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ASTHMA

B. Beghe and L.M. FabbriDept of Oncology Haematology and Respiratory Diseases, Policlinico diModena, University of Modena and Reggio Emilia, ItalyE-mail: [email protected]

Asthma is a chronic inflammatory disease of

the airways, characterised clinically by

recurrent respiratory symptoms: dyspnoea,

wheezing, chest tightness and/or cough,

almost always associated with reversibleairflow limitation. Other characteristics of

asthma are an exaggerated responsiveness of

the airways to various stimuli, and in most cases

a rather specific chronic inflammation of the

airways characterised by an increased number

of CD4+ Th2 lymphocytes, eosinophils and

methacromatic cells in the airway mucosa, and

increased thickness of the reticular layer of the

epithelial basement membrane.

Familial predisposition, atopy, and exposure to

allergens and sensitising agents are important

risk factors for asthma, even though the

causes of asthma the factors responsible for

the development of asthma rather than itsexacerbations remain largely undetermined.

Asthma is a heterogeneous syndrome that,

over the years, has been divided into manyclinical subtypes, e.g. allergic asthma, adult-onset asthma that is usually nonallergic,occupational asthma, asthma in smokers andasthma in the obese.

Minimum requirements for thediagnosis of asthma

The diagnosis of asthma is based on clinicalhistory and lung function tests, particularly

peak expiratory flow (PEF) and spirometry,with assessment of variable and/or reversible

airflow limitation. Allergy tests are alsousually performed during the first assessmentof a patient with suspected asthma to identifypossible triggers of asthma and to guide theiravoidance.

Asthma clusters in families, and its geneticdeterminants appear to be linked to those ofother allergic immunoglobulin (Ig) E-mediated

diseases. Thus, a personal or family history ofasthma and/or allergic rhinitis, atopicdermatitis or eczema increases the likelihoodof a diagnosis of asthma.

Symptoms and medical history

Most patients with asthma seek medicalattention because of respiratory symptoms. Atypical feature of asthma symptoms is their

variability. One or more of the following

symptoms: wheezing, chest tightness, and/orepisodic shortness of breath are reported by.90% of patients with asthma. However, the

presence of these symptoms is not diagnostic,because identical symptoms may be triggered

Key points

N Asthma is diagnosed based on clinical

history and lung function testing.

Allergy testing may also have a role.

N The differential diagnosis is extensive.

In particular, COPD may be difficult to

distinguish from asthma.

N The goal of pharmacological asthma

treatment is to achieve and maintain

control of symptoms and prevention of

exacerbations.

N Asthma is a chronic, lifelong disease

and must therefore be managed in

partnership with the patient.

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by different stimuli in nonasthmatics, e.g. byacute viral infections. In some asthmatics,wheezing and chest tightness are absent, andthe only symptom the patient complains of is

chronic cough (cough-variant asthma).

Symptoms of asthma may be triggered orworsened by several factors, such as exercise,exposure to allergens, viral infections andemotions. Recurrent exacerbations ofrespiratory symptoms, worsening of lungfunction requiring change of treatment,unscheduled requests for medical assistanceand sometimes hospitalisation are alsoamong the characteristic clinical features of

asthma.

Physical activity is an important trigger ofsymptoms (wheezing and/or cough) for mostasthma patients, particularly children. Forsome, it is the only cause. Exercise-inducedasthma usually develops not during exercisebut 510 min afterwards, and it resolvesspontaneously within 3045 min. Promptrelief of symptoms after the use of inhaledb2-agonist, or prevention by pre-treatmentwith an inhaled b2-agonist before exercise,supports a diagnosis of asthma. Importantaspects of personal history are exposure toagents known to worsen asthma in the home(some types of heating or cooking system,house dust mites), workplace conditions, air-conditioning, pets, cockroaches, environmentaltobacco smoke or even the generalenvironment, e.g. diesel fumes in traffic.

Since the respiratory symptoms of asthma arenonspecific, the differential diagnosis is quiteextensive. The main goal for the physician isto consider and exclude other possiblediagnoses (table 1). This is even moreimportant if the response to a trial of therapy(bronchodilators) has been negative.

