06 paediatric and child health june2009 pulmonology

8/7/2019 06 Paediatric and Child Health June2009 Pulmonology

1/51

Egyptian_Pediatric yahoo group

http://health.groups.yahoo.com/group/

egyptian_pediatric/

Egyptian_

http://health

eg


2/51

SympoSium: reSpiratory medicine

paediatricS and cHiLd HeaLtH 19:6 249 2009 elsv L. all ghs sv.

Paediaric appliedrespiraory pysiology e esseials

Kv m

rb G Kh

chsh JL nwh

Absrac

Gl s wll s bls

g h s. a bs kwlg ssl s hs-

lg, s sbsq gs ss ss hw ssss hs bls wll hl h hl.

ths wll bg wh vvw l s hslg

hw h gs xhg. i wll ls sss

hs -vsv g lg ls x,

b x g, l ss s

lhsgh. Fll, ss ss wll b

s ll h s bw hhslg, ll

ss g bls.

Keywords lg vl ss; x; s; lhs-

gh; l vl; s ssIrodcio

Bearing in mind the diversity and prevalence o respiratory ill-

nesses in children, paediatricians should understand the basics

o respiratory physiology and how to monitor respiratory unc-

tion. This discussion will review normal respiratory physiology

and explore non-invasive orms o respiratory monitoring. With

this oundation, the paediatrician can accurately diagnose and

assess the severity o illness.

Kevin Madden MD is at the Department of Anesthesia and Critical Care

Medicine, Childrens Hospital Los Angeles, Los Angeles, USA.

Robinder G KhemaniMD MSCI is Assistant Professor of Pediatrics,

University of Southern California, Keck School of Medicine, Childrens

Hospital Los Angeles, Department of Anesthesia and Critical Care

Medicine, Los Angeles, USA.

Christopher JL Newth MD FRCPC FRACP is Professor of Pediatrics, University

of Southern California, Keck School of Medicine, Childrens Hospital

Los Angeles, Department of Anesthesia and Critical Care Medicine, Los

Angeles, USA.

Brief overview of ormal respiraory pysiology

Mscles of respiraio

The most important and powerul muscle during the inspiratory

phase o respiration is the diaphragm, a dome-shaped musculo-

brous septum that separates the thorax rom the abdominal cav-

ity. When the diaphragm contracts, abdominal contents move

downward and the lung expands in the vertical and horizon-tal planes. During normal tidal breathing the diaphragm moves

approximately 1 cm, but with orced inspiration and exhalation,

it can move up to 10 cm.

During inspiration, external intercostal muscles elevate and

move the ribs orward. This increases the lateral and anteropos-

terior diameters o the thoracic cavity. The two most common

accessory muscles o inspiration are the sternocleidomastoid and

scalenes. The sternocleidomastoid raises the sternum while sca-

lenes elevate the rst two ribs. During normal respiration these

muscles do not participate in inspiration, but during exercise

or in pathological processes they can play an important role in

maintaining normal alveolar ventilation.

While expiration is normally passive due to the elastic proper-ties o the lungs and chest wall, both exercise and certain patho-

physiological conditions invoke both the internal intercostal and

abdominal muscles including the internal and external obliques,

the transversus abdominis and the rectus abdominis. These mus-

cles work to decrease the thoracic volume and assist in orcing

air rom the lungs.

Both the lungs and chest wall are elastic, and each compo-

nent has a natural propensity; the lung to collapse inward and

the chest wall to spring outward. The equilibrium point o lung

volume where these orces are balanced is the unctional residual

capacity (FRC).

Lg volmes ad capaciiesThe various lung volumes and capacities can be measured during

dierent phases o the respiratory cycle and change under dier-

ent pathophysiological conditions. Spirometry is used to record

the volume o air moved during respiration.

The are our lung volumes which, when added together, equal

the total lung capacity (TLC) (Figure 1):

tidal volume (VT) volume o air inspired or expired during anormal breath

inspiratory reserve volume (IRV) the additional volume oair that can be inspired in addition to a tidal breath

expiratory reserve volume (ERV) the additional volume oair that can be expired ater the end o a tidal breath

residual volume (RV) volume o air remaining ater the mostorceul expiration.

In evaluating a patients clinical status and understanding patho-

physiology, it is sometimes advantageous to consider two or

more lung volumes together as capacities. The our lung capaci-

ties (Figure 1) are:

inspiratory capacity (IC) equals tidal volume plus inspira-tory reserve volume

unctional residual capacity (FRC) equals expiratory reservevolume plus residual volume, or the volume o air remaining

at the end o a normal expiratory breath

vital capacity (VC) equals inspiratory reserve volume plustidal volume plus expiratory reserve volume


3/51



total lung capacity (TLC) equals vital capacity plus residualvolume.

Note that since by denition residual volume cannot be exhaled

rom the lungs, it cannot be measured by spirometry. FRC and

TLC also cannot be measured by spirometry alone but instead

are measured by gas-dilution techniques or plethysmography.

Gas excage

The primary purpose o the respiratory system is gas exchange

to maintain cellular homeostasis. The two principal componentsare delivery o oxygen and removal o carbon dioxide.

Oxygeaio

The respiratory system helps to extract oxygen rom the atmo-

sphere and deliver it to mitochondria. The partial pressure o

oxygen in the alveolus (PAO2) is a primary determinant o arterial

oxygen tension (PaO2).

P O (P P FO P CO RQA 2 b H O i 2 A 22= [ ) ] /

where Pb is barometric pressure, PH O2 is the partial pressure o

water vapour and FiO2 is the raction o inspired oxygen. PACO2

is the partial pressure o carbon dioxide in the alveolus and RQis the respiratory quotient. For most purposes RQ is assumed to

be 0.8.

Substituting normal values or an individual breathing room

air at sea level, the PAO2 is approximately 100 mmHg. As oxygen

crosses the alveolar membrane into the pulmonary capillary net-

work a negligible amount o oxygen tension is lost (around 10

mmHg). Thus, the PaO2 o a normal individual is approximately

90 mmHg. By examining the alveolar gas equation closely, one

can see that three conditions can cause a decrease in P AO2:

altitude (low Pb), hypoxic gas mixture (low F iO2) and hypoven-

tilation (high PACO2). The most common aetiology o hypox-

aemia is neither altitude nor hypoventilation, however, but a

disturbance in the number o alveoli participating in matched

ventilation/perusion (V/Q). With either compromised ventila-

tion with adequate perusion (shunt) or adequate ventilation

with compromised perusion (dead space), oxygen residing in

the alveolus cannot move into the pulmonary capillary network

and hypoxaemia will ensue. A wide variety o clinical condi-

tions can cause derangements in V/Q, and interventions such

as continuous positive airway pressure (CPAP), biphasic posi-tive airway pressure (BiPAP) or endotracheal intubation with

mechanical ventilation correct hypoxaemia by restoring normal

lung volumes, assisting cardiac unction and improving the

V/ Q relationship.

Veilaio

The respiratory system also eliminates carbon dioxide rom

the blood through the alveolus. Arterial carbon dioxide ten-

sion (PaCO2) is directly proportional to minute ventilation (VE)

where:

V respiratory rate tidal volumeE =

V fVE T=

It is worth noting that VT comprises dead-space volume (VD)

and alveolar volume (VA).

Dead-space volume is the portion o the tidal breath that does

not participate in gas exchange with pulmonary capillaries. Dead

space comprises anatomical dead space and non-anatomical

dead space. Anatomical dead space is ound within the conduct-

ing airways nose, mouth, oropharynx, trachea, bronchi and

bronchioles and accounts or approximately 2030% o a tidal

breath, although it is relatively larger in inants. Non-anatomi-

cal dead space approaches zero in healthy individuals, as most

lung units are equivalently ventilated and perused. In inantsand children with respiratory disease, however, total dead space

may approach 6070% o a tidal breath.

In contrast, alveolar volume is the portion o inspired breath

that arrives at the alveoli and participates in gas exchange with

pulmonary capillaries. Thereore, it is more accurate to state that

PaCO2 is proportional to alveolar minute ventilation (MVA):

MV f V VA T D= ( )

Hence, an elevated PaCO2 can arise rom a decrease in respiratory

rate, a decrease in tidal volume, or an increase in dead space.

Meods of assessig respiraory fcio i o-ibaed paies

Plse oximery

Cyanosis is the hallmark clinical sign o hypoxaemia, but it can

only be recognized condently when the oxygen saturation is

below 75% and cannot be recognized i the haematocrit is less

than 15%. Pulse oximetry allows or non-invasive and continu-

ous monitoring o arterial oxygen saturation (SaO2). The basic

principles o pulse oximetry are that oxygenated haemoglobin

(HbO2) absorbs mostly inrared light while deoxygenated hae-

moglobin (Hb) absorbs mostly red light. Pulse oximeters exploit

the pulsatile nature o arterial blood and successully ignore the

FRC

VT

RV

ERV

IRV

IC

VC

TLC

Figre 1 th vs lg vls s b b

s. ic, s ; Vc, vl ; Vt, l vl;

tLc, l lg ; rV, sl vl; irV, s sv

vl; erV, x sv vl; Frc, l sl

.


