Nazish Dissertation

8/21/2019 Nazish Dissertation

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Comparison between Inhaled Corticosteroid and Montelukast in

Uncontrolled Asthma among the Children below 5 Years Age.

INTRODUCTION:

Asthma in childhood is a heterogeneous disease with diferent phenotypes

and variable clinical maniestations, which depend on the age, gender,

genetic background, and environmental inuences o the patient (1-3!

Asthma is the most common chronic disease in children("! #he burden o

asthma is e$perienced not only in terms o healthcare costs but also as lost

productivity and reduced participation in amily lie(%. Asthma is characterized

physiologically by variable airlow obstruction and airway hyperresponsiveness !"#. &or

patients with symptoms consistent with asthma, but normal lung unction,

measurements o airway responsiveness to methacholine, histamine,

mannitol, adenosine monophosphate or e$ercise challenge may help to

establish a diagnosis o asthma('-! Asthma is a condition characteri)ed by

variable airow obstruction, airway hyper-responsiveness (A*+ and airway

inammation which is usually, but not invariably, eosinophilic (1, 11! Clinical

diagnosis o asthma is oten based on the presence o symptoms$ such as cough$ wheeze$

breathlessness$ and chest tightness and other diagnostic testing is essential!%&$ %'#.

Asthma is the most common chronic disease in children in many low( and middle(income

countries !%)#. In these settings$ the burden o childhood asthma is increasing and is associated


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with severe disease because o many actors. *hese include under(diagnosis o childhood

asthma$ access to care$ ability o healthcare workers to manage asthma$ availability and

aordability o inhaled therapy$ environmental control o potential triggers$ education o

healthcare providers and o the public$ and cultural or language issues!%)#.

*he global prevalence o asthma ranges %+%,- o the population although it varies widely in

dierent countries !%5#. *he /0 has estimated that %5 million disability(ad1usted lie(years

are lost annually due to asthma$ representing %- o the total global disease burden! %"#. Annual

worldwide deaths rom asthma have been estimated at &52$222 and mortality does not appear to

correlate well with prevalence !%3#. *here has been a sharp increase in the global prevalence$

morbidity$ mortality$ and economic burden associated with asthma over the last )2 years$

particularly in children !%,(&2#. *he increasing number o hospital admissions or asthma$ which

are most pronounced in young children$ relect an increase in severe asthma$ poor disease

management$ and poverty!&%(&'#. ith an increase in prevalence comes an increased burden o

disease in terms o morbidity$ mortality and compromised 4uality o lie. *he economic burden

in terms o utilization o healthcare resources and limitation o the earning capacity o the

individuals and amilies is an added problem !&)$ &5#. *he data rom Asian countries regarding

these parameters is scarce$ underlining the need or systematic studies in these countries$

especially those that are resource poor !&"#.

*he chronic inlammation o asthma is associated with airway hyperresponsiveness that leads to

recurrent episodes o wheezing$ breathlessness$ chest tightness$ and coughing$ particularly at

night or in the early morning!&3# . Most asthmatics have hyperresponsive airways!"#. *his

makes them more sensitive than non(asthmatics to bronchoconstricting environmental eposures

which$ in their turn$ may enhance responsiveness!&,#. *he main inducers o airway inlammation


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are viral inections$ antigens$ occupational stimuli and pollutants!&6#. Although eercise$ airway

cooling and hyper( or hypotonic aerosols are potent stimuli o bronchoconstriction$ it is

4uestionable i airway inlammation is involved in their mode o action! '2#.*his narrowing is

almost always reversible in children with treatment. *he symptoms occur or worsen in the

presence o Aeroallergens like house dust mites$ pets$ cockroach$ pollens and ungi$ eercise$

respiratory inections$ tobacco smoke and strong emotional epressions like laugh$ cry$ shouting

etc !'%#.7amily history o atopy$ maternal history o asthma$ and the presence o smokers in the

house were risk actors or the maniestation o asthma!'&(')#. 8arly rhino viral wheezing is the

predictor o subse4uent asthma development in high(risk children !'5#.

A clinical diagnosis o asthma is suggested by symptoms such as episodic breathlessness$

wheezing$ cough and chest tightness !'"#. 8pisodic symptoms ater an incidental allergen

eposure$ seasonal variability o symptoms and a positive amily history o asthma and atopic

disease are also helpul diagnostic guides!'3#.

Airway responsiveness can be deined as the ease with which airways narrow in response to

various no allergic and no sensitizing stimuli$ including inhaled pharmacologic agents$ such as

histamine and methacholine$ and physical stimuli$ such as eercise!',#. Interactions between

environmental and genetic actors result in airway inlammation leading to airway obstruction in

the orm o bronchospasm$ mucosal edema$ and mucus plug !'6#. Airway obstruction causes

increased resistance to airlow and decreased epiratory low rates. *hese changes lead to a

decreased ability to epel air and may result in hyperinlation!)2#. *he resulting over distention

helps maintain airway patency$ thereby improving epiratory low9 however$ it also alters

pulmonary mechanics and increases the work o breathing!)%#. Childhood asthma is a ma1or


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concern or the patient and the care given. *he morbidity leads to greater number o school days

o aecting daily activities and simultaneously the impact on child:s psyche !)&())#.

8vidence suggests that appropriate treatment o asthma leads to less morbidity with less number

o school absteeinism in children!5#. *he goals o asthma treatment are to limit the re4uency$

severity and costliness o asthmatic episodes through etensive education o physicians$ children

and caregivers. *he our components o asthma management include regular assessment and

monitoring$ control o actors that contribute to or aggravate symptoms$ pharmacologic therapy

and education o children and their care givers. Asthma education is an essential part o the

treatment o this disease. *he eective management o asthma implies eective partnership

between the patient and the health care providers !)5#. Asthma sel(management education

improves patient (outcomes and can be cost eective!)"#. ;educing a patient:s eposure to risk

actors !e.g.$ smoking cessation$ reducing eposure to second hand smoke$ reducing or

eliminating eposure to occupational agents known to cause symptoms$ and avoiding

oods


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REVIEW OF LITERATURE

EPIDEMIOLOGY

Asthma is a common chronic disease o childhood which causes considerable morbidity. Asthma

aects % in %' school(age children and is a leading cause o oice and emergency department

visits$ hospitalizations$ and school absenteeism. 8stimating the prevalence o asthma in the

community is important in assessing the impact o asthma at the level o population! '#. *he

prevalence o Asthma varies widely.

Asthma is now one o the most important diseases o childhood in developed countries. In the

International =tudy o Asthma and Allergies in Childhood !I=AAC# study$ the highest asthma

prevalence was observed in westernized 8nglish(speaking countries !e.g.$ the United >ingdom$

Australia$ and ?ew @ealand#$ with much lower prevalence rates in 8astern 8urope$ India$ China$

other countries in Asia$ and Arica!5%#. Although there are considerable geographical dierences

in its presentation$ bronchial asthma is an illness in constant increase in the entire world! . *he

prevalence o asthma has gradually increased over the past &2 years in developed countries.

esternization o way o lie is associated with increased prevalence o atopy$ allergic rhinitis

and asthma !5. In a landmark study signiying the eect o geography and lie style conducted

in Chine showed Asthma symptoms in Chinese adolescents were lowest among residents o

mainland China$ were greater or those in /ong >ong and those who had immigrated to Canada$

and were highest among those born in Canada. *hese indings suggest that environmental actors

and duration o eposure inluence asthma prevalence !5'#. =imilarly colleagues rom 8cuador

have shown that the prevalence o asthma increases with increasing levels o urbanization in

transitional communities$ and actors associated with greater socioeconomic level and changes


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towards a more urban liestyle may be particularly important!5)#. In ?etherlands a estern

diet was ound to increase the risk o re4uent respiratory symptoms at ' and ) years o age !55#.

Malmstorm rom 7inland showed that while the prevalence o mild and moderate asthma has

increased$ the occurrence o severe asthma has remained essentially unchanged !5"#. In a

multicenter study noted the prevalence o childhood asthma and availability o indoor swimming

pools in 8urope are linked to pool chlorine in the rise o childhood asthma in industrialized

countries!53#.

In India the prevalence o Asthma was reported to be &.)-!5,#. In another study conducted in

*amil ?adu it was ound that though the prevalence o diagnosed childhood asthma was about

5- in both urban and rural areas$ the prevalence o Bbreathing diicultyB and nocturnal cough was

signiicantly higher among urban children in the age group o "(%& year! 56#. In another study

rom rural India the prevalence o %2.3- in children o grade 3 and ,!"2#.

A study rom /ong >ong 4uoted the prevalence o Asthma to be %%-! "%#. In apan *anaka and

other workers noted a prevalence o 3."-!". *he highest prevalence o asthma was also

reported rom apan which was &5."- in children aged %'(%) years. ! "'#. In *aiwan Diao and

others ound the prevalence o asthma was 3.2-!")#. Another epidemiological study rom

*aipei$ *aiwan showed the prevalence o asthma to have risen rom %.'2- in %63) to 5.23- in

%6,5$ with boys dominating in both studies!"5#. oreover some studies have suggested

that a diet with a high intake o at and simple sugars and low intake o ruit$ vegetables and rice

is associated with an increased risk o asthma in *aiwanese children!""#.orkers rom *urkey

reported the prevalence o Asthma to be %.6- !"3#. A *hai study showed the prevalence o

asthma to be ,.,!",#. orkers rom =iri Danka showed the prevalence o asthma to be %3-! "6#.


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/owever$ recent studies have shown that the prevalence in Asia is increasing$ although the rate

o increase has slowed in the more developed Asian cities!%#.

