Pediatry 2 (Licari) 08.10.

19
Sbob: Parisotto
Topics covered:
Rev: Bertazzoni
 Acute viral bronchiolitis
- Definition and epidemiology
- Etiology, pathogenesis and risk factors
- Clinical evolution
- Investigations and severity assessment
- Treatment, immunoprophylaxis and prevention
 Asthma
- Etiology and pathobiology
- Classification and diagnosis
- Asthma control and treatment

RESPIRATORY DISORDERS IN CHILDREN1

ACUTE VIRAL BRONCHIOLITIS

Bronchiolitis and asthma are the major obstructive diseases seen in children.

Definition and epidemiology

Bronchiolitis is one of the most common respiratory disorders in the first year of age.
It is an acute viral respiratory infection involving the terminal bronchioles, the smallest part of the respiratory
tract. The infection and inflammation involving bronchioles results in small airway obstruction, determining an
obstructive respiratory disease.
The diagnosis is clinical, based on typical clinical history and on typical findings at physical examination:
therefore, the diagnosis can be reached thanks to clinical symptoms.
According to the clinical definition, it is a seasonal viral illness: viruses are the major pathogens targeting the
small bronchioles, causing fever, nasal discharge, dry cough and respiratory distress, which is the main reason
for hospitalization. On examination there are diffuse fine inspiratory crackles and rare pitched expiratory
wheezing.
From a pathological point of view, bronchiolitis is determined by acute inflammation, edema and necrosis of
epithelial cells lining terminal and respiratory bronchioles, leading to increased mucous production and
mononuclear cell infiltrates that cause airway obstruction.
Bronchiolitis is the most frequent infectious disease in the first year of age: 90% patients are younger than 9
months; this disease is the leading cause of hospitalization in these children. The main respiratory viruses
causing bronchiolitis are Respiratory Syncytial Virus (RSV) and Rhinovirus: they account for 80% of bronchiolitis
cases, and they are typically endemic from autumn until spring. Around 70% of all infants will be infected with
RSV or a respiratory virus in their first year of life.
Despite being a very common disease, only 22% of affected children will develop respiratory symptoms that
involve the lower airways: the most common clinical presentation is common cold. Of these 22%, only 2-3% are
admitted to the hospital, the most part of such patients can be treated at home, of the hospitalized children,
only 2% will require intubation and mechanical ventilation in intensive care unit.
As already said, there is a seasonal epidemic of bronchiolitis in the months from November to April.
The transmission is frequent and person-to-person, through airborne droplets with secretions and hand contact
after touching infected material: it is important to wash hands after visiting patients to prevent the diffusion of
respiratory viruses.
The incubation period lasts about 5 days.

1
The professor works in the pediatric allergology, immunology and respiratory disorders clinic
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Etiology
Bronchiolitis is a viral disease, and the main respiratory viruses are:
 Respiratory Syncytial Virus, accounting for 50-80% of bronchiolitis cases. There are two phenotypes, A and
B, and their virulence is the same: there are not many differences between these two types
 Human Rhinovirus, the main pathogen of common cold in adolescents and adults
 Parainfluenza virus, which is responsible for 5-25% bronchiolitis cases
 Human metapneumovirus
 Coronavirus
 Adenovirus
 Influenza virus
 Enterovirus

Pathogenesis
Viruses cause a direct injury to the airways, leading to epithelial cell necrosis. Those cells desquamate and
collect in the airways, forming mucous plug that obstructs the airways themselves.
Viruses attach to cells through fusion proteins, which are pathogenic, causing epithelial cell inflammation
resulting in necrosis and mucous formation.
In the obstructive phase, inflamed cells cause obstruction in the small bronchi, and alveolar collapse (a sort of
atelectasis): a large area of the lung can be collapsed, so O2 does not mix with blood.

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In the healthy bronchiole, the lumen is open, instead
in bronchiolitis there is obstruction caused by mucous,
sloughed cells and fibrin.

It is very important to know the pathogenesis of this

disease because the therapeutic management is not
specific: the treatment is supportive.
It is not possible to use corticosteroids nor
bronchodilators because they cannot act in this phase:
even with bronchodilators, most of the bronchial
obstruction is not resolved.