4/51



contributions o the skin, tissues and venous blood. Each stroke

volume ejected rom the heart corresponds to an increase in arte-

rial blood volume across the measuring site. During systole light

absorption peaks, while during diastole it nadirs. The amplitude

o the waveorm generated is proportional to the amplitude o

arterial blood volume. Pulse oximeters, thereore, can detect

pulsus paradoxus, an important nding in certain pulmonary

dysunctions.Pulse oximeters can produce spuriously high or low readings

when a patient has a dyshaemoglobinaemia. In carbon monox-

ide intoxication, carboxyhaemoglobin (HbCO) absorbs light in

the red wavelength and is interpreted by the pulse oximeter as

oxygenated haemoglobin, alsely elevating the SpO2. Methae-

moglobin (Hbmet) is absorbed at a wavelength between red and

inrared light, leading to a alsely lowered SpO2 that generally

plateaus between 85 and 88%. The partial pressure o oxygen,

however, is not changed by the various dyshaemoglobinaemias.

Co-oximetry perormed on arterial blood samples will accurately

measure SaO2 as this technique can measure the proportion o

other orms o haemoglobin. Under normal conditions, however,

pulse oximetry measurements correlate well with co-oximetrywhen the saturation is between 70 and 100%.

Veilaio

The ability to monitor the eciency o ventilation by non-

invasive methods provides the clinician with critical inormation.

Oten the underlying disease masks signs o CO2 retention and

clinical diagnosis can be extremely dicult. The eatures only

appear when the PaCO2 is above 100 mmHg and can occur only

when the inspired air is enriched with oxygen, as the highest

PCO2 possible while breathing room air is about 90 mmHg. This

degree o hypercapnia by itsel does not appear to be dangerous,

and death usually results rom the associated hypoxia.

Transcutaneous CO2 monitors (TCOMs) oer a reliable, non-

invasive method or estimating arterial carbon dioxide. A small

adhesive patch, usually placed on the abdomen, warms the skin

and allows CO2 to diuse readily where it is read by the TCOM.

In general, TCOM monitoring correlates well with PaCO2,

although overestimations can occur due to heat and local CO2

production. While the accuracy o TCOMs has been historically

poor in obese patients, newer-generation TCOMs have improved

reliability.

Nasal cannula end-tidal CO2 detection: an easy and non-inva-

sive way o measuring end-tidal CO2 in spontaneously breathing,

non-intubated patients is by using divided nasal cannulas thatsimultaneously deliver oxygen via one prong and sample exhaled

gas through the other. Studies have shown that the end-tidal CO2

correlates highly with PaCO2. Such monitoring is useul or pro-

cedural sedation or to monitor children at risk or impending

respiratory ailure. It is physiologically impossible or end-tidal

CO2 monitors to read greater than PaCO2, so any elevated value

should be taken seriously and urther investigated by obtaining

an arterial blood gas.

Plmoary fcio ess

In addition to measuring lung volumes and capacities, spirom-

etry can be utilized with a orced expiratory manoeuvre that

can help clinicians determine mechanical disorders o the respi-

ratory tract, quantiy the degree o disorder and classiy it as

obstructive, restrictive or mixed in aetiology. Using a variety o

techniques, these can be done on even uncooperative (albeit

sometimes sedated) inants and young children.

Forced expiratory volume: as discussed earlier, vital capacity

(VC) is the lung volume that can be exhaled ater a ull inspira-tion. In contrast, orced vital capacity (FVC) is the lung volume

that can be exhaled ater a ull inspiration as quickly and orc-

ibly as possible, and is highly reproducible. When compared to

orced expiratory volume (FEV1), which by convention is the

amount o gas orcibly exhaled in one second, one can quickly

classiy the nature o respiratory disease. In cooperative children

over the age o 5 years the FEV1/FVC ratio is normally 0.8; values

less than 0.8 represent obstructive lung disease, whereas restric-

tive diseases have proportional decreases in FEV1 and FVC, pre-

serving the ratio o 0.8. Forced expiratory volumes provide an

objective standard to monitor response to treatment or clinical

improvement.

Flowvolume curves: by plotting expiratory and inspiratory

fows against lung volume instead o time, the clinician can

obtain more inormation about underlying lung or airway dys-

unction. Unortunately, orced expiratory spirometry provides

inormation solely about expiratory dysunction. Flowvolume

curves, on the other hand, can reveal both inspiratory and expi-

ratory dysunction and aid in the classication o the disease as

obstructive or restrictive.

Respiraory idcace pleysmograpy

The inspiratory cycle begins as the diaphragm moves downward.

The abdomen and rib cage then expand in concert, known as

thoraco-abdominal synchrony. However, various respiratory con-ditions will alter the timing o these events, resulting in thoraco-

abdominal asynchrony (TAA). The asynchrony can be quantied

using respiratory inductance plethysmography, and the degree

o asynchrony correlates well with the amount o respiratory

dysunction.

Two elastic belts into which a wire is sewn are worn around

the chest and abdomen. A current is passed through the belts,

generating a magnetic eld. The act o breathing changes the

cross-sectional area o the abdomen (ABD) and the rib cage

(RC), altering the shape o the magnetic eld generated by the

belts and inducing a measurable opposing current. A computer

analyses the current produced and generates (1) the phase angle,

which is the degree o synchrony o the ABD and RC and (2) thedirectional loop.

In a normal child, the phase angle is typically less than 22 and

the directional loop is anticlockwise. As the asynchrony worsens,

the phase angle gets larger, although maintaining the anticlock-

wise direction. When there is complete asynchrony the phase

angle is 180. In the case o bilateral diaphragmatic paralysis,

the directional loop becomes clockwise (Figure 2). In unilateral

paralysis, a gure 8 is created, and no phase angle can be mea-

sured. The clinical correlate is known as Hoovers sign, which is

the paradoxical inward movement o the lower lateral rib cage

during inspiration or in the neonate an abnormal movement

o the umbilicus to the contralateral side.


5/51



Pressrerae prodc

A small water- or air-lled catheter o similar size to a nasogastriceeding tube can be inserted with its tip in the mid-oesophagus

to measure, relatively non-invasively, both the peak-to-trough

swings in oesophageal pressure with respiration, and the respi-

ratory rate. The product o the two is called the pressurerate

product and is an excellent surrogate or work o breathing

measurements.

Case sdies

Obsrcive airways disease

The primary pathological deect in obstructive airways disease

is airfow limitation. This limitation can occur during expira-

tion, inspiration or both. Both large airways obstruction (croup,epiglottitis, oreign-body aspiration, laryngomalacia, tracheoma-

lacia) and medium (asthma) and small (bronchiolitis) airways

obstruction have hallmark ndings on physical examination and

in the tests discussed above. Knowledge o these patterns assists

the physician to localize the obstruction, determine disease sever-

ity, monitor disease progression and determine treatment.

Extrathoracic obstructions can be clearly dierentiated rom

intrathoracic obstructions based on characteristic patterns in

fowvolume curves. The primary abnormality o an extratho-

racic obstruction is with inspiratory fow. There is a fatten-

ing o the inspiratory fow limb with a airly normal expiratory

fow pattern. Intrathoracic obstructions can be subdivided into

variable or xed lesions. A variable lesion such as intrathoracic

tracheomalacia will have abnormalities with expiratory fow andproduce a fattening o the expiratory limb, while the inspira-

tory limb will appear normal. Fixed lesions such as oreign-body

aspiration, external compression rom extratracheal masses or

tracheal stenosis have inspiratory and expiratory fow limitation

maniested as a fattening o both the inspiratory and expiratory

limbs o the fowvolume curve (Figure 3).

Croup

Physical examination the major abnormality in croup (an

extrathoracic obstruction) is inspiratory airfow limitation. Air-

fow is generated by lowering intrathoracic and intratracheal

pressures below extrathoracic atmospheric pressure. According

to Poiseuilles law, the change in pressure is inversely propor-tional to the ourth power o the radius o the airway. Thereore,

decreasing a childs airway radius rom 5 mm to 2.5 mm leads to

a 16-old increase in the pressure or airfow. To accomplish this,

children will increase their work o breathing by using accessory

muscles (i.e. supraclavicular retractions). Moreover, childrens

subglottic submucosa is non-brous, and the mucous membrane

is attached more loosely than in adults, allowing or oedema to

accumulate more easily. The sot supporting cartilage o the lar-

ynx and the narrow radius o the childs airway also allow or

dynamic collapse o airways during inspiration. This maniests

clinically with the classic inspiratory stridor that oten accompanies

viral croup.

Rib cage

Synchronous

ABD

m/s = 0

= 0RC

Abdomen

Rib cage

Asynchronous

ABD

m/s = 0.71

= 45

m

s

RC

Abdomen

Phase shift

Rib cage

Paradoxical

ABD

m/s = 0

= 180RC

Abdomen

Figre 2 rs lhsgh wh

h rs. o h l-h s, b

g (rc) b (aBd) vs

l s , h

gh-h s ghll ss hhs gls h l. n

h sl s wh h hg

ls s. as bhg vs

shs shs, h sz

h hs-gl l ws, lhgh

svg lkws . Hwv,

wh hg lss (xl), h rc

aBd xl 180 hs, wh

lkws v.


6/51



Pulsus paradoxus as intrathoracic pressure becomes more

negative, aterload on the let ventricle increases and cardiac

output decreases. Since the pulse oximeter waveorm ampli-

tude is proportional to arterial blood volume, there is a decrease

in amplitude during inspiration known as pulsus paradoxus

(Figure 4). The magnitude o depression during inspiration has

been consistently correlated with the severity o extrathoracic

airway obstruction and can be used to monitor disease progres-

sion or resolution.