In Iran a study ound that the pooled prevalence or girls$ boys$ and the two genders was

obtained as '.&- !CI9 &.5 to '.6-#$ ).'- !CI9 '.5 to 5.%-# and '.6- !CI9 '.& to ).3-#$

respectively!'#.In *urkish Cyprus the prevalence o physician diagnosed asthma was %%.)-! 32#.

In the *urkish study conducted in Ankara the prevalence o asthma was ,.%-!3%#. In 8dirine $

*urkey prior physician diagnoses o asthma was ).%- or preschool children!3. In ordan the

prevalence o physician diagnosed asthma was ).%-!3'#.Moreover it was ound that the

prevalence among Eedouin children was more than city children!6.5- versus ,.,-#!3)#. *he

prevalence o asthma in school age children age %'(%) years old was %'.3- in the state o Israel

!35#. In a Debanese study by Musharaae the prevalence o asthma was ,.%- !3"#. Eehbehani

rom >uwait showed the prevalence o asthma to be %".,- !33#. In a Malaysian study the

prevalence o asthma was ,.'-!3,#. 8ven in a particular country$ the prevalence o asthma

varies by race e.g. an 8nglish study showed that %,.&- o Elack Caribbean children and 5.2- o

Eangladeshi children reported ever asthma compared with %%."- o hite children!36#.

Colleagues rom ?orway concluded that lietime prevalence o asthma was &2.&-9 current

asthma %%.%-$ doctor diagnosis o asthma %".%- and wheezes ever '2.'-!,2#. *he prevalence

o physician(diagnosed asthma was 6.5-$ while 6."- reported the use o asthma medicine !,%#.

.everal large =wiss epidemiologic studies conirmed both$ the high prevalence o

asthma!6.%-#$ and the health impact o moderate air pollution levels and o actors associated

with the Bwestern liestyleB!,.

*here are also gender dierences in the prevalence o asthma. A study conducted in *aiwan

ound that boys had signiicantly higher prevalence o wheezing and rhinitis than girls while


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younger children tend to have higher prevalence o the disorders than those that are older in age

!,'#.


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RISK FACTORS FOR DEVELOPING ASTHMA

7actors inluencing Fevelopment and 8pression 0 Asthma can be classiied as precipitating

actors and /ost actors.

Precipitatin !act"r#

a$ Allergens like ood$ animal$ mold$ spores$ pollens$ insects!,)#

%$ Frugs!,5#

c$ Irritants!)3# like paint odors$ sprays$ perumes$ chemicals$ smoke!,"#$ cold air$ cold

water and cough

&$ eather changes

e$ Inection like viral$ ungal !aspergillosis#$ bacterial !E. Gertussis#$ and parasitic

!*oocara$ ascariasis#!,)#

!$ 8ercise !32 - o all asthmatics#!,3#

$ 8motional actors!,,#

'$ Hastro esophageal relu!,6# ( !?octurnal =ymptoms#

i$ Allergic rhinitis!62#

($ 8ndocrine!6%# ( menstrual cycles$ oral contraceptive pills and hyperthyroidism

)$ =inusitis!6 !?octurnal symptoms#

H"#t !act"r#

Gene#: Henetic studies indicate that multiple genes are involved in the pathogenesis o this

disease$ and chromosomal regions likely to harbor asthma currently susceptibility genes have

been replicated in several studies !6'#. 7urthermore$ interaction between susceptibility genes and

environmental actors is probable and is a challenge being pursued by investigators worldwide

!6)$ 65#. 7amily studies have identiied a number o chromosomal regions associated with

asthma susceptibility. *he most consistently replicated regions are on chromosomes &4$ 54$ "p$

%&4 and %'4 !6"#. =imilarly$ Gatient response to the asthma drug classes$ bronchodilators$ inhaled

corticosteroids and leukotriene modiiers$ are characterized by a large degree o heterogeneity$

which is attributable in part to genetic variation!63$ 6,#.


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O%e#it*: Epidemiological data indicate that obesity increases the prevalence and incidence

of asthma (99). Obesity results in important changes to the mechanical properties of the

respiratory system, and these obesity-related factors appear to exert an additive effect to the

asthma-related changes seen in the airways(!!). "revalence of asthma and overweight has

increased simultaneously during the past decades .Obesity is capable of reducing pulmonary

compliance, lung volumes, and the diameter of peripheral respiratory airways, and may

influence on airway hyperresponsiveness(!). #he increase of adipose tissue in obese

sub$ects leads to a systemic inflammatory state, which produces a rise in the serum

concentrations of several pro-inflammatory cyto%ines, chemo%ines and adipo%ines (!&).

Se+: Male se is a risk actor or asthma. Eeore the age o ) years the prevalence is twice as

great in boys as in girls but ater this the dierence narrows and by adulthood the prevalence is

greater in women !%2'#.

A,,eren#: Allergens$ such as pollen$ dust mites and animal ur or eathers$ can trigger asthma in

children who are allergic to them!%2)#. Airborne irritants$ such as cigarette smoke$ chemical

umes and atmospheric pollution may trigger asthma. Indoor conditions$ such as mold or damp

and occasionally chemicals in carpets and looring materials$ may trigger asthma!%25#. /owever$

the relationship between the allergen eposure and sensitization is not straight orward. It

depends on the allergen$ the dose$ time o eposure$ child:s age and possibly genetics. =ome

children have allergies to nuts or other oods. A child with a ood allergy may have an asthma

attack as part o an allergic reaction to a ood!%2"#. hen this is severe$ it is known as

anaphylais. 7oods containing sulphites ( sulphites are naturally occurring substances ound in

some ood and drink. *hey are also sometimes used as a ood preservative. 7ood and drinks that

are high in sulphites include concentrated ruit 1uice$ 1am$ prawns and many processed or pre(


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cooked meals. Most children with asthma will not have this trigger. Medicines$ such as the class

o painkillers called non(steroidal anti(inlammatory drugs !?=AIFs#$ which includes aspirin

and ibuproen$ occasionally trigger asthma in children!%23#.

Vira, In!ecti"n#: ;=$ ollowed by the Gara inluenza viruses$ is the chie cause o

hospitalization or respiratory tract illness in young children!%2,#. =ome types o viral inections

can also trigger asthma. Gara inluenza virus aects the respiratory tract in children$ sometimes

causing bronchitis !inlammation o the bronchi# or pneumonia. A number o long term

prospective studies o children admitted to the hospital with documented ;= inection have

shown that approimately )2- o these continue to wheeze or have asthma in later

childhood!%26#.

E+erci#e: 8ercise(induced bronchoconstriction !8IE# has a high prevalence in children with

asthma$ and this is a common problem$ even in case o controlled asthma$ because o the high

levels o physical activity in the childhood !%%2#. 8ercise induced asthma is the conventional

term or transient airway narrowing in a known asthma in association with strenuous eercise

usually lasting 5(%2 minutes with a decline in pulmonary unction by at least %2- ! %%%# ./eat

loss$ water loss$ post(eertional airway rewarming$ and the role o several mediators have been

proposed as possible mechanisms responsible or the airway obstruction induced by eercise!'2#

. *he kind o physical activities that can bring on asthma symptoms include not only eercise$

but also laughing$ crying$ holding oneBs breath and hyperventilating. *he symptoms o eercise(

induced asthma usually go away within a ew hours. ith proper treatment$ a child with

eercise(induced asthma does not need to limit his or her overall physical activity !%%.


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Diet: Studies reveal that inants ed ormulas o intact cowBs milk or soy protein compared with

breast milk have a higher incidence o atopic dermatitis and wheezing illnesses in early

childhood!%%'#. Increased consumption o linoleic acid$ ound in polyunsaturated atty acids

!GU7As#$ is thought to be linked to asthma$ eczema and allergic rhinitis through increase in the

synthesis o prostaglandin(8& !GH8$ resulting in allergic sensitization!%%)#.

PATHOPHYSIOLOGY


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*he pathophysiology o asthma is comple and involves interlinked connection o airway

inlammation$ intermittent airlow obstruction and bronchial hyper responsiveness.

Air-a* in!,a..ati"n: Airway hyperresponsiveness !A/;# and airway inlammation are key

pathophysiological eatures o asthma. Asthma is characterized by reversible airway obstruction$

airway hyperresponsiveness$ and airway inlammation!%%5#. *he irst mechanism identiied as

important or asthma was bronchial hyperresponsiveness. In a second step$ asthma was

recognized also as an inlammatory disease$ with chronic inlammation inducing structural

changes or remodeling!%%"#. Asthma is a comple chronic inlammatory disease o the airways

that involves the activation o many inlammatory and structural cells$ all o which release

inlammatory mediators that result in the typical pathophysiological changes o asthma. *hese

include mast cells$ macrophages$ eosinophils$ * lymphocytes$ dendritic cells$ basophils$

neutrophils$ and platelets!%%3#. Airway epithelial cells$ smooth muscle cells$ endothelial cells$

and ibroblasts are all capable o synthesizing and releasing inlammatory mediators acute

conse4uences o asthma are bronchoconstriction$ plasma eudation$ and mucus

hypersecretion!%%,#. Inlammatory cells$ such as activated eosinophils and neutrophils identiied

in sputum and bronchial lavages !ED# in severe acute asthma rom children and adults are

associated with increased levels o ID(5$ ID(,$ and o proinlammatory mediators. iruses$ but

also endotoin or allergen eposure$ are able to recruit neutrophils$ via an ID(, production by

activated macrophages or epithelial cells. *ogether$ these inlammatory mediators are responsible

or the diuse bronchial inlammation$ which involve large and small airways!%%,# . *his

chronic inlammation may result in structural changes in the airway$ such as ibrosis !particularly

under the epithelium#$ increased thickness o the airway smooth muscle layer !hyperplasia and

hypertrophy#$ hyperplasia o mucus(secreting cells$ and new vessel ormation !angiogenesis#


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.*he initial physiopathological event o inlammatory response in the production o primary

cytokines$ *?7(alpha$ ID(% and ID(" by macrophages!%%6#. *hese and other cytokines trigger

the progress and ampliication o inlammatory process involving secondary mediators and

inlammatory cells !*h%


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mechanisms in response to inection. *h&$ in contrast$ generates a amily o cytokines !ID()$ ID(

5$ ID("$ ID(6$ and ID(%'# that can mediate allergic inlammation.