Risk factors for severe disease

Some patients are at higher risk of bronchiolitis, particularly of severe disease:
 Age < 3 months of life (neonates)
 Significant comorbidities
˗ Prematurity (< 35 weeks of gestational age)
˗ Cardiopathic: hemodynamically significant congenital heart disease
˗ Chronic lung disease
˗ Neuromuscular disease, particularly at risk of ICU admission
˗ Immunodeficiency
 Atopy
 Social factors
˗ Parental smoking: bronchiolitis is more common in children whose parents smoke because they are
more at risk of many respiratory infections
˗ Number of siblings and nursery or daycare attendance: sharing the same environment and close
contacts predispose to severe bronchiolitis
˗ Breastfeeding: it is a protective factor. Mothers are usually advised to breastfeed their child because
it is a protective factor for other childhood infections
˗ Socioeconomic deprivation

Clinical evolution
Disease evolution is very long: bronchiolitis can last up to 22 days, presenting with symptoms.
Usually the symptomatic peak occurs after five days of incubation, with rhinorrhea and fever (the latter might
or might not present).
From day 5 to day 10, there is persistent cough, increased work of breathing with respiratory distress and a
typical clinical examination with fine crackles at auscultation.
The coryzal prodromes last 1-3 days.
Peak respiratory symptoms and dehydration occur between day 3-5.
Cough resolves in 90% infants within 3 weeks.
Children with acute bronchiolitis might present with a wide range of clinical symptoms, from mild respiratory
distress to incipient respiratory failure.
Therefore, a careful physical examination (rhinorrhea, crackles, cough, wheezing, dyspnea, polypnea, feeding
difficulties, apnea, lethargy) combined with the collection of clinical history (to assess the course of the disease
and to capture any high risk condition) are warranted as the cornerstone of the diagnosis of bronchiolitis.
Despite lasting up to 22 days, bronchiolitis and respiratory symptoms usually resolve.

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Symptoms and signs
Fever is an uncommon symptom (high fever in 30% patients), and especially if it is high it should raise the
suspicion of bronchiolitis complicated by pneumonia: the most common pathogens of pneumonia in children
are viruses, so if bronchiolitis extends to a whole lobe or to the whole lung, then the patient has a pneumonia
caused by the same pathogen as bronchiolitis. Pneumonia usually requires hospitalization. In the presence of
high fever, it is crucial to carefully evaluate other causes. Only 1.2% infected children are superinfected by
bacteria, so in case of pneumonia the first suspected causative agent should be viruses, only if these are
excluded it is possible to suspect bacteria.
Another typical and early symptom is dry wheeze cough (wheezing); it resembles asthma, but these patients
are too young to be affected by such a disease.
The cornerstones at physical examination are fine crackles (inspiratory crackles in all lung fields are common;
high pitched wheezes are not common) and wheezing.
Patients with respiratory distress will present with a higher respiratory rate, increased work of breathing
(subcostal, intercostal and supraclavicular recessions as well as nasal flaring are commonly seen) and apnea.
Apnea is a negative prognostic factor, that must be considered as one of the mandatory criteria when making
the decision of hospitalizing these children. It is important to ask parents if their child has apnea while sleeping.
Apnea can be the presenting feature.
Some patients present with poor feeding: many infants have feeding difficulties, and this is another mandatory
criterion for hospital admission.
Another sign is rhinorrhea, i.e. nasal discharge that precedes the onset of acute respiratory symptoms.

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Droplets from infected contact, combined with possible risk factors for severe disease, cause injury in small
bronchioles: this worsens patient’s conditions leading to hospitalization if the child presents with poor feeding,
increase in work of breathing or moderate to severe respiratory distress.
Such children can also develop dehydration and metabolic acidosis: it is important to perform an hemogas
analysis and a metabolic evaluation. Hyponatremia is also associated with dehydration and lung disorders in
children. SIADH (syndrome of inappropriate antidiuretic hormone secretion) is common in infants with severe
respiratory distress and can cause hyponatremia and accidental fluid overload.

Bronchiolitis is a dynamic disease and its clinical characteristics can quickly change.

When to suspect pneumonia

 High fever (above 39° C)
 Persistent focal crackles
 Antibiotic therapy is justified in children who require intubation and mechanical ventilation for respiratory
failure

Investigations
What is to be considered is O2 saturation, blood gases and clinical history, to decide if the patient can be
hospitalised.

O2 saturation
One of the cornerstones in evaluation of children with respiratory distress syndrome in general: it should be
performed in every child attending the hospital with acute bronchiolitis. When its value is < 92%, this is the cut
off recommended by several guidelines (valid also for asthma and other respiratory conditions) that is required
inpatient care. When SaO2 is between 92-94%, it is possible to consider other factors, such the clinical
assessment, family availability and level of support in taking care of the child (social factors), and illness phase.
When SaO2 is 94-100%, the patient can be discharge if he does not present any other risk factor or complication
at examination.