While respiratory symptoms suggest asthma,the sine qua non for the objective diagnosis ofasthma is the presence of reversible airflow

limitation in subjects with persistent airwayobstruction, and/or airwayhyperresponsiveness or increased PEF

variability in subjects without airwayobstruction.

Physical examination

In mild asthma, physical examination isusually normal under stable conditions but

becomes characteristically abnormal duringasthma attacks and when asthma is moresevere or uncontrolled. Typical physical signsof asthma attacks are wheezing onauscultation, cough, expiratory rhonchithroughout the chest and signs of acutehyperinflation (e.g. poor diaphragmaticexcursion at percussion, use of accessorymuscles of respiration). Some patients,particularly children, may present with apredominant nonproductive cough (cough-

variant asthma). In some asthmatics,wheezing which usually reflects airflowlimitation may be absent or detectable onlyon forced expiration, even in the presence ofsignificant airflow limitation; this may be dueto hyperinflation or to very marked airflowlimitation. In these patients, however, theseverity of asthma is mostly indicated by othersigns, such as cyanosis, drowsiness, difficulty inspeaking, tachycardia, hyperinflated chest, use

of accessory muscles and intercostal recession.

Lung function tests

Spirometry Lung function tests play acrucial role in the diagnosis and follow-up ofasthma. Spirometric measurements FEV1and slow vital capacity (VC) or forced vitalcapacity (FVC) are the standard means forassessing airflow limitation. Spirometry isrecommended at the time of diagnosis and for

the assessment of the severity of both asthmaand chronic obstructive pulmonary disease(COPD). It should be repeated to monitor thedisease and when there is a need forreassessment, such as during exacerbations.

Measurements of residual volume and totallung capacity may also be useful indetermining the degree of hyperinflation and/or enlargement of airspaces. Lung volumes

may help in the differential diagnosis withCOPD, but are not necessary for the diagnosisnor for the assessment of severity of asthma.In asthma, airflow limitation is usuallyreversible, either spontaneously or after

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treatment, except for moderate/severe asthmawith fixed airway obstruction (see below).

An important tool for the diagnosis andsubsequent monitoring of asthma treatment is

the PEF meter. If spirometry does not reveal

airflow limitation, the home monitoring of PEFfor 24 weeks may help to detect anincreased variability of airway calibre, and

thus to diagnose. Daily monitoring of PEF (atleast in the morning at awakening and in theevening hours, preferably after bronchodilatorinhalation) is also useful to assess the severity

of asthma and its response to treatment, andit can help patients to detect early signs ofasthma deterioration. Diurnal variability iscalculated as follows:

(PEFmax PEFmin) / [(PEFmax+ PEFmin) / 2]6 100

A diurnal PEF variability of.20% isdiagnostic of asthma, and the magnitude ofthe variability is broadly proportional todisease severity. PEF monitoring may be of usenot only in establishing a diagnosis of asthmaand assessing its severity but also inuncovering an occupational cause for asthma.

When used in this way, PEF should bemeasured more frequently than twice daily,and special attention should be paid tochanges occurring in and out of theworkplace.

Reversibility to bronchodilatorsReversibility to bronchodilators (i.e. a .12%reversibility response and .200 mL in FEV1after bronchodilator) confirms the diagnosisof asthma. Poorly reversible airflow limitation

is usually defined by the absolute reduction ofpost-bronchodilator FEV1/FVC ratios to ,0.7.However, because this parameter decreaseswith ageing, it should be confirmed withpostbronchodilator FEV1/VC values below thelower limit of normal. Reversibility is often notpresent at the time of examination,

Table 1. Differential diagnosis of asthma

Localised pathologyInhaled foreign body

Endobronchial tumour

Vocal cord dysfunction

Diffuse airway pathologyChronic obstructive pulmonary disease

Eosinophilic bronchitisPost-infectious airway hyperresponsiveness

Cystic fibrosis

Bronchiectasis

Left ventricular failure

Other pathologiesGastro-oesophageal reflux

Pulmonary embolismPulmonary eosinophilia syndromes

Drug-induced airway hyperresponsiveness

Table 2. History, symptoms and results of pulmonary function tests in the differential diagnosis between asthma andCOPD

Asthma COPD

Onset Mainly in childhood In mid to late adult life

Smoking Usually nonsmokers Almost invariably smokers

Chronic cough and

sputum

Absent Frequent (chronic bronchitis)