Air!,"- O%#tr/cti"n: Airlow obstruction can be caused by a variety o changes$ including

acute bronchoconstriction$ airway edema$ chronic mucous plug ormation$ and airway

remodeling. Acute bronchoconstriction is the conse4uence o Ig 8(dependent mediator release

upon eposure to aeroallergens and is the primary component o the early asthmatic

response!%&5#. Airway edema occurs "(&) hours ollowing an allergen challenge and is reerred

to as the late asthmatic response. Chronic mucous plug ormation consists o an eudate o serum

proteins and cell debris that may take weeks to resolve. Airway remodeling is associated with

structural changes due to long(standing inlammation and may prooundly aect the etent o

reversibility o airway obstruction!%&"#. Airway obstruction causes increased resistance to

airlow and decreased epiratory low rates. *hese changes lead to a decreased ability to epel

air and may result in hyperinlation!%&3#. *he resulting over distention helps maintain airway

patency$ thereby improving epiratory low9 however$ it also alters pulmonary mechanics and

increases the work o breathing.

Air-a* H*perre#p"n#i0ene##: Airway hyperresponsivenessan eaggerated

bronchoconstrictor response to a wide variety o stimuliis a ma1or$ but not necessarily uni4ue$

eature o asthma. *he degree to which airway hyperresponsiveness can be deined by contractile

responses to challenges with methacholine correlates with the clinical severity o asthma!%&,#.

*he mechanisms inluencing airway hyperresponsiveness are multiple and include inlammation$

dysunctional neuro(regulation$ and structural changes9 inlammation appears to be a ma1or

actor in determining the degree o airway hyper responsiveness !%&6#. *reatment directed


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toward reducing inlammation can reduce airway hyperresponsiveness and improve asthma

control.

Figure 1: The Interplay and Interaction Between Airway Inflammation And The Clinical Symptoms And

Pathophysiology Of Asthma

From: Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma

Epert Panel !eport ": #uidelines for the Diagnosis and $anagement of Asthma.

National Asthma Education and Pre%ention Program, &hird Epert Panel on the Diagnosis and $anagement of Asthma.

'ethesda ($D): National Heart, *ung, and 'lood +nstitute (S)- 2/ Aug.

Steps at 0ellular *e%el K Ig8 antibodies are synthesized by the plasma cells$ which are present on

the surace o the respiratory tract. *hese Ig8 antibodies have become reversibly ied to the

surace receptors o mast cells and basophils !%'2#. Antigens attaches to surace Ig8 on

sensitized mast cells resulting in activation o mast cells and a cascade o biochemical reactions.


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*his results in degranulation and release o preormed mediators !early phase mediators(

histamine$ 8C7$ ?C7$ heparin$ GA7# within '2 minutes !'6#. Arachidonic acid is ormed through

the activation o phospholipase. 7rom arachidonic acid$ leukotrienes are ormed via the

lipoygenase pathway and prostaglandins via the cyclooygenase pathway !%'%#. *hese late

phase mediators are responsible or the late reaction$ which develops " to , hours ater the

eposure to allergen.!D8U>0*;I8?8= C)$F)$8) collectively called slow releasing substances

o anaphylais#

*he development o allergic asthma eists o three phases$ namely the induction phase$ the

early(phase asthmatic reaction !8A;# and the late(phase asthmatic reaction !DA;#. 8ach phase

is characterized by the production and interplay o various cell(derived mediators. Crucial in

the development o airway inlammation in allergic asthma is the allergic cascade!%'. Inhaled

allergens that escape the mucociliary clearance are taken up and processed by antigen presenting

cells !AGCs#$ which are distributed throughout the respiratory tract$ rom the nasal mucosa to the

lung pleura!%''#. *hese AGCs then migrate to the draining lymph nodes where the processed

allergen is presented to allergen( speciic * and E cells. Interactions between those cells elicit

responses that are characterized and inluenced by secreted cytokines and the presence or absence

o cell(bound costimulatory molecules. Activation o * helper !*h# cells by AGCs leads to the

production o cytokines that regulate the iso( type switch o E cells in their production o

Ig8!%')#. 0nce synthesized$ Ig8 antibodies circulate in the blood binding to the high(ainity

Ig8 receptor 7c ;I that is present on mast cells in tissue or on peripheral blood basophils. Ater

re(eposure$ allergens cross(link to mast cell( bound speciic Ig8$ thus causing the activation o

membrane and cytosolic pathways$ which subse4uently trigger the release o preormed

mediators$ such as histamine$ the synthesis o prostaglandins !GHs# and leukotrienes !D*s#$ and


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the transcription o cytokines by mast cells. *hese mediators cause the so(called 8A;$ which is

characterized by constriction o A=M cells$ vascular leakage$ mucus production$ enhanced

A/; and recruitment o inlammatory cells. *his 8A; is immediate$ lasting '2+"2 min and )+"

h later ollowed by the DA;. *he late(phase is characterized by ecessive inlammation o the

airways$ resulting in structural changes$ including airway wall thickening$ subepithelial ibrosis$

goblet cell hyperplasia$ myoi( broblast hyperplasia$ A=M cell hyperplasia and hypertrophy$ and

epithelial hypertrophy. *his is collectively known as airway remodeling!%'5#.

Figure 2: Factors *imiting Airflo1 +n Acute And Persistent Asthma.


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Source: Adapted and reprinted from &he *ancet, "3, Holgate S&, Polosa !. &he mechanisms, diagnosis, and management of

se%ere asthma in adults, /345". 0opyright (2), 1ith permission from Else%ier.

From: Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma

Epert Panel !eport ": #uidelines for the Diagnosis and $anagement of Asthma.

National Asthma Education and Pre%ention Program, &hird Epert Panel on the Diagnosis and $anagement of Asthma.

'ethesda ($D): National Heart, *ung, and 'lood +nstitute (S)- 2/ Aug.

+nduction of the allergic reaction:

Furing the induction phase$ allergens enter the airways$ are processed by AGCs$ and are brought

to the lymph nodes. /ere$ they are presented to * and E cells. Activation o *h cells leads to

the production o various cytokines$ such as interleukin !ID#(&$ ID('$ ID()$ ID(5$ ID("$ ID(6$ ID(

%2$ ID(%&$ ID(%'$ ID(%,$ intereron !I7?#( $ tumor necrosis actor !*?7#( $ *?7( and HM(

C=7!%'"#. 0 these$ ID()$ ID(5$ ID(6 and ID(%' are the most important in the development o

asthma. ID() and ID(%' play a role in isotope switching to Ig8 production. *ogether with ID(6$

they are also important in mast cell development$ mucus overproduction and A/;!%'.

Early6phase asthmatic reaction

$ast cells: *he most crucial cell types in the 8A; are mast cells. Mast cells are involved in the

pathophysiology o asthma through their capacity to secrete a wide variety o mediators ater

activation by allergens!%'3#. ;e(eposure to a previously met allergen leads to its binding on

Ig8 antibodies that are attached to mast cell 7c ;I receptors. *his causes cross(linking o 7c

;I receptors$ where( upon mast cells degranulate and synthesize pro(inlammatory molecules.

Mediators produced by mast cells can be divided into preormed mediators !e.g. histamine#$

newly synthesized lipid mediators !e.g. GHs and D*s#$ and cytokines and growth actors !e.g.


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*?7$ 8H7!%'2#. Greormed mediators are packaged within secretory granules in the mast

cell and$ on activation$ are released into the etracellular environment within minutes. Grincipal

granule constituents include histamine$ proteases !tryptase$ chymase$ and carboypeptidase#

and proteoglycans !heparin and chondroitin sulphate 8#. /istamine eerts eects on smooth

muscle cells !contraction#$ endothelial cells$ venule permeability$ nerve end( dings$ and mucus

secretion. *he unction o tryptase in %i%o is unknown$ but in %itro it can cleave complement

C' and C'a$ activate ibroblasts$ promote accumulation o inlammatory cells and potentiate

histamine(induced smooth muscle contraction!%',#. *ryptase is used as a marker o mast cell

degranulation. Chymase has a procollagen proteinase activity and is probably directly toic to

the airway cells!%',#. 0ther mast cell proteases likely contribute to activation o protein

cascades and inlict local tissue damage

*ipid $ediators include GHs and D*s$ inlammatory metabolites derived rom the peroidation

o arachidonic acid!%'6#. *hese molecules have various eects in the asthmatic airway$ e.g.

recruitment o inlammatory cells$ bronchoconstriction and mucus secretion.

& *ymphocytesK * lymphocytes play a very important role in coordinating the inlammatory

response in asthma through the release o speciic pattern o cytokines resulting in the

recruitment and survival o eosinophils and maintenance o mast cells in airway .*he

programming o * lymphocytes is due to antigen presenting cells such as dendritic cells which

may migrate rom epithelium to regional lymph nodes or which interact with lymphocytes

resident in airway musosa. Children with atopy are more likely to retain */& type

phenotype!%)2#.

;egulatory * cells suppresses the immune response through the release o inhibitory cytokines

such as ID(%2 and transorming growth actor beta and play an important role in immune


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regulation with suppression o */% responses!%)%#. /owever$ their role in allergic diseases has

not been well deined.