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Blood gases
Blood gases evaluation is not a standard of care in diseased children, this is usually performed when the patient
is admitted in ICU: they may have a role in the assessment of infants with severe respiratory distress. SaO2 and
arterial PaCO2 values must be considered in the context of ventilation: the child in ICU can be intubated and
mechanically ventilated, or he can be supported by high positive pressure ventilation. These two parameters
best predict the need for high concentration O2 therapy.

Chest X-Ray
Not routinely performed, only in selected cases when there is a
suspicion of pneumonia, a complicated course of infection, a
suspicion of pneumothorax or a complication during the hospital
stay: therefore, it is carried out in case of diagnostic uncertainty or
atypical disease course.
In the ER, X-Ray is not performed on all children with bronchiolitis
because the diagnosis is clinical.
The typical findings of bronchiolitis are:
 Flattening of diaphragm (blue)
 Lung hyperinflation (yellow)
 Peribronchial infiltrate (red)
However, there are also non-specific findings that are common also
to asthma and other obstructive lung diseases.

Haematology and biochemistry

The guidelines do not recommend performing a full blood count nor biochemistry. Urea and electrolytes are
carried out only in case of severe disease, when the child is dehydrated or when there is the need of
distinguishing between a viral of bacterial infection: when a bacterial superinfection is suspected, it is important
to perform PCR or procalcitonin.

Microbiological examination: virological and bacteriological testing

A rapid microbiological examination is performed via nasal swab. It is possible to perform a PCR to detect RSV,
rhinovirus and other respiratory viruses in order to reach a microbiological diagnosis, although the majority of
affected children assisted at home do not need this type of exam. Rapid testing for RSV is recommended in
infants who require hospital admission with acute bronchiolitis.
The same is true for bacteriological testing: exams on blood and urine are not routinely indicated in infants with
typical acute bronchiolitis; they are performed only in cases in which the course of the disease is complicated,
for example, by sepsis or bacterial pneumonia with sepsis, particularly in young infants. Bacteriological testing
of urine should be considered in febrile infants < 60 days old.

Severity assessment
It includes the evaluation of feeding, the respiratory rate, chest wall recession, the nasal flare or grunting (heard
at clinical examination), SaO2, general behaviour. This chart is specific for bronchiolitis, but the same assessment
can be used for any kind of respiratory distress.
The disease can be classified as mild, moderate or severe according to the value of these parameters.

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Admission criteria
Hospital
 Persistent oxygen saturation of less than 92% when breathing air.
 Inadequate oral fluid intake (50-75% of usual volume)
 Persisting severe respiratory distress (grunting, marked chest recession, respiratory rate of more than 70
breaths/min)
 Apnoea (observed or reported)
 Risks factors for more severe bronchiolitis

ICU
 Failure to maintain oxygen saturations of greater than 92% with increasing oxygen therapy.
 Deteriorating respiratory status with signs of increasing respiratory distress and/or exhaustion
 Recurrent apnoea

Treatment
Every child with bronchiolitis should be hospitalised when he presents with moderate to severe disease (1-3%
cases); in case of mild bronchiolitis, it is possible to consider all the disease factors as well as the family and
social factor (the capacity of the parents to assist their child at home).
There is great variability in the clinical approach to treatment of bronchiolitis.
In the hospital, saturation is monitored and O2 is administered: O2 support is essential when SaO2 < 92%.
Affected children must also be supported by hydration: a nasogastric tube or the endovenous route of hydration
is usually considered.
In case of apnoea or respiratory distress, patients are admitted to ICU, particularly when simple O2 or high-flow
nasal cannula fail to maintain a normal SaO2, or in case of a deteriorating respiratory status, the so-called
impending respiratory failure, or a full-blown respiratory failure.

Supportive therapy
The treatment is essentially supportive, there is no specific therapeutic agent against RSV nor rhinovirus: the
only possibilities are prevention and supportive treatment.
It is based on fluid administration by nasogastric tube or intravenously (if patients cannot take enough fluids by
mouth). Consider upper airways suctioning, because bronchiectasis might obstruct the upper airways, too: it
has been demonstrated that when upper airways are suctioned, SaO2 improves; this is usually performed in
children who have respiratory distress or feeding difficulties because of upper airway secretions. Perform upper
airway suctioning in children with bronchiolitis presenting with apnoea even if there are no obvious upper
airway secretions. Do not routinely perform upper airway suctioning in children with bronchiolitis.
Suctioning should be superficial, gently and not frequent.
Chest physiotherapy on children with bronchiolitis who do not have relevant comorbidities is not indicate.
Physiotherapy consists in moving secretions, and it is usually a passive physiotherapy in young infants; it is
possible to perform clapping, so that the mucous moves up and down: the child coughs. Chest physiotherapy is
therefore not usually recommended.