Flow and pressure curve against time the limitation o

inspiratory airfow can be visualized when fow and pressure are

simultaneously plotted against time (Figure 5). Respiratory inductance plethysmography phase angles

increase signicantly in viral croup and continuous phase-angle

monitoring can demonstrate clinical improvement as resolution

o the obstruction correlates with decreasing phase angles and

improving pulmonary unction.

Pressurerate product this value increases signicantly

in croup and can be used continuously to ollow response to

therapy.

Asthma

Physical examination the major abnormality in asthma is

expiratory airfow limitation. Underlying airway hypersensitivity

causes reversible narrowing and an increase in airways resis-tance up to 500% o normal values. This increased resistance

causes distal air trapping, ultimately leading to elevated end-

expiratory lung volumes and a prolonged expiratory phase with

wheezing. On visual inspection, patients with poorly controlled

asthma oten have a barrel-chest deormity due to the chronically

Expiration

Inspiration

50

40

30

20

10

0500

10

20

30

40

50

Flow

(litres/minute)

Tidal volume (mL)

400 300 200 100

Figre 3 Flwvl v x h w bs.

(nl vs , ss vs sl.) th s fw

l g s x s s fg

bh lbs h fwvl v.

B

A

F

E

CD

Plethysmographic wave

Blood pressure (mm Hg)

100

0

Inhale

Exhale

Breathing cycle

Figre 4 plss xs hl wh . psA B s ssl bl ss, whl s C D s sl bl

ss. ps E F s h k l h ls-x wv. n h h k s (b l) h s

s bh ssl sl ss (l l, s D B) g h ls x wv (

l, F); hs s kw s lss xs.


7/51



elevated end-expiratory lung volumes. During an acute asthma

exacerbation, children will breathe at a lower respiratory rate

than normal to minimize work o breathing and will commonlyhave pursed lip breathing. The increased resistance prevents the

dynamic collapse o the airways on expiration. As the airway

resistance increases urther and initial compensatory mechanisms

ail, patients will become tachypnoeic and use accessory muscles

to generate more negative inspiratory pressure to overcome the

increased elastic recoil o the lungs and chest wall rom hyperin-

fation and increased lung volumes. Eventually, lie-threatening

respiratory muscle atigue leads to hypoventilation, hypercarbia

and hypoxaemia.

Pulsus paradoxus the elevated airways resistance raises

intrathoracic pressure and, much as in croup, causes a transient

decrease in cardiac output during inspiration. The consequential

pulsus paradoxus correlates with the severity o the asthma

exacerbation.

Forced expiratory spirometry and fow-volume curves

spirometry represents the most accessible way to gauge the

severity o obstruction and monitor the eects o therapy. The

measured FEV1/FVC is less than 0.8 since the reduction in air-

fow (FEV1) is greater than the reduction in lung volume (FVC),

with the degree o reduction correlating with disease severity.The expiratory limitation is readily visible on fowvolume curves

as reduced peak expiratory fow and a characteristic concave

appearance on the expiratory limb. Note the change in shape in

the expiratory limb ater bronchodilator therapy rom concave to

straight, the increase in peak expired fow and FEV1 (Figure 6).

Resricive lg disease

Whereas obstructive airways diseases are rooted in airfow limi-

tation, the hallmark o restrictive lung disease is decreased TLC.

The aetiologies are diverse increased elastic recoil (interstitial

infammation/brosis), decreased outward recoil o the chest wall

(scoliosis), respiratory muscle weakness (spinal muscular atro-

phy), alveolar destruction (pneumonia), thoracic space-occupyinglesions (tumour, blood, air, eusion, cysts), signicant abdominal

distension (acute abdomen, intra-abdominal masses) but the

consequences are the same: decreased TLC with preservation o

normal airfow.

Scoliosis

Physical examination deormities o the thoracic cage in

scoliosis lead to decreased lung capacities. In act, the degree o

restrictive pulmonary disease is clearly correlated with the sever-

ity o scoliosis, and those with severe thoracic cage deormities

are prone to more rapid decompensation when aficted with

respiratory inections. Initial attempts at compensation prompt

patients to breathe with aster respiratory rates and deeper than

Pre-epinephrine nebulization

Time (seconds)

100

80

60

40

20

0

20

40

60

80

0.0

8

0.

2

0.3

2

0.4

4

0.5

6

0.6

8

0.8

0

0.9

2

1.0

2

1.1

4

1.2

6

1.3

8

1.5

0

1.6

2

1.7

4

1.8

6

1.9

8

Post-epinephrine nebulization

Time (seconds)

Flow (ml/s) Pressure (cmH2O)

100

80

60

40

20

0

20

40

60

80

0.

06

0.

20

0.

34

0.

48

0.

62

0.76

0.

90

1.

02

1.

16

1.

30

1.

44

1.58

1.72

1.

86

2.

00

2.

14

Figre 5 Flwss v hl wh . Flw ss

vs l gs . t l: b h s

sg s fw l. dg l s

h s sv s s fw ss wh hg

shgl ss (left of solid arrow). t h right of the solid

arrow, l s ss (open arrow), h s vll

h s s fw s lg s

gv ss. dg x, h s ls v fwl, wh shgl ss hgh fws lw h

hs s h h hl. Lw l:

h. F h bgg s, fw ss

kl h k b hsolid arrows ss

ss. th, h s h sll l shgl

ss s b s gv vl (open arrow).

dg x, v s ss ss ss

wh lvl hgh fws.

Expiration

Inspiration

50

40

30

20

10

0500

10

Diseased After response

to bronchodilator

Normal

20

30

40

50

Flow(litres/minute)

Tidal volume (mL)

400 300 200 100

Figre 6 Flwvl v hl wh sh. th x

l s s s k x fw h

hs v h x lb. n h

hg sh h x lb bhl h

v sgh h s k x fw.


8/51



their normal tidal volume. As they begin to atigue, baseline end-

expiratory lung volumes decrease. Alveolar collapse, worsening

V/Q mismatch and hypoxia soon ollow.

Forced expiratory spirometry and fow-volume curves given

the insidious nature o scoliotic deormities, measurement o lung

volumes and capacities is an eective way to gauge the result-

ing decline in pulmonary unction over time. It has been shown

that postoperative pulmonary complications increase with dete-rioration in pulmonary unction tests. Since restrictive diseases

produce a proportional reduction in airfow and lung volume,

the FEV1/FVC remains unchanged or even slightly greater than

normal. However, the lung volumes obtained will be lower than

predicted.

Neuromuscular disorder (e.g. spinal muscular atrophy, infant

botulism)

Physical examination most children with neuromuscular

disorders do not exhibit prominent respiratory symptoms. Simi-

larly to patients with scoliosis, their respiratory abnormalities

usually become apparent when they are aficted by an inection

o the respiratory tract. Unlike patients with scoliosis, however,their restrictive lung disease is urther complicated by underlying

muscular weakness. I disease progression is severe enough, they

will maniest other signs on physical exam unique to neuromus-

cular disorders. The diaphragm is initially seemingly spared

compared with the weaker intercostal muscles and children will

use their accessory muscles to breathe at higher respiratory rates

than normal individuals to minimize work o breathing. Eventu-

ally this will progress to paradoxical breathing, usually apparent

clinically and on respiratory inductance plethysmography.

Respiratory inductance plethysmography patients with spi-

nal muscular atrophy will oten progress to complete thoraco-

abdominal asynchrony. The rib cage is neither stabilized nor

expanded during inspiration and the resulting negative intratho-racic pressure causes the rib cage to collapse. The phase angle

will be above normal or up to 180 and the directional loop

anticlockwise (Figure 2).

Coclsio

There is a wide array o non-invasive tools available to the pae-

diatrician or diagnosis and management o various respiratory

diseases. With a basic knowledge o respiratory physiology and

how pathophysiological states can be monitored, the clinician

can optimize therapeutic interventions and readily track disease

progression.

FuRthER READInG

ag ac, Hhll m, nwh cJ, Kl m. th h

b blz ss w bs s wh

sv . Intensive Care Med2008; 34: 13847.

Bk SJ, t KK. th b x hl

ls x ss po2.Anesthesiology1987; 66:

6779.

Bk SJ, t KK, H J. es hglb ls

x x vs x.Anesthesiology1989; 70:

1127.

ck cW, Bk Ga, es JF, l. rgh hl

ss s : bjv

sg ss. Crit Care Med1981; 9: 58790.

F B, B W. pls x ssss lss xs:

ll s hl. Intensive Care Med1998; 24: 2426.

Gg S, J a, m r. pl s s b

sl s g h slss. Spine 1989; 14:

48690.H J, nwh cJ. i lg sg h sv

. Intensive Care Med1995; 21: 74452.

H J, eb e. p l sg. Bsl: Kg,

2005.

Hs u. Vl, gs xhg, hs bhg

s wk bhl sh.Acta Soc Med Ups

1971; 76: 24870.

Hv cF. th s h sl sls.JAMA 1919; 73:

1720.

K yJ, Lk LG, Bwll KH, l. pl ls

h slss lv h sgl .J Bone Joint

Surg Am 2005; 87: 153441.

Lk LG, Bwll KH, Blk K, Bls c. alss l hs g s hgs hls

h slss. Spine 1995; 20: 134350.

msl m, Z a, F S, l. evl

ss b x sv bs. Intensive

Care Med2008; 34: 13404.

mh Jc, Bss oG, thbl dW, m Gd. th ll

s lvl vl.Am Rev Respir Dis 1968; 98:

86871.

nwh cJL, H J. mss h-bl sh

wk bhg hl. i: H J, eb e, s.

p l sg. Bsl: Kg, 2005.

nhls mm. Shg bls l h ls (h bll

s sg). Clin Pediatr1976; 15: 3423.nhls dG. rs sl s hl.