' *ymphocytes: In allergic diseases$ E lymphocytes secrete Ig8. ID() is responsible or

switching E cells to Ig8!%).

0yto7ines: Mast cells play a role in more persistent or chronic inlammatory responses through

the release o multiunctional cytokines. *?7( is a ma1or cytokine produced by mast cells9 it

up regulates endothelial and epithelial adhesion molecules$ increases A/;$ and has antitumor

eects !%)'#. 0ther cytokines produced by mast cells include ID()$ which is associated with *h&

cell dierentiation and Ig8 synthesis$ ID('$ HM(C=7$ and ID(5$ which are critical or

eosinophil development and survival$ and ID("$ CNC(chemokine ligand !CNCD# , !ID(,#$ and

ID(%".

*ate6phase asthmatic reaction

*he late(phase o the asthmatic reaction is characterized by ecessive inlammation o the

airways resulting in structural changes induced by various mediators derived rom

inlammatory cells$ like eosinophils$ neutrophils$ * cells$ macrophages$ dendritic cells !FCs#$

endothelial cells$ A=M and E8Cs.

Increased numbers o eosinophils eist in the airways o most$ but not all$ persons who have

asthma !%))#. *hese cells contain inlammatory enzymes$ generate leukotrienes$ and epress a

wide variety o pro(inlammatory cytokines. Increases in eosinophils oten correlate with greater

asthma severity. *hey may release basic proteins that may damage the airway epithelial cells.

*hey also have a role in release o growth actors and airway remodeling . In addition$ numerous


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studies show that treating asthma with corticosteroids reduces circulating and airway eosinophils

in parallel with clinical improvement!%)5#.

Neutrophils: ?eutrophils are increased in the airways and sputum o persons who have severe

asthma$ during acute eacerbations$ and in the presence o smoking!%)"#. *heir

pathophysiological role remains uncertain9 they may be a determinant o a lack o response to

corticosteroid treatment !%)3#. *he regulation o neutrophil recruitment$ activation$ and

alteration in lung unction is still under study$ but leukotriene E) may contribute to these

processes.

$acrophages: Macrophages are the most numerous cells in the airways and also can be activated

by allergens through low(ainity Ig8 receptors to release inlammatory mediators and cytokines

that ampliy the inlammatory response !%%6#.

!esident cells of the air1ay: A=M is not only a target o the asthma response !by undergoing

contraction to produce airlow obstruction# but also contributes to it !via the production o its

own amily o pro(inlammatory mediators#. As a conse4uence o airway inlammation and the

generation o growth actors$ the airway smooth muscle cell can undergo prolieration$

activation$ contraction$ and hypertrophyevents that can inluence airway dysunction o

asthma!%&"#.

Epithelial 0ellsK Airway epithelium is another airway lining cell critically involved in asthma.

*he generation o inlammatory mediators$ recruitment and activation o inlammatory cells$ and

inection by respiratory viruses can cause epithelial cells to produce more inlammatory

mediators or to in1ure the epithelium itsel. *he repair process$ ollowing in1ury to the


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epithelium$ may be abnormal in asthma$ thus urthering the obstructive lesions that occur in

asthma!'2#.

Air1ay !emodeling: 0ngoing inlammation may result in structural remodelingK wall

thickening$ subepithelial ibrosis$ metaplasia$ hypertrophy and hyperplasia o airway cells$

cartilage breakdown and angiogenesis. *he most prominent mediators o airway remodeling are

$atri metalloproteinases, 0yto7ines, 0hemo7ines, .Endothelin68, 9ascular endothelial gro1th

factor, *ipid mediators (Prostaglandin D2, Prostaglandin E2, 36+soprostane), 0ysteinyl

leu7otrienes, *eu7otriene ' and ADA$""( 83 ).

$atri metalloproteinasesK Connective tissue cells produce and secrete an array o macro(

molecules orming a comple network illing the etracellular space o the submucosa$ called

the 8CM. *he 8CM is a dynamic structure$ and e4uilibrium between synthesis and degradation

o 8CM components is re4uired or the maintenance o its homeostasis. MMG:= are responsible

or the development$ morphogenesis$ reproduction$ and tissue resorption and remodeling !%)6#.

*he balance MMGs are thought to play a central role in between MMGs and *IMGs$ which

is critical in tissue repair and remodeling$ and its homeostasis plays an important role in the

breakdown and deposition o 8CM in the airway wall!%52#. MMGs are also implicated in

alteration o angiogenesis and smooth muscle hyperplasia processes.

0yto7ines: Firect and modiy the inlammatory response in asthma and likely determine its

severity. *h&(derived cytokines include ID(5$ which is needed or eosinophil dierentiation and

survival$ and ID() which is important or *h& cell dierentiation and with ID(%' is important or

Ig8 ormation!%5%#. >ey cytokines include ID(%O and *?7(L$ which ampliy the inlammatory

response$ and HM(C=7$ which prolongs eosinophil survival in airways. ;ecent studies o


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treatments directed toward single cytokines !e.g.$ monoclonal antibodies against ID(5 or soluble

ID() receptor# have not shown beneits in improving asthma outcomes.

0hemo7inesK Among them$ CCD& is increased in asthma$ and is a well(established

proibrogenic mediator in %itro and in %i%o by inducing *H7( release and collagen deposition

rom lung ibroblasts$ and by recruiting *h& cells in the lung!%&)#. 0ther CC(chemokines$ such

as CCD3 and CCD&& also contribute to the development o pulmonary ibrosis.

Endothelin 8: 8ndothelin !8*#(% may be involved in airway remodelingK it is mitogenic or A=M

cells and ibroblasts$ and also stimulates collagen synthesis !%5.

9ascular Endothelial #ro1th Factor: vascular endothelial growth actors !8H7# induce epression o

connective tissue growth actor and collagen !%5'#. Macrophages$ eosinophils and CF')P cells

are the ma1or source o 8H7. *he epression o 8H7 is up regulated in the bronchial mucosa

o mild to moderate asthmatic patients$ compared with that o control sub1ects$ and is related to

the number o vessels and mast cells$ as well as to the basement membrane thickness!%),#.

*ipid $ediators: Prostaglandin D26 Grostaglandins appear to have several eects on the

airways$ including bronchoconstriction$ plasma eudation$ sensitization o nerve endings$ and

eects on inlammatory cells. GHF& is involved in the recruitment o inlammatory cells because

it stimulates the chemotais o *h& cells$ eosinophils$ neutrophils and basophils$ GHF& and

GH7& cause bronchoconstriction in asthmatic patients$ but not in healthy sub1ects!%5)#.

Prostaglandin E2 is also an important GH produced in inlammatory processes!%55#. It is the

most important bronchoprotective metabolite yet identiied in the airways!%5"#. GH8& inhibits


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the release o mediators rom mast cells$ monocytes$ neutrophils and eosinophils. GH8& and

GHI& are vasodilators and thereore should theoretically increase leakage in asthmatic.

36+soprostane: Isoprostanes are inlammatory metabolites derived rom arachidonic acid. It

plays a role in non(speciic smooth muscle hyperresponsiveness$ bronchoconstriction and

edema!%53#.

0ysteinyl *eu7otrienes: *here is substantial evidence that cys(D*s !D*C)$ D*F) and D*8)#

play an important role in asthma!%'%#. Cys(D*s mediate several steps in airway inlammation$

including inlammatory cell recruitment$ vascular leakage and possibly also airway

remodeling!%5,#. *hey decrease mucociliary clearance and are potent mediators o

bronchoconstriction9 plasma eudation and mucus secretion also increase eosinophilic

inlammation.

*eu7otriene ': Deukotriene E) is a potent neutrophil chemoattractant that enhances neutrophil(

endothelial interactions and stimulates neutrophil activation. *his leads to degranulation and the

release o mediators$ enzymes and superoides.

ADA$"": A disintegrin and metalloproteinase !AFAM# '' has been a ocus o interest in the last

ew years!%56#. AFAM'' has been linked to asthma in a study o )"2 white amilies. Abnormal

activity o this gene can lead to altered airway unction$ inlammation$ and remodeling!%"2#.

Alterations in AFAM'' activity may underlie abnormalities in the unction o A=M cells and

ibroblasts linked to airway remodeling and A/;.