O2 administration
Infants with oxygen saturation levels <92% should receive supplemental O2 by nasal cannula or face mask.
Humidified, heated, high-flow nasal cannula (HFNC) is the mainstay of treatment: it allows to deliver a mixture
of air and O2 at high flow, which mechanically opens the small airways (collapsed alveoli) by pressure. This can
also be performed in intensive care, although they prefer to use C-PAP or intubation and mechanical ventilation
in case of severe disease.
HFNC therapy has been introduced in management because it is feasible and well-tolerated; most patients are
scared of this treatment because the high O2 flow might cause discomfort to children, but this therapy solves
the respiratory distress in a short time (few minutes-hours).

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HFNC improves respiratory effort and generate continuous positive airway pressure. HFNC reduces work of
breathing and may decrease need for intubation.

Bronchodilators
There are several international guidelines for bronchiolitis2, as well as an Italian consensus on bronchiolitis
management. All of these guidelines suggest not to use bronchodilators, because the pathogenesis of
bronchiolitis is based on obstruction by mucous plugs, so there is not a constrictive muscle inflammation (as in
asthma), but rather an inflammation causing cell necrosis. Therefore, bronchodilators do not work: they do not
improve oxygen saturation, do not decrease the need for and length of hospital stay, nor do they reduce overall
duration of symptoms.
It is possible to perform a therapeutic trial in the ER, since a favourable response to bronchodilators may be
observed in a number of cases, with salbutamol: if it works, it can be used 2/3 times/day to support the
treatment (however, this is not usually the case). A single therapeutic trial with salbutamol by aerosol may be
considered, in particular in children with a family history of allergy, asthma and/or atopy. This therapy should
not be continued lacking a documented clinical improvement (decrease of respiratory rate and/or respiratory
effort) 15-30 minutes after the trial inhalation treatment.
3
This is true also for mucolytics: they are not recommended in any obstructive respiratory disease in children,
because they usually worsen mucous plugs, since mucolytics increase mucous production. Mucous moves up
and down in the airways, leading to plug formation and extensive atelectasis. Children cough more with
mucolytics, but they are not able to expectorate as efficiently as adults.

Nebulised hypertonic saline solution

Nasal suction is performed with nebulised therapy with saline solution: it is possible to use either they
hypertonic 3% saline solution or the normal saline. Hypertonic saline has an osmotic power, so it recalls mucous
and it is anti-edemigen: it improves clinical scores and length of hospital stay; however, the use normal or
hypertonic saline does not lead to differences in outcome.
Nebulized hypertonic saline has been used both in the mild and in the moderate-severe forms of the disease in
the outpatient settings and in hospital. The mechanism of action of nebulized hypertonic saline solution seems
to be linked with a decrease of airway edema, improved ciliary clearance of mucus and decreased respiratory
secretion viscosity.
It is administered by aerosol, and it is effective and well-tolerated also in neonates and in young children.
Aerosol administration of hypertonic 3% saline solution is effective and well tolerated (uncomplicated by onset
of bronchospasm) even when not administered in association with bronchodilators. According to available
studies, examined in a recent Cochrane, hypertonic saline has been administrated every 2 hours in hospitalized
patients during the initial treatment phase (the first 6-8 hours), and every 4-6 hours thereafter. At the
Emergency Room, instead, 2-3 consecutive doses have been administrated even less than every 2 hours (30
minutes). The most widely used saline solution volume in these studies is 4 mL. No significant adverse events
related to hypertonic saline inhalation, such as tachycardia, hypertension, pallor, tremor, nausea, vomiting and
diarrhea were observed in these trials. The inhalation therapy was administered via pneumatic nebuliser in
most of the studies, but further studies are required to compare different nebulisers.
What is important to make clear with the parents is that bronchiolitis solves alone, it is only possible to perform
a supportive therapy.

The American Academy of Paediatrics (AAP) has recently published a paper summarising the therapeutic
management of bronchiolitis. All therapeutic agents have been studied in large, multicentre, randomised trials
and the conclusion is that Bronchodilators and epinephrine4 are not recommended, as well as corticosteroids5:
they do not provide any evidence of benefitting the patients. The same is true also for chest physiotherapy.

