:12–16.

6. Dennis JH, Hendrick DJ. Design characteristics Nebulisers. J Med Eng Technol 1992; 16:63–8Thomas SHL, Langford JA, George RJD, Geddes DM.Aerosol distribution in the human lung: effect of high frequency oscillation on the deposition characteristics of an inhaled nebulised aerosol. Clin Sci. 1988; 75:535–42.