=ummary o mediators released by the various cell types that are involved in the early and late


26/102

asthmatic reaction

Cell source ;eleased mediators

+nduction phase

* cells Cytokines !ID()$ ID(5$ ID(6$ and ID(%'#

Early asthmatic reaction

Mast cells /istamine9 proteases !tryptase$ chymase$ and

carboypeptidase#9 proteoglycans !heparin$

chondroitin sulphate 8#9 prostaglandins !GHF

leukotrienes !D*C)#9 cytokines !*?7( $ ID('$ ID()$

ID(5$ ID("$ ID(,$ ID(%"$ and HM(C=7#9 chemokines

!CCD&$ CCD'$ CCD%%#

Easophils /istamine9 leukotrienes !cys(D*sK D*C)$ D*F)$

D*8)#9 cytokines !ID()$ ID(%'#

*ate asthmatic reaction

8osinophils MEG9 8CG9 8F?9 8G9 leukotrienes !cys(D*sK D*C)$

D*F)$ D*8)#9 cytokines !ID(%$ ID(&$ ID('$ ID()$ ID(5$

ID("$ ID(%2$ ID(%%$ ID(%&$ *?7( $ *H7( $ *H7( $ HM(

C=7#9 chemokines !CNCD,$ CCD'$ CCD5#

?eutrophils Deukotrienes !D*A)$ D*E)#9 GA79 *NA&9 cytokines


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!ID(% $ ID("$ *?7( $ *H7( #9 chemokine !CNCD,#9

proteases !elastase$ collagenase$ gelatinase E#9

microbicidal products !lactoerrin$ myeloperoidase$

lysozyme#9 reactive oygen intermediates !superoide$

hydrogen peroide#9 ?0

* cells Cytokines !ID('$ ID()$ ID(5$ ID("$ ID(6$

ID(%2$ ID(%'$ HM(C=7#9 chemokines

!CCD%$ CCD&

Macrophages Cytokines !ID(%$ ID("$ I7?( $ *?7( #9

chemokines !CNCD,#9 lipids9 GA79

;0=9 ?0 Fendritic cells

Chemokines !CCD&$ CCD'$ CCD)$

CCD%3$ CCD&&$ CNCD,#

8ndothelial cells ICAM(%$ ICAM(&9 G8CAM(%9 CAM(%9 selectins !8(

selectin$ G(selectin#

Airway smooth muscle cells Chemokines !CCD5$ CCD3$ CCD%%$ CCD%'$ CNCD,#9

cytokines !HM(C=7$ ID("#9 prostaglandins !GH8 8CM

proteins

Eronchial epithelial cells Cytokines !ID("$ HM(C=7#9 chemokines !CCD%%$ CCD%3$

CCD&&$ CNCD%$ CNCD"$ CNCD,#9 ICAM(%


28/102

CLASSIFICATION AND DIAGNOSIS OF ASTHMA1

A clinical diagnosis o asthma is suggested by symptoms such as episodic breathlessness$

wheezing$ cough and chest tightness!'"#. Intermittent dry coughing and epiratory wheezing are

the most common chronic symptoms o asthma!%"%#. Younger children are more likely to report

intermittent$ non(ocal chest pain!%". 8pisodic symptoms ater an incidental allergen eposure$

seasonal variability o symptoms and a positive amily history o asthma and atopic diseases are

helpul diagnostic studies. *he patterns o these symptoms that strongly suggest an asthma

diagnosis areK variability9 precipitation by nonspeciic irritants$ such as smoke$ umes$ strong

smells or eercise9 worsening at night9 and responding to appropriate asthma therapy!%"'# . A

clinician should consider asthma i the child has physical activity induced cough or

wheeze!%")# . A useul method or conirming the diagnosis o asthma in children aged Q5 years

is a trial o treatment with short(acting bronchodilators and inhaled glucocorticosteroids. Marked

clinical improvement during the treatment$ and deterioration when treatment is stopped$ supports

a diagnosis o asthma!%"5#.

;espiratory symptoms that begin at or persist through ages ' to ) years are highly diagnostic o

asthma. Cough(variant asthma !patients have chronic cough as their principal$ i not only$

symptom# is particularly common in children and is oten more problematic at night9 evaluations

during the day can be normal!%""# . Children with cough variant asthma do not wheeze .A

simple clinical inde based on the presence o a wheeze beore the age o ' and the presence o

one ma1or risk actor !parental history o asthma or eczema# or two o three minor risk

actors!eosinophilia$ wheezing without colds and allergic rhinitis# has been shown to predict the

presence o asthma in later childhood !%"3#.


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*hree categories o wheezing have been described in children 5 years and younger.

Tran#ient Ear,* W'ee2in outgrows in the irst three years. *his is oten associated with

prematurity and parental smoking!%",#.

Per#i#tent Ear,* On#et W'ee2e !beore the age o '# these children have recurrent episode o

wheeze associated with acute viral upper respiratory tract inections$ have neither evidence nor

amily history or atopy !%"6$ %32#. *he symptoms normally persist through school age and

sometimes till the age o %&. *he cause o episode is usually respiratory syncytial virus in those

under the age o & and other viruses in older children. . *here is now convincing evidence that

children who develop lower respiratory symptoms during inection with respiratory syncytial

virus !;=# in early lie are at increased risk o developing asthma(like symptoms during the

school years!%3%#.

Late On#et W'ee2e3A#t'.a *hese children have asthma which oten persists throughout

childhood and into adult lie. *hese patients have atopic background oten with eczema and

airway pathology which is characteristic o asthma !%32#.

Cough Variant AsthmaK Gatients with cough variant asthma have chronic cough as their

principal symptom. It is more problematic at night$ evaluations during the day time can be

normal.

E+erci#e In&/ce& 4r"nc'"c"n#tricti"nK *ypically develops within 5 to %2 min ater completing

eercise!it rarely occurs during eercise#.Gatients eperience typical asthma symptoms which

resolves spontaneously within '2 to )5 min. 8ercise induced bronchoconstriction can develop

in any climatic condition but is more when patient is breathing dry $cold air and less common in


30/102

hot$ humid climate. ;apid improvement o symptoms ater inhaled beta & agonist use supports

the diagnosis o asthma!%%2#.

Di!!erentia, Dian"#e#

*able %.Fierential diagnosis


31/102

Upper respiratory tract conditions

Allergic rhinitis

Chronic rhinitis

=inusitis

Adenoidal or tonsillar hypertrophy

?asal oreign body

Middle respiratory tract conditions

Daryngotracheobronchomalacia

Darayngotracheobronchitis !e.g. pertusis#

Daryngeal web$ cyst or stenosis

ocal cord dysunction

ocal cord paralysis

*racheoesphageal istula

ascular ring$ sling or eternal mass compressing the airway!tumor#

7oreign body aspiration

Chronic bronchitis rom tobacco smoke eposure

*oic inhalations

Dower ;espiratory *ract Conditions

Eronchopulmonary dysplasia!chronic lung disease o preterm inants#

iral bronchiolitis

Hastroesophageal relu

Eronchiectasis


32/102

La%"rat"r* Fin&in#:

Dung unction tests help to conirm the diagnosis o asthma and to determine disease severity.

P/,."nar* !/ncti"n te#tinK Use o spirometry and other lung unction measures are

diicult to perorm in young children below the age o 5 years old and are not suitable or

routine use!%3. A trial o treatment with short(acting bronchodilators and inhaled

glucocorticosteroids with marked clinical improvement supports the diagnosis o asthma

7or patients R5 yrs o age$ measurements o lung unction to conirm airlow limitation$ and

particularly the demonstration o reversibility o lung unction abnormalities$ greatly enhance

diagnostic conidence!%3'#. *he degree o reversibility in orced epiratory volume in one

second !78%# that indicates a diagnosis o asthma is generally accepted as %&- and &22 mD

rom the pre(bronchodilator value .

51 Spir".etr* is helpul as an ob1ective measure o airlow limitation. alid spirometric

measures depends on a patient:s ability to properly perorm a ull$ orceul and prolonged

epiratory maneuver$ easible in children R" years o age. I the 78 % !orced epiratory volume

in % sec# is within 5 - on ' attempts$ then the highest 78 % eort o the three is used!%3)#.

Henerally an 78%


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&. 4r"nc'"&i,at"r re#p"n#e to inhaled beta agonist !albuterol# is greater in asthmatic patients

than non(asthmaticK an improvement in 78% o more than or e4ual to %&- or R&22 ml is

consistent with asthma !%3)#.

'. 4r"nc'"pr"0"cati"n c'a,,ene#K Gatients with symptoms consistent with asthma$ but normal

lung unction$ measurements o airway responsiveness to methacholine$ histamine$ mannitol$

adenosine monophosphate or eercise challenge may help to establish a diagnosis o asthma can

be helpul in diagnosing asthma and optimizing asthma management!%3"#.

). E+erci#e c'a,,ene# !aerobic eercise or running or " to , min# can help identiy children

with an eercise induced bronchospasm. In asthmatic patients$78% typically decreases during

or ater eercise by R%5-.*he onset o eercise induced bronchospasm in usually within %5

minutes ater a vigorous eercise challenge and can spontaneously resolve within '2 to "2 min.

=tudies o eercise challenges in school aged children typically identiy an additional 5(%2 -

with eercise induced bronchospasm and previously unrecognized asthma!%33#.

5. Mea#/rin e+'a,e& nitric "+i&e 6FENO$

8aled nitric oide !7e?0# is considered a good noninvasive marker to assess airway

inlammation in asthma and allergic rhinitis. In asthma$ ehaled ?0 is very useul to veriy

adherence to therapy$ and to predict upcoming asthma eacerbations !%3,#. It has been also

proposed that ad1usting anti(inlammatory drugs guided by the monitoring o ehaled ?0$ could

improve overall asthma control!%36#.


34/102

?o tests diagnose asthma in this age group. *he therapeutic trial o treatment with 4uick relievers

and inhaled steroids or , + %& weeks showing improvement during therapy and relapse ater

stopping therapy is diagnostic o asthma!%,2#.

P'*#ica, E+a.inati"nK

*he most usual abnormal physical inding is wheezing on auscultation! %,%#. Furing asthma

eacerbations$ epiratory wheezing and a prolonged epiratory phase is heard on auscultation

!%,. Fecreased breath sounds in some o the lung ields$ indicate areas o hypoventilation due

to obstruction!%,2#. Crackles indicate ecess mucus production and inlammatory eudate in

airways in severe eacerbations$ the greater etent o airways obstruction causes labored

breathing and respiratory distress$ poor air entry$ suprasternal and intercostal recessions$ nasal

laring and accessory respiratory muscle use!%,'#. In etreme cases$ airlow may be so limited

that wheezing cannot be heard.

Ra&i","*K

*he indings o chest radiographs !poster anterior and lateral view# in children with asthma oten

appear to be normal ecept o nonspeciic indings o hyperinlation !lattening o diaphragm#

and per bronchial thickening !%,)#. Chest radiographs can be helpul in identiying abnormalities

that are hallmarks o asthma mas4ueraders !aspiration pneumonitis$ hyper(lucent lung ields in

bronchiolitis obliterans# and complications during asthma eacerbations !%26#.