J Pediatr1991; 118: 493502.

n aH, nwh cJ. a s s hl.

J Appl Physiol 1996; 80: 14859.

pz a, ml r, V G, l. thbl

bhg sl ss. Chest1996; 110: 45461.

p S. S hslgl ss sh: bhsl

ws lb. Ciba Found Study Group 1971; 38:

6385.

r J, tsls F, mh J, l. cs vsv

s lss xs ls l s

kg ssss sh sv. Chest2006; 130:

75465.

Sv y, dks tW, nwh cJ. thbl sh

w bs sll hl.Am Rev Respir Dis 1990;

142: 5404.

Sv y, elh mK, chh te, nwh cJ. es l

b x b -l ss pco2

ss vl hl. Pediatr Pulmonol 1992;

12(3): 1537.

Sl Sa, mlls rB. mhl s g l

sh. N Engl J Med1977; 297: 5926.

Sl dW, S Ka, Wgh ro, l. d. plss xs:

bjv s sv .Am J Respir Crit Care Med

1998; 157: 3314.


9/51



tbs Jd, Flg JF, Whl tJ, l. nvsv g

-l co2 v sl ls ssl bhg hl

g h v . Crit Care Med1994; 22: 18058.

Ws JB. mhs bhg. i: rs hslg:

h ssls. Bl: L, Wlls Wlks,

2003. yl m, nw W J. evl ls x.

Anesthesiology1983; 59: 349352.

Zhg JG, Wg W, Q GX, l. th l v l ss h sgl slss. Spine 2005; 30:

21821.

Pracice pois

pls x, tcoms sl l -l co2vs s lbl ws gs xhg

chs hgs l sss lssg lg s s

ogg s l ss llw g ss gss


10/51



T atiology o cilooastmaW L

Abstact

ash s hs ss ll s b h

chs h Gks. i vl s h vl hl-

s v hgh, b h vl hs b sg l h vl-

g s v h ls 30 s. th lg s ll

s b g vl s. Gll,

h h ls g h h h, b sgl g

lhs ss xbs sl-

. i s bg v h s vl s l s vl, l hvl s, ,

s, xs, ssl, ll, l skg, bs.

rsh hls s s s h hss vlv, b

hs hss wll v hgl /l h.

usg hs v s k sl g h

vl sh l hs v glbl ss.

Kywos lg; hlh sh; llg; gs; bs;

s; lls; b sk; vs sItoctioChildren with asthma demonstrate episodic symptoms and

variable airow obstructions which occur spontaneously or in

response to various environmental trigger actors. There is also a

strong genetic inuence which is determined more by the childs

mother than by the ather. The Oxord English Dictionary defnes

aetiology as the assignment o a cause and that part o medi-

cal science which investigates the causes o disease. The latter

defnition dates back to 1684, but there has been a consider-

able increase in our understanding o the causations o asthma

since then. In 1860, Henry Hyde Salter published his Treatise

on Asthma. Allergy and atopy had not been propounded at that

time, but he was clearly aware o the hereditary nature o the

disease and o the association with contact and emanationsrom cats and dogs. In 1892, Sir William Osler drew attention

to the wide variety o pathological changes occurring in asthma,

such as mucosal oedema, inammation, and the production

o gelatinous mucus. He also noted the relationship between

these changes and their corresponding symptoms demonstrated

during exposure to dust, cats, oods, inections, and emotional

extremes. He was well inormed that asthma usually commenced

Warren LenneyMBChB DCH MRCP MD FRCP FRCPCH is Professor of Respiratory

Child Health, Keele University and Academic Department of Child

Health, University Hospital of North Staffordshire, Stoke-on-Trent, UK.

in childhood and that it appeared to run in amilies. Today this

exaggerated response to various stimuli is accepted as one o the

key characteristics seen in both children and adults with asthma,

namely bronchial hyper-responsiveness (BHR). The main thrust

o this review is to highlight the main genetic and environmental

inuences which result in the production o symptoms and exac-

erbations in children with asthma: in other words, the relevant

actors to consider in the aetiology o the disease.

Gtic ifcs

Although asthma has been known to run in amilies or centu-

ries, twin studies have shown that BHR is inherited indepen-

dently. It is the BHR mechanisms which are critical to asthma

aetiology, as these are what truly determine the symptoms, the

expression o the disease. The pathological expression has been

shown as mucosal oedema, inammation, hypertrophy o the air-

way smooth muscles, smooth-muscle shortening, and increased

muscle contractions.

The complexity o the above processes suggests there may

be hundreds o potentially attractive candidate genes associatedwith asthma, and this has been confrmed by the large num-

bers o genetic mapping studies which have been published over

recent years.

Some areas o the human genome have more consistently

been associated with many o the recognized asthma pheno-

types. These are 6p21-24 (the major histocompatibility complex),

11q13-21 (clara cell secretory protein, IgE high-afnity receptor

and glutathione S-transerase genes) and 20p13 (ADAM 33). It

was particularly exciting in relation to the identifcation o ADAM

33 that two subsequent candidate gene studies confrmed an

association between BHR and ADAM 33 polymorphism.

Groups o candidate genes which have been shown to be

relevant to asthma are those encoding cytokines and chemo-kines, those encoding receptors associated with the T Helper cell

2 (TH2) response, and those genes related to oxidative stress.

These associations are complex, however, and can be inuenced

by many simple actors such as the size and age o the child. I

BHR is not corrected or such parameters, the associations can

change dramatically and even disappear completely. The risk o

transmission o asthma is greater through the childs mother, and

this has been recently confrmed in relation to polymorphism

in glutathione S-transerase (GSTP1), one o the genes respon-

sible or the detoxifcation o drugs and products o oxidative

stress. Some studies have ound correlations with the athers

genetic make-up in relation to BHR, and one requires an in-depth

knowledge o asthma genetics to ully interpret all the publishedfndings.

One o the issues in attributing specifc genetic relationships

to asthma in children can best be summarized by Figure 1. These

relationships depend on the many and complex interactions

between in-utero, neonatal and external environmental actors,

all o which vary depending on the specifc asthma phenotype,

and even in a single patient these do not remain constant but

vary over time. The phenotype may well vary between the sea-

sons, some worsening in the spring and early summer, others

worsening in the winter. Asthma symptoms in children are more

variable than those in their adult counterparts, and they may

well change signifcantly rom one year to the next. Long-term


11/51



symptomatology and severity are very hard to predict clinically

in the individual young patient.

The above clearly shows that the genetic associations are

complex, asthma aetiology is multiactorial, and despite the

insistence o the media that one day we will fnd the gene or

asthma, there is no such thing.

Foo allgy a it

In surveys o patients attending asthma clinics, over two-thirds

think their asthma is triggered by specifc oods. When ood

allergy challenge studies are undertaken, however, the fgure is

much lower, usually less than 25%. The reason or the high fg-ure in epidemiological surveys is probably the inclusion o oods

such as ice-cream and fzzy drinks, where the causation o the

bronchospasm is more likely to be related to very low tempera-

tures or a low/acidic pH. Foods implicated most commonly in

causing asthma symptoms, ollowing challenge studies, are pea-

nut, milk, egg, and tree nuts.

Both ood allergy and asthma are considered to have an

important allergic component mediated through immunoglobulin

E (IgE), but as with genetics, the relationships are not straight-

orward. When dierent countries are surveyed to establish the

prevalence fgures or atopy and asthma, even i the prevalence

o atopy is similar in each country the prevalence o asthma can

vary enormously. Conversely, over a number o years, the preva-lence o asthma can rise steadily with no similar change in atopy

prevalence.

The role o diet has been investigated extensively in relation

to asthma prevalence over recent years. Anti-oxidants such as

vitamin C and E, atty acids, and magnesium and potassium have

been studied, as have avourings, colouring agents, and addi-

tives such as monosodium glutamate, tartrazine and sulphites.

A Cochrane review o fsh-oil 3 atty acid supplementation

could not fnd any consistent benefcial eect when compared

to placebo. The evidence or the eect o the other compounds

(colouring agents and additives etc) is also not clear, although

some patients can be adversely aected by them. As with other

actors related to the development o asthma in children, the role

o our diet has to be considered as a trigger which may inu-

ence prevalence and/or severity, but which needs careul assess-

ment in each patient or in each patient group, depending on the

asthma phenotype.

Vial ictios

Respiratory viruses are the most common cause o asthma exacer-

bations in children and in adults with asthma. Viruses are respon-

sible or 85% o all childhood exacerbations. The most important

virus is the rhinovirus (RV), which is now known to inect the

lower as well as the upper airway. The innate immune response

to RV inection was postulated as being defcient in asthmatic

patients. Production o intereron (IFN-) was investigated and

shown to be low. Patients with asthma thereore probably have

decreased immunity to RV, resulting in increased cell lysis and

more severe lower-airway symptoms ollowing inection. RV

inection may also act synergistically with allergic inammation,

and the fnding o RV together with high allergen exposure in

children results in increased risk o hospitalization with asthma.Respiratory syncytial virus (RSV) has traditionally been con-

sidered the most important virus or severe wheezing in the frst

2 years o lie, and indeed it is still the commonest pathogen

to produce acute viral bronchiolitis (AVB) in this very young

age group. In the UK alone RSV is responsible or the major-

ity o the 20,000 inants admitted to our paediatric wards with

AVB each winter. However, in elegant prospective studies in the

USA, Lemanske et al ound that RV isolated during wheezing ill-

nesses in inancy were the strongest predictor o wheezing in the

third year o lie. We must be careul to try to separate recurrent

respiratory symptoms o cough and wheezing ollowing AVB

rom wheezing in association with allergic sensitization and the

development o true atopic asthma. In practice, however, in theclinic or surgery in primary or secondary care such dierential

diagnoses are almost impossible to make, and fnal dierentia-

tion can only be confrmed in the ullness o time. The reality or

clinicians is much less obvious than many epidemiological stud-

ies would have us believe.