Dyspnoea on effort Variable and reversible to

treatment

Constant, poorly reversible and

progressive

Nocturnal symptoms Relatively common Relatively uncommon

Airflow limitation Increased diurnal variability Normal diurnal variability

Response tobronchodilator

Good Poor

Airway

hyperresponsiveness

In most patients, with or with-

out airflow limitation

In most patients with airflow limitation

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particularly in patients on treatment, and thusthe absence of reversibility does not excludethe diagnosis. However, repeated testing ofreversibility of both clinical features andfunctional abnormalities may be useful in

obtaining the best level of asthma controlachievable and/or the best lung function forindividual patients. Achieving andmaintaining lung function at the best possiblelevel is one of the objectives of asthmamanagement.

Airway hyperresponsiveness In patientswho have symptoms consistent with asthma

but who have normal lung function, bronchialprovocation tests with methacholine,histamine or exercise are helpful in measuringairway hyperresponsiveness and therebyconfirming or excluding the diagnosis of

active asthma. These measurements are verysensitive, but poorly specific for a diagnosis ofasthma. This means that while a negative testcan be used to exclude a diagnosis of activeasthma, a positive test does not always meanthat a patient has asthma. While themeasurement of airway hyperresponsiveness

may be useful to confirm asthma in subjectswith normal baseline lung function, it is notuseful in presence of nonreversible airflowlimitation, and thus in the differentialdiagnosis between asthma and COPD.

Arterial blood gases

In severe asthma and, more importantly,during acute exacerbations of asthma, themeasurement of arterial blood gases while thepatient is breathing air and/or after oxygen

administration is essential for the diagnosis ofchronic and/or acute respiratory failure. Thistest should be performed in all patients with

clinical signs of acute or chronic respiratoryand/or heart failure, and anyway in patientswith a PEF ,50%, those who do not respondto treatment and those with an arterial

oxygen saturation f92%.

Allergy tests

The presence of allergic disorders in apatients family history should be investigatedin all patients with symptoms of asthma. A

history provides important information aboutthe patients lifestyle and occupation, both ofwhich influence exposure to allergens and the

time and factors possibly involved in onsetand in exacerbations of asthma. Skin testswith all relevant allergens present in thegeographic area in which the patient lives are

the primary diagnostic tool in determiningallergic status. Measurement of specific IgE isnot usually more informative than a skin test,and is more expensive. Measurement of total

IgE in serum has no value as a diagnostic test

Table 3. Ancillary tests in the differential diagnosis between stable asthma and COPD

Ancillary test Asthma COPD

Reversibility to bronchodilator and/or

glucocorticosteroids

Usually present Usually absent

Lung volumes

Residual volume, total lung

capacity

Diffusing capacity

Usually normal or, if increased,

reversible

Normal

Usually irreversibly

increased

Decreased

Airway hyperresponsiveness Increased Might be increased but

usually not measurable due

to airflow limitation

Allergy tests Often positive Often negative

Imaging of the chest Usually normal Usually abnormal in

advanced stagesSputum Eosinophilia Neutrophilia

Exhaled nitric oxide Increased Usually normal


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for atopy. The main limitation of methods to

assess allergic status is that a positive test

does not necessarily mean that the disease is

allergic in nature or that it is causing asthma,

as some individuals have specific IgE

antibodies without any symptoms and it maynot be causally involved. The relevant

exposure and its relation to symptoms must

be confirmed by patient history.

Additional tests

While the diagnosis and assessment of severity

of asthma and COPD can be fully established

on the basis of clinical history and lung function

tests (including arterial blood gases see

below), additional tests might be helpful to

better characterise individual patients.

Imaging While chest radiography may beuseful to exclude diseases that may mimic

asthma, it is not required in the confirmationof the diagnosis and management of asthma.

The utility of chest radiography is to excludeother conditions that may imitate orcomplicate asthma, particularly acute asthma.

Examples include pneumonia, cardiogenicpulmonary oedema, pulmonarythromboembolism, tumours (especiallythose that result in airway obstruction with

resulting peripheral atelectasis) andpneumothorax.