35/102

A#t'.a c"ntr",:

As the goal o asthma treatment is to achieve control$ all patients must be continually reviewed

to monitor that control has been achieved and is maintained. *his can be achieved with various

tools such as a symptom assessment 4uestionnaire or Asthma Control *est !AC*# !%,5#or

monitoring o pulmonary unction with peak epiratory low rates$ spirometry$ or ehaled nitric

oide. Frug therapy can then be ad1usted according to the patient:s level o control. Children

who are very well controlled on low doses o inhaled corticosteroids may be able to come o

treatment. Complete control o asthma is commonly achieved with treatment$ the aim o which

should be to achieve and maintain control or prolonged periods with due regard or the saety o

treatment$ potential or adverse eects$ and the cost o treatment re4uired to achieve this

goal!%3%#. Its assessment should incorporate the dual components o current clinical control !e.g.

symptoms$ reliever use and lung unction# and uture risk !e.g. eacerbations and lung unction

decline#

Clinical studies have shown that asthma can be eectively controlled by intervening to suppress

and reverse the inlammation$ as well as treating the bronchoconstriction and related symptoms

!%,"#. 7urthermore$ early intervention to stop eposure to the risk actors that sensitized the

airway may help improve the control o asthma and reduce medication needs

*he goal o asthma treatment is to achieve and maintain clinical control. Medications to treat

asthma can be classiied as controllers or relievers !%,3#. Controllers are medications taken daily

on a long term basis to keep asthma under clinical control chiely through their anti(

inlammatory eects. *hey include inhaled glucocorticosteroids$ leukotriene receptor

antagonists$ and combination therapies with long(acting beta agonists and glucocorticosteroids$


36/102

anti(Ig8 and other steroid(sparing therapies !&&$ %,,#. ;elievers are used on an as needed basis

to 4uickly reverse bronchoconstriction and relieve symptoms. *he most commonly used

relievers are inhaled short(acting beta agonists and short acting oral beta &.!%,6#

Ta%,e 7: Le0e,# "! A#t'.a C"ntr",1

Assessment o current clinical control !preerably over ) weeks#

0HA!A0&E!+S&+0 0;N&!;**ED

(all of the

follo1ing)

PA!&*


37/102

acti%ities active childK plays

and runs without

symptoms#

or diicult breathing

during vigorous play$

laughing#

diicult breathing during

vigorous play$ laughing

Need for relie%er

medication

& d per week More than & days per

week

More than & days per week

A==8==M8?* 07 7U*U;8 ;I=> !risk o eacerbations$ instability$ rapid decline in lung

unction$ side eects#

7eatures that are associated with increased risk o adverse events in the uture includeK

Goor clinical control$ re4uent eacerbations in the past year$ ever admission to critical care or

Asthma$ low 78%$ eposure to cigarette smoke$ high dose medications

ROUTES OF ADMINSTRATION:

Asthma treatment can be administered in a variety o waysK inhaled$ orally or parenterally !by

subcutaneous$ intravenous and intramuscular routes# !%,,$ %62# .*he ma1or advantage o inhaled

therapy is that the drug is directly delivered to the airways producing higher local concentrations

and less systemic side eects.

Fierent age groups re4uire dierent inhalers or eective therapy. *he choice o inhaler device

should include consideration o the eicacy o the drug delivery$ cost$ saety$ ease o use$


38/102

convenience and documentation or it:s in patient:s age group. Although nebulizers have been the

mainstay o inhalation therapy in childhood asthma or many years$ these devices are

cumbersome$ bulky$ time(consuming$ and epensive to use. As a result$ over the past decade the

emphasis o inhalation therapy in children has shited rom nebulizers to metered(dose inhalers

!MFI# in combination with spacer devices!%,6# .=pacers retain large drug particles that would be

deposited in the oropharyn$ so reducing oropharyngeal side(eects and systemic absorption and

availability o inhaled drug. *his consideration is especially important or IC= with poor irst(

pass metabolism such as beclomethasone dipropionate !EFG# and budesonide !%6%#. *he vast

ma1ority o children o all ages with acute severe asthma can be managed eectively and saely

by O& agonists delivered via MFI


39/102

Controller Medications

Controller medications or children include inhaled and systemic glucocorticosteroids$

leukotriene modiiers$ long acting inhaled O&(agonists$ theophylline$ cromones$ and long(acting

oral O&(agonists.

In'a,e& ,/c"c"rtic"#ter"i

Inhaled glucocorticosteroids are the most eective controller therapy or asthma in children with

rapid improvement in symptoms and lung unction$ even at low doses o inhaled

glucocorticosteroids !%6 .Furation o treatment should continue till bronchial hyper(

responsiveness improves !%6'#. In children o all ages$ maintenance treatment with inhaled

glucocorticosteroids controls asthma symptoms$ reduces the re4uency o acute eacerbations

and the number o hospital admissions$ improves 4uality o lie$ lung unction$ and bronchial

hyperresponsiveness$ and reduces eercise(induced bronchoconstriction!%6)#. Fose(response

studies and dose titration studies in children demonstrate marked and rapid clinical

improvements in symptoms and lung unction at low doses o inhaled glucocorticosteroids !e.g.$

%22(&22 Tg budesonide daily#$ and mild disease is well controlled by such doses in the ma1ority

o patients!%6. Inhaled steroids are now used at a much earlier stage in asthma therapy$ and

there is a strong argument or their early introduction in both adults and children to prevent

asthma morbidity and mortality and possibly the structural changes resulting rom uncontrolled

chronic inlammation$ which may lead to irreversible airlow obstruction in some

patients!%65# .8arly intervention with inhaled budesonide is associated with improved asthma

control and less additional asthma medication use . ?ebulized budesonide reduced the need or


40/102

oral glucocorticoid therapy and also improved lung unction in children under the age o three

years !%6"# . Increasing to higher doses provides little urther beneit in terms o asthma control

but increases the risk o side(eects. /owever$ there is marked individual variability o

responsiveness to inhaled glucocorticosteroids$ and because o this and the recognized poor

adherence to treatment with inhaled glucocorticosteroids$ many patients will re4uire higher doses

to achieve ull therapeutic beneit!%63# 1 =ymptom control and improvements in lung unction

occur rapidly !ater % to & weeks#$ although longer treatment !over the course o months# and

sometimes higher doses may be re4uired to achieve maimum improvements in airway

hyperresponsiveness !%2#. hen glucocorticosteroid treatment is discontinued$ asthma control

deteriorates within weeks to months !%6,#.

Fesirable properties in an inhaled glucocorticoid are high topical potency$ low systemic

bioavailability o the portion o the dose swallowed by the patient$ and rapid metabolic clearance

o any glucocorticoid that reaches the systemic circulation. Ater inhalation a large proportion o

the inhaled dose$ ,2 to 62 percent$ is deposited on the oropharyn and swallowed. It is then

available or absorption into the systemic circulation through the liver.! %66# *his raction is

markedly reduced i the glucocorticoid is administered through a large(volume spacer attached to

a metered(dose inhaler.

Corticosteroid *rade

name

Children !" to %% years o age# Adults !%& years o

age and over#


41/102

Eeclomethasone

dipropionate /7A

A;

Q&22 &2%+)22 R)22

Inhaled corticosteroid !IC=# dosing categories in children and adults

Dow Medium /igh Dow Medium /igh

V Q&52 &5%+522 R522

EudesonideW Gulmicort *urbuhalerX Q)22 )2%+,22 R,22 Q)22 )2%+,22

R,22

CiclesonideW Alvesco Q&22 &2%+)22 R)22 Q&22 &2%+)22 R)22

7luticasone 7lovent MFI and spacer9 7lovent FiskusZ Q&22 &2%+522 R522 Q&52

&5%+522 R522


42/102

Si&e e!!ect# (*he ma1ority o studies evaluating the systemic eects o inhaled

glucocorticosteroids have been undertaken in children older than 5 years.

• HrowthK Asthma and its level o control may directly aect growth in the same way as

most chronic diseases o childhood! Continuous administration o IC=s in low to medium

dose over many years is well tolerated. . Dow doses do not have clinically deleterious

side eects on the bones$ growth$ eye$ or hypothalamo(pituitary(adrenal(ais!&22#.

/owever$ they do not normalize lung unction and prevent structural changes in the

airway wall in all asthmatic patients !&2%#. 8ect o IC= on growth depends on dose and

duration o intake as well as the susceptibility o the growth phase during which the child

inhales steroids!&2 . ith all inhaled corticosteroids given at high dosage$ there is

likely to be a dual eect due to topical bioactivity rom the airway dose as well as

prednisone like activity rom the systemic bioavailable dose!&2'#. *he use o a large

spacer device has been shown to reduce the incidence o both topical and systemic

adverse eects rom inhaled steroids !&2. /eight measurements made over a period o

less than % year are liable to error and misinterpretation. *he delay in pubertal growth is$

however$ also associated with a delay in skeletal maturation so that the bone age o the

child corresponds to the height !&2)#. Ultimately$ there is no decrease in attained adult

height$ though it is reached at a later age than normal !&25#. *his dierence in growth

pattern seems to be unrelated to the use o inhaled corticosteroids and is more

pronounced in those children with the most severe asthma!&2"# . In school(age children

asthma should be treated irst with inhaled steroids. It is probable that the best

combination o eicacy and saety can be achieved by using low steroid doses ! &25#.