Clearly, RSV and other respiratory viruses may be ound in

inants with a uture diagnosis o atopic allergic asthma, but the

research evidence at present points to RV as the key virus in

the aetiology o true symptoms o atopic asthma. Whether it is

the genetic make-up o the child which is the real determinant

o asthma status remains an unanswered question, but this may

well be the most important actor in the uture progression o

asthma symptoms. By that I mean that RV or any other virusmay produce symptoms in inants, but those inected who then

develop atopic asthma are those with the susceptible genetic

make-up in the frst place.

There is increasing interest in bacterial inections, such as with

Mycoplasma pneumoniae and Chlamydia pneumoniae, which are

known to cause respiratory inections in all ages. In one study,

20% o 215-year-old children admitted to hospital with asthma

were ound to have mycoplasma present as assessed by culture

through nasopharyngeal aspirates and paired serum titres or

mycoplasma antibodies. We need more inormation on these

organisms as potential inective agents which may be actors in

the development o asthma in both children and adults.

Mothers genes

Neonatal immunophenotype

Asthma phenotype

In-utero environment Fetal genes

External environment Childs genes

Fig 1 ps l gv s

g sh h.


12/51



Psts, pts a otoxis

In the 1970s it was generally believed that the aetiology o asthma

was mainly determined by the house-dust mite and, in particu-

lar, its allergenic aeces. Cats were considered to requently con-

tribute to symptoms, and the answer seemed simple get rid

o the amily cat and take specifc measures to keep levels o

house-dust mite low. Remove carpets, cover the mattress withpolythene, regularly damp-dust the bedroom and living rooms,

and buy non-allergenic bedding and pillows. Studies rom moun-

tainous regions o the world, however, inormed us that at levels

over 8000 eet above sea level, such as in the Andes, house-

dust mites could not survive, but asthma prevalence was high.

In countries where cats were not domesticated the prevalence

o asthma was as high as in other countries where cats were

the commonest household pet. Numerous cohort studies have

now evaluated the relevance o dust, house-dust mites, urry

and eathered pets and endotoxins (inammatory lipopolysac-

charides rom gram-negative bacteria that are ubiquitous in the

indoor environment) in the development o allergic sensitization

and childhood asthma. Some studies, but not others, have showna doseresponse relationship or mite allergen exposure and sen-

sitization. In the study by Simpson et al, the higher the endotoxin

allergen exposure the greater the risk o sensitization, but when

the results were re-analysed by genotype only the children with a

particular genotype o the CD14 gene confrmed the relationship,

emphasizing the complex interaction between environmental

and genetic backgrounds.

Perhaps the most convincing evidence o environmental inu-

ences in relation to asthma prevalence is the consistent fnding

that children reared on arms have a lower incidence o asthma.

The most likely explanation or these fndings is that exposure

to irritant, allergenic and inectious actors in early childhood

somehow encourages tolerance to common aeroallergens, per-haps by promoting T-helper-cell type 1 (TH1) as opposed to TH2-

type immunological responses early in lie. Much research has

taken place over the past 20 years, oten involving large cohort

studies, to assess the importance o aeroallergens in the develop-

ment o asthma in children. We now understand the mechanisms

involved ar better, but in practical terms we are little closer to

knowing whether we can alter/manipulate the indoor and out-

door environments to inuence asthma prevalence.

Obsity

The incidence o asthma and that o obesity have increased in

parallel over the last our decades. There are mechanical, immu-nological, hormonal and inammatory eects o obesity that

may well play a role in the persistence o asthma. Although the

relationship is not completely clear, many prospective studies

suggest that increased body mass index (BMI) is associated with

an increase in asthma. However, ew studies have adjusted or

physical activity, and in some the association is seen only in

males, in others it is seen only in emales. Whilst diet and BMI

are relatively easy to measure, the assessment o physical activ-

ity is more challenging, and it could be that lack o activity is the

primary explanation or the increased levels o asthma symp-

toms, and not the obesity itsel. There is no doubt that obesity

is a major present-day health hazard, but whether it is directly

related to increased levels o asthma in childhood populations

requires urther study.

Tobacco smok

Cigarette smoke contains particulate matter and more than 2000

chemical compounds. Tobacco smoke in the environment is

incompatible with good respiratory health. A systemic review oparental smoking revealed an odds ratio or asthma o 1:21 and

or wheeze o 1:4. Although maternal smoking is not consistently

associated with an increase in asthma prevalence, it is associ-

ated with more severe disease, and childhood asthma symptoms

oten improve when the mother stops smoking. Similarly, BHR is

increased in children whose parents smoke, and increased BHR

at 1 month o age has been shown to predict lower lung unction

at 6 years o age. Wheezing and doctor-diagnosed asthma are

more closely related to passive/environment tobacco smoke in

the preschool age range than in schoolchildren 516 years o age,

but such fndings should not detract rom the statement that the

single most important measure to improve the health o children

would be the exclusion o tobacco smoke rom their indoor andoutdoor environments.

Ot polltats

It is known that nitrogen dioxide, sulphur dioxide, ozone, diesel

exhaust and particulate matter can all increase BHR and inam-

mation. The mechanisms may involve oxidative stress, epithelial

damage, and an increase in pro-inammatory mediators. As with

other triggers, such actors are unlikely to work alone, and an

interesting study o children 811 years old who wore nitrogen

dioxide monitors throughout the study showed that respiratory

symptoms increased and lung unction ell as nitrogen dioxide

levels increased. These changes occurred in the week beore arespiratory inection became clinically obvious, once again dem-

onstrating the complex interactions which may be necessary in

the patients environment i they are to inuence the develop-

ment o asthma symptoms.

Ot isss

Asthma is a syndrome with dierent triggers, dierent outcomes

and dierent responses to medications. Recent studies have iden-

tifed actors such as paracetamol usage and rhinitis in children

as important in progression to adult asthma. Progress in under-

standing mechanisms responsible or asthma symptomatology is

slow and cure is still a pipedream.

Smmay

Asthma is a classical multiactorial disease whose aetiology is

complex, involving both genetic and environmental triggers. The

prevalence has risen steeply over the last 30 years at a rate that

cannot be explained simply on genetic grounds. Clearly there

are important environmental actors which have inuenced this

sharp rise, and I have tried to allude to a number o these. Each

patient is dierent, and trying to assess which environmental

actors are important or that individual may result in improve-

ment in asthma control i identifed triggers can be eliminated


13/51



or reduced. O equal importance is the relationship between

such environment triggers and specifc genetic polymorphisms.

Asthma aetiology typifes the comment one glove does not ft

all. There will not suddenly be a miracle cure or this common

yet very complex disease. Each patient behaves in a dierent

way, making asthma a ascinating disease in which to study the

true meaning o the word aetiology.

Cofict o itst

The author has no conict o interests which may have any inu-

ence on the content o this article.

FurTher reAdInG

Bs Ja, alxs n, Bs c, l. Hlh s ll.

J Allergy Clin Immunol 2004; 114: 111623.

Bs S, L m, m e, l. Mycoplasma pneumoniae

sh hl. Clin Infect Dis 2004; 38: 13416.

chh aJ, isk Hm, Lk cH, l. psl xs g

x (no2) h sv vs- sh hl.Lancet2003; 361: 193944.

chl F, L W, cl S, l. c bhl hllg

g sz h sls g ss

ss hl. Pediatr Allergy Immunol 2003; 14: 193200.

chl F, L W, cl S, l. ml b l v

GStp1 s ss wh sh hs hl. Respir

Med2003; 97: 124756.

dls Se, Bhh S, Js a, l. a g-w sh

qv l lg sh. Nature 1996; 383: 24750.

es p, c y. rlv s sh g l

lss s .Am J Respir Crit Care Med2000; 161:

15636.

erS th L. a s-hg sh. Lancet2008; 372:1009119.

Fl SL, Bss WW. th l hvs sh

xbs.J Allergy Clin Immunol 2005; 116: 26773.

F aa, B a, Hl m, l. plhs glh

S-ss GStp1 ls: w k bhl

hssvss sh.Am J Respir Crit Care Med2000;

161: 143742.

Gvs pe, Kbsh m, Hl m, l. a ls sv ghl

lk lhss h iL-13 g s ss wh l

s ige lvls h ls wh hl.J Allergy

Clin Immunol 2000; 105: 50613.

Hg a, Bjk t, Shz po, l. ash l

g s sh ssbl gs.Allergy2002; 57:

6806.

Jhs SL, p pK, Ss G, l. c s

l vl s xbs sh 911 l

hl. BMJ1995; 310: 12259.

Ls Sr, pl-mlls tae. p sh bs. Paediatr

Respir Rev2006; 7: 2338.