Assessment of airway inflammationWhile airway biopsies and bronchoalveolarlavage may provide useful information in

research protocols, they are considered tooinvasive for the diagnosis or staging of

asthma. By contrast, noninvasive markers ofairway inflammation have been increasinglyused in research protocols, particularly to

Figure 1. Asthma management approach based on control for children aged .5 yrs, adolescents and adults.Alternative reliever treatments include inhaled anticholinergics, short-acting oral b2-agonists, some long-acting

b2-agonists, and short-acting theophylline. Regular dosing with short and long-acting b2-agonist is not advisedunless accompanied by regular use of an inhaled glucocorticosteriod. ICS: inhaled corticosteroids; IgE:

immunoglobulin E. #: Preferred controller options are shown in shaded boxes; ": inhaled glucorticosteroids;+: Receptor antagonist or symthesis inhibitors. Reproduced from the Global Strategy for Asthma Management

and Prevention, with permission.

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differentiate asthma from COPD and measureresponse to treatment.

Exhaled nitric oxide Exhaled nitric oxide(NO) is increased in atopic asthma, but less soin nonatopic asthma. It is reduced byglucocorticosteroids, but not bybronchodilators. Measurement of airwayinflammation is not required for the diagnosis,assessment of severity and/or treatment ofasthma in clinical practice.

Differential diagnosis between asthma

and COPD

In most patients, the clinical presentation andparticularly the history provide the strongestdiagnostic criteria to distinguish asthma fromCOPD (table 2). Pulmonary function tests,particularly spirometry, that show a nearlycomplete reversibility of airflow limitation mayhelp to confirm a diagnosis of asthma, andthose that show poorly reversible airflowlimitation may help to confirm the diagnosis

of COPD (table 2). Differential diagnosisbetween asthma and COPD becomes moredifficult in elderly patients, in whom somefeatures may overlap, such as smoking andatopy and, more importantly, when the

patient develops poorly reversible airflowlimitation that responds only partially to

treatment. In these cases, symptoms, lung

function, airway responsiveness, imaging andeven pathological findings may overlap andthus may not provide solid information for the

differential diagnosis. Because the differentialdiagnosis mainly aims to provide bettertreatment, it is important in these cases to

undertake an individual approach and toperform additional tests. Reversibility tocorticosteroids alone or in combination with

long-acting bronchodilators, measurements of

lung volumes and diffusing capacity, analysisof sputum and exhaled NO, and imaging ofthe chest may demonstrate whether asthma or

COPD is the predominant cause of airflowlimitation (table 3). In contrast, reversibility to

bronchodilator and assessment of airwayhyperresponsiveness or skin testing may notbe useful in these patients.

Comorbidities of asthma

The coexistence of chronic rhinitis, nasalpolyposis and sinusitis may contribute to theseverity of asthma.. There is broad evidence toshow that adequate treatment of these upper

airway diseases is beneficial to asthma by

Table 4. Levels of asthma control

Characteristic Controlled(all of the following)

Partly controlled(any measurepresent in any week)

Uncontrolled

Daytime symptoms None

(twice or less per week)

More than twice per

week

Three or more features

of partly controlled

asthma present in any

weekLimitations of

activities

None Any

Nocturnal symptoms/awakening

None Any

Need for reliever/rescue treatment

None

(twice or less per week)

More than twice per

week

Lung function

(PEF or FEV1)#

Normal ,80% predicted or per-

sonal best (if known)Exacerbations None o1 per year" One in any week+

PEF: peak expiratory flow; FEV1: forced expiratory volume in 1 s. #: Lung function is not a reliable test for children

aged f5 yrs; ": any exacerbation should prompt a review of maintenance treatment to ensure it is adequate;+: by definition, an exacerbation in any week makes that an uncontrolled asthma week. Reproduced from the Global

Strategy for Asthma Management and Prevention, with permission.