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• H*p"t'a,a.ic8pit/itar*8a&rena, 6HPA$ a+i#. Dong(term ollow(up studies in children

concluded that inhaled steroids are well tolerated$ with little or no eect on growth and

hypothalamic(pituitary(adrenal ais unction!&22#. *hus it is a valuable therapeutic

alternative to systemic corticosteroid therapy in inants and young children. ith

sensitive techni4ues$ dose(dependent adrenal suppression has been documented in

children treated with inhaled steroids but generally this eect has no clinical relevance

!&23#. Most children develop biochemical evidence o adrenal suppression ater treatment

with medium to high doses o IC=!&2,#. At higher doses$ small changes in /GA ais

unction can be detected with sensitive methods.

• 4"ne# an& G,/c"c"rtic"#ter"i in C'i,&ren: 0ne o the greatest concerns o long(term

corticosteroid therapy or asthma is its potential or adverse eects on bone turnover$

resulting in an increased risk or osteoporosis and racture. ?o studies have reported any

statistically signiicant increase o risk o ractures in children taking inhaled

glucocorticosteroids !&2)#. Dow doses do not have clinically deleterious side eects on

the bones$ growth$ eye$ or hypothalamo(pituitary(adrenal(ais !&26#. /owever$ they do

not normalize lung unction and prevent structural changes in the airway wall in all

asthmatic patients. Calcium supplementation may be necessary in children with asthma

treated with inhaled steroids since this treatment may cause reduction in osteocalcin$ a

marker o osteoblast activity and bone ormation!&%2# .0ral Corticosteroids!continuous

or intermittent# is associated with an increased risk o racture and cataracts in children

and continuous treatment also with increased risk o adrenal insuiciency and growth

retardation!&%%#. Eone mineral density may be decreased by high doses o inhaled

glucocorticoids$ but their eect is conounded by the act that patients taking these drugs


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also receive intermittent courses o oral glucocorticoids. 0ral glucocorticoid therapy is a

well(known cause o osteoporosis and an increased risk o vertebral and rib ractures 1

Cataract#1 Dong(term administration o medium dose IC=s does not increase the risk o

cataracts or osteopenia in children and young adults !&% .

• Centra, ner0"/# #*#te. e!!ect#K Fespite the propensity o glucocorticoids to cause

psychiatric disturbance including emotional lability$ euphoria$ depression$

aggressiveness$ and insomnia inhaled corticosteroids are not associated with any

adverse eects!&23#.

•Ora, can&i&ia#i#9 '"ar#ene##9 an& %r/i#in. 0ropharyngeal candidiasis and dysphonia

are the most commonly recognized adverse eects o therapy$ but these topical

phenomena cause no signiicant morbidity and are easily managed!&%'#. =pacers reduce

the incidence o oral candidiasis. *he use o spacer devices and mouth rinsing may

reduce local and systemic adverse eects.

• Denta, #i&e e!!ect#. ;ecent studies have provided little evidence or asthma caries

causative relationship ./owever$ Asthma is one o the most common chronic medical

conditions in childhood which is considered high risk or caries. *he most recent reports

have concluded that the individualistic nature o asthmatic condition$ through either its

disease status or its pharmacotherapy !dierent combinations o medicaments#$ carries

several actors or an increased caries risk !&%)# .

E!!ect# "n C"nnecti0e Ti##/e1 *here are reports o increased skin bruising and purpura

in patients receiving high doses o inhaled beclomethasone$ but the amount o

intermittent glucocorticoids they received is not known. 8asy bruising linked to inhaled


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glucocorticoids is more re4uent in elderly patients9 there are no reports o this problem

in children!&%5#.

• Ot'er ,"ca, #i&e e!!ect#. *he long(term use o inhaled glucocorticosteroids is not

associated with an increased incidence o lower respiratory tract inections$ including

tuberculosis.

\

Le/)"triene ."&i!ier#1

*he leukotrienes are potent inlammatory mediators in asthma and contribute to increased mucus

production$ bronchoconstriction and eosinophil iniltration!&%"#. *hese compounds are produced

via the lipoygenase pathway by mast cells$ eosinophils and alveolar macrophages

Clinical studies have demonstrated that leukotriene modiiers have a small and variable

bronchodilator eect$ reduce symptoms !including cough# $ improve lung unction$ and reduce

airway inlammation and asthma eacerbations!&%3#. /owever$ when used alone as controller$

the eects o leukotriene modiiers are less than those o low doses o inhaled

glucocorticosteroids and$ in patients already on inhaled glucocorticosteroids$ leukotriene

modiiers cannot substitute or this treatment without risking the loss o asthma control!&%,#.

Deukotriene modiiers used as add(on therapy may reduce the dose o inhaled

glucocorticosteroids re4uired by patients with moderate to severe asthma$ and may improve


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asthma control in patients whose asthma is not controlled with low or high doses o inhaled

glucocorticosteroids!&%6#.

Deukotriene modiiers provide clinical beneit in children older than 5 years at all levels o

severity$ but generally less than that o low(dose inhaled glucocorticosteroids!&%,#. Deukotriene

modiiers provide partial protection against eercise(induced bronchoconstriction within hours

ater administration with no loss o bronchoprotective eect.

D*;As have been proposed as alternative irst(line therapy to IC=s or episodic or mild

persistent asthma who have diiculty in utilizing inhalation treatment$ with poor compliance$ or

where eercise(induced bronchospasm !8IE# is a dominant component o asthma!&&2$ &&%# .

D*;As are approved or treatment o both allergic rhinitis and asthma !&&.

Side effects: ?o saety concerns have been demonstrated rom the use o leukotriene modiiers in

children .

Long-acting inhaled O2-agonists.

;ole in therapy (Dong(acting inhaled O&(agonists are primarily used as add(on therapy in

children older than 5 years whose asthma is insuiciently controlled by medium doses o inhaled

glucocorticosteroids or as single(dose therapy beore vigorous eercise!&&'#. Monotherapy with

long acting inhaled O&(agonists should be avoided!%"5#. Dong(acting inhaled O&(agonists have

mainly been studied in children older than 5 years as add(on therapy or patients whose asthma is

not controlled on low to high doses o inhaled glucocorticosteroids!). =igniicant

improvements in peak low and other lung unction measurements have been ound in most

studies. /owever$ their eects on other outcomes such as symptoms and need or reliever

medication have been less consistent and have only been observed in about hal o the trials


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conducted. Combination products containing an inhaled glucocorticosteroid and long(acting

inhaled O&(agonists are preerred to long(acting inhaled O&(agonists and inhaled

glucocorticosteroids administered by separate inhalers !&&)#.

In Children 5 years and younger$ the eect o long(acting inhaled O&(agonists has not been

ade4uately studied. Combination therapy with budesonide and ormoterol used both as

maintenance and rescue has been shown to reduce asthma eacerbations in children ages ) years

and older with moderate to severe asthma!&&5#.

=ide eectsK Dong acting inhaled beta & agonists are not the recommended option when more

than one controller is re4uired!). I used$ long(acting O&(agonists should only be used in

combination with an appropriate dose o inhaled glucocorticosteroid as determined by a

physician$ preerably in a ied combination inhaler !&&"#.

THEOPHYLLINE: *heophylline has been shown to be eective as monotherapy and as add(on

treatment to inhaled or oral glucocorticosteroids in children older than 5 years!&&3#.

Maintenance treatment oers a marginal protective eect against eercise(induced

bronchoconstriction. Add(on treatment with theophylline has been ound to improve asthma

control and reduce the maintenance glucocorticosteroid dose necessary in children with severe

asthma treated with inhaled or oral glucocorticosteroids!&&3$ &&,#./owever$ the eicacy o

theophylline is less than that o low(dose inhaled glucocorticosteroids. Glasma theophylline

levels were maintained within the therapeutic range o 5(%%2 Tmol


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used or when drugs that may increase theophylline levels are also used chronically$ plasma

theophylline levels should be measured two hours beore administration o the net dose once

steady state has been !ater ' days#.

Side effects : *he most common side eects o theophylline are anoreia$ nausea$ vomiting$ and

headache!&'%#. Mild central nervous stimulation$ palpitations$ tachycardia$ arrhythmias$

abdominal pain$ diarrhea$ and$ rarely$ gastric bleeding may also occur!&'. *hese side eects

are mainly seen at doses higher than %2 mg


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better than placebo or management o asthma in children!&'3#. =tudies o the use o these

medications in children 5 years and younger are sparse and results are conlicting!&',$ &'6#.

Side effects Cough$ throat irritation$ and bronchoconstriction occur in a small proportion o

patients treated with sodium cromoglycate!&)2#. A bad taste$ headache$ and nausea are the most

common side eects o nedocromil.

Long-acting oral O2-agonists.

*reatment with long(acting oral O&(agonist such as slow release ormulations o salbutamol$

terbutaline$ and bambuterol reduces nocturnal symptoms o asthma!&)%#. Fue to their potential

side eects o cardiovascular stimulation$ aniety$ and skeletal muscle tremor$ their use is not

encouraged. I used$ dosing should be individualized$ and the therapeutic response monitored to

limit side eects.

Systemic glucocorticosteroids.

Eecause o the side eects o prolonged use$ oral glucocorticosteroids in children with asthma

should be restricted to the treatment o acute severe eacerbations$ whether viral(induced or

otherwise !&)&$ &)'#.

;eliever Medications

Rapi&8actin in'a,e& 78a"ni#t# an& #'"rt8actin "ra, 78 a"ni#t#1

;apid(acting inhaled [&(agonistss are the most eective bronchodilators available and thereore

the preerred treatment or acute asthma in children o all ages!&))#. *he inhaled route results in

more rapid bronchodilation at a lower dose and with ewer side eects than oral or intravenous


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administration. 7urthermore$ inhaled therapy oers signiicant protection against eercise(

induced bronchoconstriction and other challenges or 2.5 to & hours !long(acting [&(agonists

oer longer protection#!&)5#. *his is not seen ater systemic administration. 0ral therapy is

rarely needed and reserved mainly or young children who cannot use inhaled therapy.