Lsk J rF, Jks dJ, Gg re, l. rhvs llsss

g sbsq hlh whzg.J Allergy

Clin Immunol 2005; 116: 5717.

m cS, pl G, Kbz t, l. S fbl sk s

sh xbs: vs llg xs

s h sk sh hslz hl. Thorax2006;

61: 37682.

o J, ml n, tl c, l. plb-ll bl-bl hllg sh.J Allergy Clin Immunol 1986; 78:

113946.

osl W. Bhl sh. ls .

nw yk: d al, 1892.

pl LJ, r p, Gbs n, l. aw ssvss l

s sh, lg s ss b

shl g.Am J Respir Crit Care Med2001; 163: 3742.

pj a, Sh d, B m, l. ash llg alb

h uK. Lancet2001; 358: 14267.

Sl HH. o sh: s hlg . L: Jh

chhll, 1860.

Ss a, Jh SL, J F, l. ex xs, cd14

llg ss: bw gs h v.Am J Respir Crit Care Med2006; 174: 38692.

Sh dp, ck dG. pl skg hlh sh;

lgl s l ss. Thorax1998; 53: 20412.

V ewgh p, Ll rd, ds J, l. ass h adam33

g wh sh bhl hssvss. Nature 2002;

418: 42630.

Ws rK, th Fc, abs mJ. d s (fsh l)

sh ls hl. Cochrane Database Syst Rev

2002 (3): cd001283.

Pactic poits

th ss s hl wh sh sl xgg ss vs sl

.. bhl h-v (BHr)

th lg sh s ll, vlvg bhg vl s

th hvs s h sgl s gg g xb sh

ivl hl b vsl b h ls, b vl sss lx

sg

chl bgh s wh h ls hv lw vl sh, s shw v

s wlw

ds h h vl b sk llws sh ss, ls s bl

ls s skg


14/51


paediatricS and cHiLd HeaLtH 19:6 261 2009 pblsh b elsv L.

Avacs i tmaagmt of astmaaw Bsh

c Bssl

Ls Flg

nl Wls

Abstract

exg w sg h v bs h g

sh. t h shl whz, h

bs lss s s (vl) lgg whz,

h h g lgl (s vss -

ss) h s bs . es (vl) whz s

l, wh h hl bhls l -

lks h vl ls. i hs h ls, hgh-s hl ss b . ol sl s v

h ll b h svs ks shl s

(vl) whz, s - hs x. i

l hl h l lg-g 2 gss hs b xl. th

s s-l hl h. i hl wh

sv ss, sgl-hl sg sg bs/l

shl b s. i hl wh s vl

sh h, h gss h w whh h sb -

s bg s shl b vw h h bg

bll gv. ms ss wll v wh vl g

whh s l k, wll q vl hs.

Kywors h; ; b gs; hl s; l-k gs; l; sl; vl ;

whzItroctio

The aim o this review is to highlight recent important clinical

trials, particularly those which should lead to a change in clinical

Andrew Bush MD FRCP FRCPCH is Professor of Paediatric Respirology at the

Imperial School of Medicine at the National Heart and Lung Institute,

and Royal Brompton Hospital, London, UK.

Cara BossleyMRCPCH is a Clinical Research Fellow at the Imperial

School of Medicine at the National Heart and Lung Institute, and Royal

Brompton Hospital, London, UK.

Louise Fleming MRCPCH is a Clinical Research Fellow at the Imperial

School of Medicine at the National Heart and Lung Institute, and Royal

Brompton Hospital, London, UK.

Nicola Wilson MD is an Honorary Consultant Paediatrician at the

Imperial School of Medicine at the National Heart and Lung Institute,

and Royal Brompton Hospital, London, UK.

practice in the treatment o wheezing disorders throughout child-

hood. Familiarity with the updated version o the British Thoracic

Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN)

Asthma guidelines is assumed. We aim to produce an update

o treatment or children seen in primary and secondary care in

particular, based on new evidence; space precludes a review o

the recent advances in the basic science o asthma.

Prscool wz

Potypig prscool wzig syroms

There are at least three ways in which wheeze phenotypes have

been characterized: by epidemiological descriptions o the change

in wheeze over time, by the presence or absence o atopy, and by

current symptom pattern, i.e. episodic (viral) versus multitrigger.

Epidemiology: the classic epidemiological phenotypes are

transient wheeze (rst 3 years o lie only); persistent wheeze

(throughout the rst 6 years o lie), and late-onset wheeze (start-

ing ater the rst 3 years o lie), as described in the Tucson

study. These patterns are to some extent orced in that the chil-dren were only seen three times in the rst 6 years o lie, so

no other phenotype could have been detected. The Avon lon-

gitudinal study obtained questionnaires annually, and used a

more objective mathematical technique latent class analysis

to determine rom the data whether there were dierent phe-

notypes, a more sophisticated approach. They determined

phenotypes o (1) never or inrequent (59%); (2) transient (16%)

and (3) prolonged early wheeze (9%); (4) intermediate (3%),

(5) late (6%) and (6) persistent wheeze (7%). Although these

epidemiological phenotypes have value or the epidemiologist

probing mechanisms o disease, they are useless or the clinician,

because they can only be allocated retrospectively, and thereore

cannot guide contemporaneous therapeutic decisions. The basicmessage, amiliar rom clinical practice, is that some wheezy pre-

school children will outgrow their symptoms, and some will not.

A number o predictive indices have been developed which gen-

erally have a good negative predictive value (will tell you who

will not have persistent symptoms) but a poor positive predictive

value (little better than fipping a coin at telling you who will

have persistent symptoms). So it is very dicult or the clinician

to determine whether a wheezy 2-year-old will still be wheezing

at the age o 6. The epidemiological studies have certainly taught

us a great deal about the natural history o wheezing disorders in

childhood, but are not useul in clinical practice.

Atopy: the second way o classiying wheeze is by the presenceor absence o atopy, determined either by skin-prick tests or by

the report o eczema or allergic rhinitis. This too is imperect.

Firstly, just because the child is atopic does not mean that atopy

and wheeze are connected, any more than an ingrowing toenail

in such a child could rationally be described as an atopic digi-

topathy. Indeed, in very young children with wheeze, whether

atopic or not, airway wall histology is normal. In older children

with wheezing in response to viruses and many other triggers,

airway wall histology shows typical eosinophilic infammation

and structural airway wall changes irrespective o the presence

o atopy. Atopy is also a dynamic process, with children mani-

esting it over time; so when assessing the current non-atopic


15/51



wheezer, it is impossible to know whether atopy will appear

subsequently.

Symptom pattern: the third approach, adopted by the recent

guidelines o the European Respiratory Society (ERS), switches

the ocus to symptom pattern at the time o presentation as the

way to guide treatment. The history should determine whether

the child has episodic (viral) wheeze, characterized by wheezein association with usually clinically diagnosed viral inections

only, or multitrigger wheeze, characterized by wheezing with

viral inections, but also with wheeze to typical triggers such

as exercise, allergen and smoke exposure. The implications or

treatment are discussed below; in summary, episodic problems

should be treated with intermittent therapy, whereas children

with multitrigger symptoms should be considered or continu-

ous treatment, usually with low-dose inhaled corticosteroids

(ICS), using a three-stage protocol. It should be noted that this

classication accepts that phenotypes may be modied by time

or treatment; thus an inant with episodic (viral) wheeze may

evolve into a multitrigger picture, and the inant with multitrig-

ger wheeze, when treated with ICS, may be let with episodic(viral) exacerbations, which are much more dicult to control

with prophylactic therapy. Also, although the tacit assumption

is sometimes made that the terms episodic (viral) and transient,

and also multitrigger and persistent are synonymous, there is

no evidence that this is the case. Episodic (viral) wheeze can

certainly persist even into adult lie, and multitrigger wheeze can

remit in mid-childhood.

Implicatios for tratmt of prscool wz

The ERS guidelines attempted an evidence-based approach to

treatment (hampered by the lack o much evidence!) o preschool

wheeze; subsequent to the publication o these guidelines, two

urther papers on the acute management o preschool wheezehave been published. The stimulus or the guidelines was to try

to rectiy the disconnection between the epidemiological data

and the recommendations o many previous guidelines, and also

to be o practical value or the clinician. There might be two

reasons or treating preschool wheeze: (a) to modiy the disease

and prevent persistence o symptoms and the development o

ull-blown asthma in mid-childhood, and (b) or current relie

o symptoms.

Can treatment alter the outcome of preschool wheeze?: the

short answer is, no. Although parents want to know the prog-

nosis o the child, in practice it actually makes no dierence

to therapy because we have no medication which prevents thedevelopment o persistent asthma. Studies have shown that

early use o continuous or intermittent (at the time o symp-

toms) ICS have all shown that they have no eect on outcome.

A trial o cetirizine given to inants with atopic dermatitis to try

to prevent the development o wheeze showed no dierence

or the treatment group as a whole, but some benet, based

on airly small numbers, in subgroups with radioallergosorbent

test (RAST) positivity to house-dust mite, pollen or both. This

hypothesis-generating trial was not conrmed by a repeat study

o l-cetirizine, in which no benet was shown. So treatment or

preschool wheeze should be directed by present symptoms, not

uture prognosis. It cannot be overstressed that, whatever the

evidence in adults, the early use o inhaled corticosteroids in

preschool wheeze to optimize uture outcome is not indicated.

Symptomatic treatment for preschool wheeze: given the

lack o any evidence that the prognosis o preschool wheeze

is aected by treatment, we suggest that a symptom-based

approach, as suggested by the ERS guidelines, is appropriate.