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Criteria for severe episode:

History of risk factors for near fatal asthma PEF 70% O2saturation >90%

(95% children)

Reassess at intervals

Poor response (see above):

Admit to intensive care

Incomplete response in 6_12 h (see above)

Consider admission to intensive careif no improvement within 6_12 h

Incomplete response within 1_2 h:

Risk factors for near fatal asthma

Physical exam: mild to moderate signs PEF

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mechanisms not clearly understood. The oneairway concept developed by the WorldHealth Organization ARIA Group has drawnattention to the importance of treating the

whole respiratory tract when managingasthma. Gastro-oesophageal reflux is alsooccasionally associated with asthma, both inadults and in children, but treatment of refluxusually has little overall effect on mild-to-moderate asthma. A frequent and quiteimportant comorbidity of asthma in adults isCOPD, most probably due to smoking, which isquite common in asthmatics. Smoking modifiesthe airway pathology of asthmatics to a COPD-

like pattern and reduces the response totreatment. Comorbidities may becomeimportant in severe asthma, whereas they playa much less important role overall in the clinicalmanifestations of mild-to-moderate asthma.

Management

Considering its chronic nature and lifelongduration, asthma can be effectively managedonly by developing a partnership between thepatient and his or her doctor or healthprofessional, that may provide the tools for aguided self-management (possibly written) planincluding self-monitoring, and periodic reviewof treatment and level of asthma control.Education plays a major role in this partnership.

Long-term pharmacological treatment

The main goal of pharmacological asthmatreatment is to achieve and maintain control ofsymptoms and prevention of exacerbations(table 4) using the safest treatment algorithm.While the initial treatment should be startedaccording to the level of severity at the first

visit, subsequently treatment should beadjusted according to the level of controlachieved (fig. 1). Usually regular treatment islowered only after a significant period ofacceptable control, e.g. not,3 months. Thismeans that monitoring of asthma is essentialto maintain control and to establish the lowest

step and dose of treatment. Step-up and step-down of treatment is not standardised, andthus should be tailored to the individualpatient to achieve and maintain control withthe minimum amount of medication.

Medications to treat asthma can be classifiedas controllers or relievers. Medications arepreferably administered by inhalation, as it ismore efficacious and has fewer side-effects.

Controllers (inhaled glucocorticosteroids aloneor in combination with long-acting b2-agonists)are medications to be taken daily, over the longterm, to keep asthma under clinical control. Inasthma, long-acting b2-agonists should be usedonly in combination with inhaledcorticosteroids when the latter are insufficient

to achieve control, and should be discontinuedonly when control is maintained for asufficiently long time (e.g.o3 months).

Only in patients not controlled by full doses ofinhaled glucocorticosteroids combined withlong acting b2-agonists may other secondary

agents be considered (anti-leukotrienes,theophylline, systemic steroids, monoclonalanti-IgE antibodies in very specific cases).

Relievers (rapid-acting b2-agonists alone or incombination in combination with inhaledsteroids) are medications used on an as-

needed basis that act quickly to reversebronchoconstriction and relieve its symptoms.Ideally, if patients are adequately controlled,they should not need rescue medications.

Allergen immunotherapy may be considered inpatients with asthma caused by specificallergens for which there are standardisedextracts. Only patients with single or two similarallergen sensitivities whose role is confirmed bythe history and who have preserved lung

function are candidates for this treatment(which, however, has limited efficacy and is longand relatively expensive). Specificimmunotherapy should be considered only afterstrict environmental avoidance andpharmacological interventions, including inhaledglucocorticosteroids, have failed to control thedisease. Smoking asthmatics are resistant to anti-asthma medications and should be primarilytreated for smoking addiction. Smokers with

asthma may develop features of COPD.Treatment of exacerbations

Shortness of breath, cough, wheezing, and/orchest tightness may develop or worsen


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recurrently in subjects with asthma even whenthey are under regular treatment. Milderexacerbations are usually managed by thepatient with an increased as-needed use of

rapid acting b2-agonists alone or incombination with inhaled steroids. Moresevere exacerbations or exacerbations that donot respond to the increased use of rescuemedications require repetitive administrationof rescue medication and systemic, preferablyoral, glucocorticosteroids, associated in the

very severe cases with oxygensupplementation (fig. 2). Severeexacerbations require medical attention or

even hospital admission.Special considerations

Special considerations are required forpatients with specific conditions and/orcomorbidities, e.g. rhino/sinusitis and/or nasalpolyps, aspirin-induced asthma particularly ifassociated with episodes of anaphylaxis,occupational asthma or obesity.

Additionally, patients with asthma should be

informed that they may require specificmedical attention in case of smokingaddiction, pregnancy, surgery or infections(e.g. influenza epidemics).

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