2
They can be found on PubMed
3
Answer to student question.
4
Even though epinephrine can be used in cough and pharyngitis, and it usually works thanks to its vasoconstrictive effect
in the airways, therefore it reduces the oedema and opens the airways.
5
Many children with bronchiolitis are treated with dexamethasone or prednisolone, although they do not work in this type
of inflammation.
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Antimicrobial therapy is not allowed for routine use, it is useful only when a serious bacterial infection is
suspected. Nutrition and hydration and supplemental O2 therapy are recommended.

Management algorithm (skipped)

Discharge criteria
When the clinical course of infection has resolved, children can be discharged according to the following criteria:
 Clinically stable patient
 Taking adequate oral fluids
 Maintained SaO2 > 92% in air for 4 hours (after stopping O2 supplementation), including a period of sleep
(therefore, no apnoea)

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Immunoprophylaxis
As already said, there is no specific therapy against bronchiolitis; what is possible to do is immunoprophylaxis.
One of the agents that can be considered is Palivizumab, a humanised monoclonal antibody specifically against
RSV: it has been licensed 3 year ago only for children with a very high risk of disease. It is administered during
the 5 months of viral seasonality through a monthly intrmuscular injection, performed in the hospital.
Palivizumab prevents the hospital admission for RSV infections, but does not decrease the length of stay or
oxygen requirements for those who are hospitalised.
In Italy, the patients advised for immunoprophylaxis with Palivizumab are:
 Pre-term infants, particularly when they were born < 29 weeks of gestation because they might have
bronchodysplasia, respiratory distress during the first days of life, immaturity for physiological respiratory
condition.
 Infants born < 32 week of gestation with chronic lung disease, particularly when they require O2
supplement in their first month of life, i.e. bronchodysplastic children.
 Infants with congenital heart disease, particularly acyanotic disease.
The dosage is the same for each at-risk group.
Palivizumab is not recommended in children with neuromuscular disease, it is not safe in children with
immunodeficiency or in at-risk children, for example affected by Down syndrome, who are prone to recurrent
respiratory infections.

Prevention
The other cornerstone is prevention, mainly among professional figures in the hospital by washing hands before
and after contacting patients. Patients should be admitted in the hospital in a single room in order to be
isolated; it is equally important to restrict hospital visit to these children due to the diffusion of these viruses:
they can cause epidemics within the hospital.
The hope for the future is to be able to develop a vaccine against RSV: probably in 2-3 years it will be possible
to start trials for this preventive therapy. It will be administered to mothers in the last trimester of gestation.

Key points
 Bronchiolitis is the first episode of acute viral infection of terminal and respiratory bronchioles in infants
<1 year of age.
 Symptoms of bronchiolitis are moderate-to-severe respiratory distress with rales at auscultation.
 Supportive therapies aim to keep the upper airways clear, and the infant oxygenated and hydrated.
 A bronchodilator mixed with 3% hypertonic saline might be tried and this combination should be continued
only if it achieves a documentable clinical benefit.
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 ASTHMA

Asthma is one of the most common chronic conditions in children, together with obesity. It is a common and
potentially serious disease that can be controlled but not cured.
It is characterised by typical symptoms like wheezing, shortness of breath, chest tightness and dry cough (even
though sometimes couch can also be wet). Symptoms characteristics are variable in time in occurrence,
frequency and intensity (mild or severe).
The presence of symptoms, which are useful for the clinical diagnosis, should be associated with the
demonstration of an obstructive disease by functional respiratory test, i.e. spirometry, which is typical for an
expiratory airflow obstruction. Expiratory obstruction is due to bronchoconstriction (airway narrowing), airway
wall thickening and increased mucous production. Bronchodilator test is usually performed in order to reach
the diagnosis of asthma.
Asthma is a chronic condition, but acute symptoms and attacks might be triggered by viral infections (like
bronchiolitis in other children); allergens such as house dust mites, molds or pollens; tobacco smoke; stressful
condition and emotional disorders can also manifest in children with an acute asthma attack.
Asthma is a treatable disease, although some patients do not undergo therapy as they should.
When asthma is well controlled, patients can:
 Avoid troublesome symptoms during day and night
 Need little or no reliever medication
 Lead productive, physically active lives
 Have normal or near-normal lung function
 Avoid serious asthma flare-ups (exacerbations or severe attacks)
According to Global Initiative for Asthma guidelines6, this disease is defined as a heterogeneous disease due to
the pathogenesis of inflammation and the clinical characteristics: there are patients wheezing, coughing, or
nether of them. It is defined by the history of respiratory symptoms such as wheezing, shortness of breath,
chest tightness and cough that vary over time and in intensity, associated with variable airflow limitation in
the expiratory phase.
Asthma is a major cause of school and work absence.
Healthcare expenditure on asthma is very high:
 Developed economies might expect to spend 1-2% of total healthcare expenditures on asthma
 Developing economies are likely to face an increased demand due to an increasing asthma prevalence
 Poorly controlled asthma is expensive
 Investments in prevention treatment is likely to yield cost savings in emergency care