The validity o this approach appears to be borne out by alimited amount o clinical trial data, and in practice we suggest

that in any case mothers dont want to medicate a completely

well toddler.

Treatment of episodic (viral) wheeze: bronchodilators the

rst-line treatment o episodic (viral) wheeze is with inhaled

short-acting 2 agonist and/or inhaled anticholinergics just at

the time o symptoms, depending on the response. A mask and

spacer is used; the mask can be discarded in older children.

Treatment of episodic (viral) wheeze: leukotriene receptor

antagonists i this is insucient, the use o intermittent monte-

lukast, just at the time o viral wheezing, should be considered,

ollowing the publication o the PRE-EMPT study. This group

randomized more than 200 children to receive placebo or mon-telukast at the time o a virus-induced exacerbation o wheez-

ing. The number and duration o episodes was the same in both

groups, but in the montelukast group the children lost one-third

ewer days out o school or child care, and the carers lost one-

third ewer days rom work. This strategy does not work or all

children, but is well worth considering i episodic (viral) wheeze

is seriously disruptive. The approach is more logical than using

montelukast daily or episodic (viral) wheeze, since the eleva-

tion o cysteinyl leukotrienes is present only during viral inec-

tions, and is more likely to be practical since parents are mostly

reluctant to medicate well children. It is o course possible to

use montelukast as a prophylactic medication, but no study has

shown that this approach is superior to low-dose inhaled corti-costeroids at any age.

Treatment of episodic (viral) wheeze: steroids there have

been important new studies addressing the role o inhaled and

oral corticosteroids in preschool episodic (viral) wheeze. A

Cochrane review had previously concluded that prophylactic

low-dose inhaled corticosteroids did not prevent viral exacerba-

tions o wheeze, but that there might be a role or intermittent

high-dose treatment. New evidence has been published on the

treatment o acute exacerbations o episodic wheeze in preschool

children. A Canadian study compared high-dose (1.5 mg daily)

inhaled futicasone against placebo, given at the time o viral

exacerbations o wheeze, and demonstrated benet in terms o

ewer prescribed courses o oral prednisolone. This has to beconsidered a proo-o-concept study; the futicasone-treated chil-

dren had a small reduction in linear growth over the 612-month

study period, and they could not exclude eects on adrenal unc-

tion. It should be recalled that 10% o preschool children have

more than ten viral colds a year, and symptoms may last or at

least 2 weeks, so these high doses may lead cumulatively to a

big total dose o futicasone. Dose-nding studies are needed,

with more detailed saety data, beore this strategy can be

recommended.

Oral prednisolone is the bedrock o treatment or acute exac-

erbations o asthma in older children and adults, and this med-

ication is widely prescribed or acute preschool viral wheeze.


16/51



A previous study recruited preschoolers who had been admit-

ted to hospital or an exacerbation o wheeze, and randomized

them to a parent-initiated course o either prednisolone or pla-

cebo at the time o the next episode. This intervention had no

benet. The group has now reported a randomized double-blind,

placebo-controlled trial in nearly 700 preschool children who

came to hospital with a presumed viral exacerbation o wheeze.

There was no benet o oral prednisolone in this more severegroup either. Thereore one is orced to the conclusion that, in

preschool children with episodic (viral) wheeze, prednisolone

is indicated in secondary care only in children in whom a very

severe or prolonged course is anticipated. Prednisolone should

not be prescribed in primary care or these children. It may

be that prednisolone will benet the highly atopic, multitrig-

ger wheezer who has a viral exacerbation, or children already

admitted to hospital and looking like needing admission to the

intensive care unit, but, in particular in young children, this is

probably the exception.

It may appear to be paradoxical that high-dose inhaled ste-

roids may work whereas oral steroids do not; the (speculative)

explanation may be that the steroid eect is by local vasocon-striction as a topical eect, leading to a reduction in airway cali-

bre by lessening airway oedema.

Treatment of multitrigger wheeze: what works best there

has been a single randomized controlled trial comparing the

addition o either oral montelukast or nebulized budesonide or

placebo to inhaled salbutamol in the setting o episodic (viral)

wheeze. Both budesonide and montelukast treatment led to mod-

est improvements in the severity but not requency o attacks.

Given the side-eect prole, we would recommend intermittent

montelukast as the rst line, with the use o intermittent ICS or

montelukast treatment ailures.

Treatment of multitrigger wheeze i a preschool child

is having symptoms several times per week, and symptomsrespond to inhaled bronchodilators, then a trial o ICS may

be merited. That some preschool children benet rom ICS is

indubitable, in particular those aged 3 years and over, who

are atopic, and who have multitrigger wheeze. However, ben-

et in non-atopics is unlikely, and given the evidence rom

bronchoalveolar lavage and endobronchial biopsy studies that

wheezing at age less than 3 years is usually not an eosinophilic

disease, the use o these medications in such children should

be very limited i they are used at all . I a trial is contemplated,

we recommend a three-stage protocol. The rst step is to intro-

duce ICS or an arbitrary 2-month period in a moderately high

dose (or example, budesonide 400 g twice daily). Symptoms

are assessed at stage two, and the medication discontinued. Ithere has been no response, the symptoms are not steroid-sensi-

tive; i they have disappeared, it is not clear whether this is due

to the medication or the passage o time. I symptoms appear

to respond, but then recur on stopping the medication, then

treatment is restarted, titrating to the lowest dose required to

control symptoms. Only thus will the over-diagnosis o asthma

due to an apparent response to steroid therapy be avoided.

Undoubtedly some preschool children will benet, but equally

without doubt steroids are grossly over-prescribed to young

children.

Treatment of preschool wheeze: summary it is clear that we

need radically to overhaul our current therapeutic practices with

regard to the prescription o oral and inhaled corticosteroids, and

to curtail their use drastically in preschool children.

Astma i t olr cil

Tratmt of mil astma i cilr: missio crp

Current guidelines recommend low-dose inhaled corticosteroids

as rst-line therapy in children with asthma who merit prophy-laxis. Long-acting 2 agonists are introduced at a later step, and

in children, the benets are by no means clear-cut. Data rom

Denmark has shown that, in primary care, more children are

prescribed combination inhalers (Seretide) than inhaled corti-

costeroids. Over a period o less than 10 years the proportion o

school-age asthmatic children prescribed combination therapy

has risen rom 16% to 44%, with no evidence base, and no new

trials and no new evidence-based guideline recommendations to

support such a change. One is orced to the conclusion that this

change is driven by aggressive marketing by the pharmaceutical

industry. This has implications o scal cost, but also, perhaps

more importantly, saety and ecacy. A recent meta-analysis

has highlighted the possible adverse eects o long-acting 2agonists; we accept that the main concern is when they are

used as single agents, without concomitant inhaled corticoste-

roids. Ecacy may be an issue; the Pediatric Asthma Controller

Trial (PACT) was a three-way comparison between montelukast

5 mg at night versus futicasone 100 g twice daily versus futi-

casone 100 g once daily and salmeterol 50 g twice daily. More

than 80 children were completions in each limb o the study.

Montelukast was signicantly inerior to the other regimens

(which were equivalent) in the primary outcome o days when

asthma was controlled. However, the futicasone-only regimen

was better than both the alternatives or some secondary end-

points. The number o children requiring rescue steroid therapy

showed a trend to be smaller in the futicasone group (P< 0.10),and exhaled nitric oxide levels and the improvement in pre-

bronchodilator rst-second orced expired volume (FEV1) were

signicantly better in the futicasone group than either o the

other regimens. Thus, i anything, the evidence avours the

current guideline recommendations, that rst-line prophylaxis

should be with inhaled corticosteroid monotherapy and not

combination treatment. Stand rm against the siren cry o the

marketers!

Tratmt of mor svr paiatric astma: SMART or GOAL?

Two new treatment strategies have been proposed. The data

come largely rom adult studies, but there are enough paediat-

ric data to challenge current dogma. The GOAL (Gaining Opti-mal Asthma ControL) philosophy is that all symptoms can be

abolished by increasing medication (in this case Seretide) to

ever higher levels. The SIGN/BTS target o using short-acting

2 agonist less than three times a week is replaced by the much

more stringent one o requiring no rescue medication at all.

Furthermore, in this study, the dosage having been racked up

to high levels, no attempt at reduction was made over the ol-

lowing 12 months. This strategy, seductive as it may be, seems

to us to have signicant faws. Firstly, it conuses control o

interval symptoms with prevention o exacerbations. Loss o

baseline control is not the same as an exacerbation. It is per-

ectly possible to be symptom-ree between viral colds, but


17/51



still have signicant virus-associated exacerbations. Indeed,

increasing the dose o prophylactic medications in an unavail-

ing attempt to prevent viral exacerbations may well have been

a signicant contributor to the epidemic o severe hypoglycae-

mia secondary to adrenal suppression reported in children on

high-dose inhaled steroids. Secondly, given the tendency or

much childhood asthma to improve, and hence guideline rec-

ommendations to try to reduce therapy when asthma is wellcontrolled, the strategy o no dose reduction seems rather dan-

gerous. Finally, we do not have the data to know whether it is

better in terms o long-term respiratory outcome and systemic

side-eects such as growth ailure to have a ew symptoms

requiring short-acting 2 agonists, with a lower dose o inhaled

corticosteroids, or to have a higher steroid dosage and no symp-

toms. In terms o respiratory outcomes, it should be noted that

in the Childrens Asthma Management Program (CAMP) study,

treatment with inhaled corticosteroids did not prevent around

25% o asthmatic children rom having suboptimal increases in

spirometry with growth. At the moment, this approach cannot

be recommended in children.