Side effects. =keletal muscle tremor$ headache$ palpitations$ and some agitation are the most

common complaints associated with high doses o [&(agonists in children. *hese complaints are

more common ater systemic administration and disappear with continued treatment.

Anticholinergics : Inhaled anticholinergics are not recommended or long(term management o

asthma in children!&)"#.

ASTHMA MANAGEMENT AND PREVENTION:

*he goals or successul management o asthma are toK

\ Achieve and maintain control o symptoms

\ Maintain normal activity levels$ including eercise

\ Maintain pulmonary unction as close to normal as possible

\ Grevent asthma eacerbations

\ Avoid adverse eects rom asthma medications


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\ Grevent asthma mortality.

Clinical studies have shown that asthma can be eectively controlled by intervening to suppress

and reverse the inlammation as well as treating the bronchoconstriction and related symptoms

!%3%#. 7urthermore$ early intervention to stop eposure to the risk actors that sensitized the

airway may help improve the control o asthma and reduce medication needs.

*he recommendations or asthma management are laid out in ive interrelated components o

therapy !&)3#K

%. Fevelop Gatient


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most ma1or treatment changes to their physician at the time o planned or unplanned

consultations!&),#.

ASTHMA EDUCATION

8ducation should be an integral part o all interactions between health care proessionals and

patients$ and is relevant to asthma patients o all ages!%)#. Although the ocus o education or

small children will be on the parents and caregivers$ children as young as ' years o age can be

taught simple asthma management skills but regional issues and the developmental stage o the

children may aect the outcomes o such programs.

E&/cati"n an& t'e Patient D"ct"r Partner#'ip

G"a,: *o provide the person with asthma$ their amily$ and other caregivers with suitable

inormation and training so that they can keep well and ad1ust treatment according to a

medication plan developed with the health care proessional!&)6#.

Ke* C".p"nent#:

• 7ocus on the development o the partnership

• Acceptance that this is a continuing process

• A sharing o inormation

• 7ull discussion o epectations

• 8pression o ears and concerns

• Fierence between ]relieversJ and ]controllersJ

• Gotential side eects o medications


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• Use o inhaler devices

• Grevention o symptoms and attacks

• =igns that suggest asthma is worsening and actions to take

• Monitoring control o asthma

• /ow and when to seek medical attention

T'e per#"n t'en re;/ire#:

• A written asthma action plan

• ;egular supervision$ revision$ reward$ and reinorcement.

#ood communication is essential as the basis or subse4uent good compliance


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these action plans$ the eects were also greater when the patients themselves both stepped up

inhaled glucocorticosteroids and added oral glucocorticosteroids$ based on their symptoms or or

peak low(based!&5. Gatients eperience a one(third to two(thirds reduction in hospitalizations$

emergency room visits$ unscheduled visits to the doctor or asthma$ missed days o work$ and

nocturnal wakening!&5'#. *hus$ patients who are unable to undertake guided sel(management

can still achieve beneit rom a structured program o regular medical review.

F",,"-8Up an& Re0ie-

7ollow(up consultations should take place at regular intervals. At these visits$ the patient:s

4uestions are discussed$ and any problems with asthma and its initial treatment are reviewed

!&5)#. Gatients should be asked to demonstrate their inhaler device techni4ue at every visit$ with

correction and re(checking i it is inade4uate. 7ollow(up consultations should also include

checking the person:s adherence


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A##e## *"/r ,e0e, "! A#t'.a C"ntr",

In t'e pa#t -ee) 'a0e *"/ 'a&:

Da*ti.e a#t'.a #*.pt".# ."re t'an 7 ti.e# = N" Ye#

Acti0it* "r e+erci#e ,i.ite& %* a#t'.a= N" Ye#

Wa)in at ni't %eca/#e "! a#t'.a= N" Ye#

T'e nee& t" /#e *"/r >re#c/e .e&icati"n? ."re t'an 7 ti.e#= N" Ye#

I! *"/ are ."nit"rin pea) !,"-9 pea) !,"- ,e## t'an


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EMERGENCY3SEVERE LOSS OF CONTROL

'I! *"/ 'a0e #e0ere #'"rtne## "! %reat'9 an& can "n,* #pea) in #'"rt #entence#9

' I! *"/ are 'a0in a #e0ere attac) "! a#t'.a an& are !ri'tene&9

'I! *"/ nee& *"/r re,ie0er .e&icati"n ."re t'an e0er* '"/r# an& are n"t

I.pr"0in1

51 Ta)e 7 t" p/!!#


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%. Fiiculties with inhaler devices Awkward regimes !e.g.$ our times daily or multiple

drugs#

&. =ide eects

'. Cost o medication

). Fislike o medication

5. Fistant pharmacies

N"n8&r/ !act"r#

%. Misunderstanding or lack o instruction

&. 7ears about side eects

'. Fissatisaction with health care proessionals

). Unepressed


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SELF MANAGEMENT IN CHILDREN

A systematic review ound that educational programs or the sel(management o asthma in

children and adolescents led to improvements in lung unction and eelings o sel(control$ and

reduced absences rom school$ the number o days with restricted activity$ and the number o

emergency department visits!&5'#. 7or children$ symptom(based action plans are more eective

than those based on peak lows!&5"#.

IDENTIFY AND REDUCE EBPOSURE TO RISK FACTORS

A#t'.a Pre0enti"n: Measures to prevent asthma may be aimed at the prevention o allergic

sensitization !i.e.$ the development o atopy$ likely to be most relevant prenatally and

perinatally#$ or the prevention o asthma development in sensitized people. 0ther than preventing

tobacco eposure both in utero and ater birth$ there are no proven and widely accepted

interventions that can prevent the development o asthma !&53#.

*he role o diet particularly breast(eeding$ in relation to the development o asthma has been

etensively studied and$ in general$ inants ed ormulas o intact cow:s milk or soy protein

compared with breast milk have a higher incidence o wheezing illnesses in early


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childhood!&5,#. 8clusive breasteeding during the irst months ater birth is associated with

lower asthma rates during childhood !&56$ &"2#.

8posure to cats has been shown to reduce risk o atopy in some studies!&"%#.

8posure to tobacco smoke both prenatally and postnatally is associated with measurable

harmul eects$ including eects on lung development and a greater risk o developing

wheezing illnesses in childhood!&". Gassive smoking increases the risk o allergic sensitization

in children!&"'#. Eoth prenatal and postnatal maternal smoking is problematic!&")#. Gregnant

women and parents o young children should be advised not to smoke.

Pre0enti"n "! a#t'.a S*.pt".# an& e+acer%ati"n#

Asthma eacerbations may be caused by a variety o actors$ sometimes reerred to as ]triggers$J

including allergens$ viral inections$ pollutants$ and drugs. ;educing a patient:s eposure to some

o these categories o risk actors !e.g.$ smoking cessation$ reducing eposure to secondhand

smoke$ reducing or eliminating eposure to occupational agents known to cause symptoms$ and

avoiding oods


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In&""r A,,eren#

Among the wide variety o allergen sources in human dwellings are domestic mites$ urred

animals$ cockroaches$ and ungi.

D".e#tic .ite#: Fomestic mite allergy is a universal health problem!&",#. =ince mites live and

thrive in many sites throughout the house$ they are diicult to reduce and impossible to

eradicate!&"6#. 0ne study showed some eicacy o mattress encasing at reducing airway

hyperresponsiveness in children.

%urred animals. Complete avoidance o pet allergens is impossible$ as the allergens are

ubi4uitous and can be ound in many environments outside the home$ including schools$ public

transportation$ and cat(ree buildings!&32#. Although removal o such animals rom the home is

encouraged$ even ater permanent removal o the animal it can be many months beore allergen

levels decrease and the clinical eectiveness o this and other interventions remains unproven.

Coc&roaches. Avoidance measures or cockroaches include eliminating suitable environments

restricting access !sealing entry sources such as around paperwork and doors#$ chemical control$

and traps. /owever$ these measures are only partially eective in removing residual allergens

!&3%#.

%ungi: 7ungal eposure has been associated with eacerbations rom asthma and the number o

ungal spores can best be reduced by removing or cleaning mold laden ob1ects !&3. In tropical

and subtropical climates$ ungi may grow on the walls o the house due to water seepage and

humidity. *o avoid this$ the walls could be tiled or leaned as necessary.

O/t&""r A,,eren#


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0utdoor allergens such as pollens and molds are impossible to avoid completely ! &3'#. 8posure

may be reduced by closing windows and doors$ remaining indoors when pollen and mold counts

are highest and using air conditioning i possible.

In&""r Air P",,/tant#

*he most important measure in controlling indoor air pollutants is to avoid passive and active

smoking !&3)#. =econdhand smoke increases the re4uency and severity o symptoms in children

with asthma. Garents< caregivers o children with asthma should be advised not to smoke and not

to allow smoking in rooms their children use. 0ther ma1or indoor air pollutants include nitric

oide$ nitrogen oides$ carbon monoide$ carbon dioide$ sulur dioide$ ormaldehyde$ and

biological !endotoin#!&35#.

O/t&""r Air P",,/tant#

=everal studies have suggested that outdoor pollutants aggravate asthma symptoms$ possibly

having an additive eect with allergen eposure !&3"#. Most epidemiological studies show a

signiicant association between air pollutants+such as ozone$ nitrogen oides$ acidic aerosols$

and particulate matter+and symptoms or eacerbations o asthma!&33#. 0n occasion$ certain

weather and atmospheric conditions$ e.g.

Nazish Dissertation

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