The alternative approach, SMART (Symbicort Maintenanceand Reliever Therapy), is a one-inhaler strategy which takes

advantage o the rapid onset o action o the long-acting 2 agonist

ormoterol. This is based on a study comparing three regimens:

budesonide 100 g/ormoterol 6 g once daily plus extra doses o

the same inhaler as required (SMART regimen): the same inhaler

twice daily, with rescue terbutaline; or budesonide 400 g twice

daily with rescue terbutaline. The children in the SMART regi-

men had ewer exacerbations. Perhaps surprisingly, there was

no dramatic increase in ICS use in the SMART regimen, with an

average o less than one extra inhalation per day. This regimen

has the advantage o simplicity, and might possibly increase the

adherence o recalcitrant adolescents, although as yet there is no

evidence or this. O course it relies on the adequate perceptiono symptoms, which is a problem in some asthmatics. Nonethe-

less, this is a regimen we have ound to be useul in clinical

practice. There is an urgent need or a well-designed randomized

controlled trial comparing SMART and GOAL in children with

asthma.

Tratmt of mor svr paiatric astma: gt t

basics rigt

Perhaps one o the most worrying trends in asthma therapeu-

tics is the ever-higher doses o medication being prescribed in

primary care beore a reerral to hospital is made. Perhaps this

seems like special pleading by tertiary care, but we already know

o the hypoglycaemia and adrenal ailure caused by high-doseICS prescribed inappropriately. The approach to a child with

asthma not responding to moderate doses o standard therapy is

not slavishly to increase the therapy, but to ask why there is no

response. The two usual reasons are that the diagnosis is wrong,

or that the child is not getting the treatment. This was under-

scored in a trial recruiting children with asthma uncontrolled on

a minimum o budesonide 400 g twice daily plus salmeterol

50 g twice daily, to determine whether adding azithromycin or

montelukast as supplementary therapy was benecial. Neither

was eective. However, the main signicance o the trial was

that o 292 children evaluated, only 55 went into the trial; the

commonest reasons or non-randomization were non-adherence

to treatment and improved control with proper supervision. In

another study o inner-city asthma, attention to detail in the run-in

period led to a marked attrition o symptomatic asthmatics. So

the really important take-home message is that oten therapy-

resistant asthma is no such thing.

The standard denitions o severe asthma incorporate per-

sistent symptoms or severe exacerbations or both, despite high-

dose standard therapy, usually combinations o high-dose ICS,long-acting 2 agonists and leukotriene receptor antagonists. We

suggest that children meeting this denition require systematic

evaluation rather than escalating trials o treatment. A ull work-

up or alternative diagnoses is essential. I the diagnosis is truly

asthma, then we have suggested the term problematic severe

asthma or this group. A ull multidisciplinary assessment,

including a nurse-led home and school visit, is undertaken to

urther categorize these children. Those with dicult asthma

include children who are non-compliant, have adverse environ-

mental actors, or have psychosocial issues. Their asthma may

still be dicult to treat, but they would not be candidates or

novel molecular-based therapies such as anti-IgE (Xolair). The

second group have severe therapy-resistant asthma (sometimescalled reractory asthma in adult practice), and are worked up

with a series o invasive tests, including bronchoscopy. Indeed,

we recommend this sort o detailed specialist evaluation, which

goes beyond even the NICE (National Institute or Clinical Excel-

lence) guidelines, beore Xolair is prescribed. In our experience,

more than 50% o problematic severe asthmatics need attention

to the basics rather than expensive and potentially dangerous

therapies.

FuRTheR ReAdInG

Bh LB, phlls Br, Zg rS, l. care nwk. es s hl s lk gs

shl hl wh --sv whzg.

J Allergy Clin Immunol 2008; 122: 112735.

B ed, Bsh Ha, Bsq J, l. GoaL ivsgs G.

c gl- sh l b hv? th Gg

ol ash cL s.Am J Respir Crit Care Med2004;

170: 83644.

Bsg H, Hs mn, Ll L, l. i hl

ss s wh s whzg. N Engl J Med

2006; 354: 19982005.

Bsg H, L rx p, Bj d, l. Bs/l

ls lv h: w sg

sh. Chest2006; 130: 173343.

B pL, Bl e, Bsg H, l. d, ssss

whzg ss shl hl: v-

bs h. Eur Respir J2008; 32: 1096110.

dh Fm, L c, n FJ, l. pv s hgh-s

fs vs- whzg g hl. N Engl J

Med2009; 360: 33953.

Glb tW, mg WJ, Zg rS, l. Lg- hl

ss shl hl hgh sk sh. N Engl

J Med2006; 354: 198597.

Hs J, Gll r, H J, l. asss whzg

hs h s 6 s l wh , lg

w ssvss -hlh. Thorax2008; 63: 97480.


18/51



m cS, Wk a, Lgl SJ, l. S v

sh b h s hl fs whz

s (iWWin): bl-bl, s ll s. Lancet

2006; 368: 75462.

o a, Lb pc, Ggg J. e sh s

- l sl vl whz hl

g 15 s: s ll l. Lancet2003; 362:

14338.pk J, Lkhl m, Lb pc, l. ol sl

shl hl wh vs- whzg. N Engl J Med

2009; 360: 32938.

rbs cF, p d, H r, l. Sh-s lks

sh hl: z ll l.Am J

Respir Crit Care Med2007; 175: 3239.

Skss ca, Lsk J. rF, mg dt, l. chlh ash

rsh e nwk h nl H, Lg,

Bl is. Lg- s 3 ll

gs l ss hlh sh: h

p ash cll tl.J Allergy Clin Immunol 2007; 119:

6472.

Sk rc, Bh LB, phlls Br, l. care nwk. azh lks s hl s-sg gs

--sv hlh sh s.J Allergy Clin Immunol

2008; 122: 113844.

Szf SJ, mhll H, Skss ca, l. mg sh bs

xhl x gl-bs

- lss g ls: s ll

l. Lancet2008; 372: 106572.

Practic poits

pshl whz s s sll sb h bss ss s (vl) vss lgg

h h b h s bs

elgl hs (s vss ss)

l b l svl, ll s lg

es (vl) whz shl b wh h

ol sl shl b s b h vsvs k s (vl) whz; s not

- g hs x

i hl ss s shl hl, h-s l, lg l sg h

, shl v gs lbllg

hl s sh

Fs-l hl shl-g hl whsh s lw-s hl ss

i svl sh hl, s x-s b h wh bs/l s

sgl hl g l b s

ms hl wh sh sg sl not q , b vw

h gss vsg hw wll h sb

s ll bg s


19/51



Maaemet of brochiolitisml as

il dll

Abstract

Bhls s h s s hsl ss .

Sv vs l sl-lg hgh s l

qg sv vl. m vss s bhl-

s, h s bg s sl vs (rSV). Sv

s h s , wh hss l

xg h. ags wh v bf b-

hls l 2 gss, , lks, ss,

vl gs sh s bv rSV glbl, hsh,blz xbls bs. i s ssbl h blz

h hs sll sh- , h blz 3% h-

sl s wh bhl s lgh

s hsl. pvv sgs sh s rSV glbl

h -rSV ll b lvzb s ss

sv.

Keywors bhls; bhls; ss; h

sl; rSVItroctioIn 1963 EOR Reynolds concluded that oxygen therapy is vitally

important in bronchiolitis and there is little convincing evidence

that any other therapy is consistently or even occasionally use-

ul. It is arguable that there has been little progress in the sub-

sequent 46 years. Treatments that might be eective include

nebulized 3% hypertonic saline mixed with a bronchodilator,

and ventilatory support or respiratory ailure. For the major-

ity o patients, however, supportive management is the main-

stay, with emphasis on treating insucient fuid intake and

hypoxia.

EpiemioloyBronchiolitis is the commonest cause o hospitalization in

inancy. It usually aects inants aged 16 months, although it

can occur up to 2 years o age, and is usually a mild sel-limiting

illness that does not require medical intervention. It is a clinical

syndrome characterized initially by coryzal symptoms ollowed

Madeleine AdamsMRCPCH is a Specialist Registrar in Paediatrics at the

Cystic Fibrosis/Respiratory Unit, Childrens Hospital for Wales, Cardiff, UK.

Iolo DoullDM FRCPCH is a Consultant Respiratory Paediatrician at the

Cystic Fibrosis/Respiratory Unit, Childrens Hospital for Wales, Cardiff, UK.

by onset o harsh cough, tachypnoea and wheezing. On exami-

nation there may be chest hyperinfation with costal recession,

and ne inspiratory crackles and polyphonic expiratory wheeze

on auscultation.

A signicant contributor to conusion over the management

o bronchiolitis is the absence o an internationally agreed com-

mon denition. In the United Kingdom, Australasia, and parts

o Europe, bronchiolitis is interpreted as the presence o tachy-pnoea, hyperinfation o the chest, and characteristically wide-

spread ne end inspiratory crackles on auscultation. Wheeze is

commonly but not invariably present. The pattern o illness is

virtually always seen in the rst year o lie, most commonly in

the rst 6 months o lie. In contrast, in North America and other

parts o Europe, bronchiolitis is a term or any viral inection o

the lower respiratory tract in the rst 2 years o lie, and may

include children with recurrent wheeze. The conusion over de-

nition is compounded by dierent ty

06 paediatric and child health june2009 pulmonology

Documents