The asthma epidemic

There is a kind of asthma epidemics, because the global incidence and prevalence are increasing every year in
children (estimated 300 million affected individuals).
Asthma in children is a disease of low and middle income, as well as high income countries; however, it is more
severe in low and middle income countries, where disease prevalence is also increasing due to the increasing
urbanisation; the prevalence is also correlated to atopic eczema and rhinoconjunctivitis. Further asthma
surveillance research is needed.
Prevalence in children is about 5-10%, with a male to female ratio M:F = 1.4:1.
The disease is associated with considerable morbidity and socioeconomic costs; it is one of the most common
causes of ER visits and hospitalisations.

Aetiology
Paediatric asthma is mostly allergic or virally-triggered: these are the two main entities seen in clinical practice.
However, there are also genetic factors that can predispose to asthma, even though it is not well known how
these genetic agents interact with the environment or triggers to determine asthma.
Some genes involved in the immune pathway of asthma are known, for example genes encoding for IL-4, IL-5
and IL-13, which are the main cytokines involved in the pathogenesis of allergic airway inflammation; other

6
They can be easily found on the internet, and Global Initiative for Asthma website is a good source for studying the disease
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genes are those having a role in response to therapy: some patients respond well to β2 receptor agonists, other
to 5-lipoxygenase: this predisposes to a response to therapy with either anti-inflammatory drugs or
bronchodilators.
Other possible genes are those involved in antigen presentation (ex. HLA class I-II), or those genes involved in
tissue response (ex. ADAM 33).

Environmental risk factors

Triggers or environmental factors favouring asthma development are allergens, upper respiratory tract
infections (usually viral), cold air, exercise and hyperventilation (exercise-induced asthma): this is particularly
common in adolescents, rather than in young children. Other agents are: irritants (ex. smoke), drugs (ex. aspirin-
induced asthma7).
Exposure to indoor and outdoor allergens contributes to asthma development, aggravation or exacerbation.
The irritant effects of environmental tobacco smoke and other indoor and outdoor air pollutants contribute
significantly to asthma morbidity. Climate change and extreme weather conditions impact on asthma directly
and indirectly.

Infections and asthma

Many acute attacks are triggered by viral
infections, and viral agents vary according to age.
The main ones are rhinovirus and RSV, which are
common in children < 5 years old (preschool
children).

Pathobiology
In children there is an eosinophilic inflammation, common to all patient phenotypes: eosinophils are the main
drivers of inflammation triggered by allergens.
The classification is important for the therapeutic management of asthmatic children, which is a precision
medicine approach: it is important to consider all the cytokines involved and to use biomarkers in order to
discriminate patients.

Allergic eosinophilic airway inflammation

It involves the activation of airway epithelium, which stimulates dendritic cell production of allarmins, i.e. IL33,
IL25, TSLP (Thymic Stromal Lymphopoietin); these are inflammatory cytokines produced by the epithelium in
asthmatic children: they prime mast cells to bind to IgG and they also activate naïve T cells into Th2 cells, which
in turn produce IL4, IL5 and IL13. IL5 is the main cytokine activating eosinophils, which leads to an
hypereosinophilic inflammation.

Non-allergic eosinophilic airway inflammation

When asthma is triggered by pollutants, microorganisms (viruses or bacteria) or smoke. In this case, epithelial
cells activate the allarmins in the same way as for the other inflammatory pathway, and they stimulate ILC2
cells (sort of T cells, innate lymphoid cells in between innate and adaptive immunity) which activate eosinophils
producing IL13. IL13 acts on smooth muscle cells, activating them determining bronchoconstriction. When
smooth muscle cells are very inflamed, cell remodelling occurs and they change their phenotype to fibrotic cells:
older patients experience progression of the disease from asthma to broncho-obstructive disease; adults
usually do not present with bronchodilation, which is instead typical in asthmatic children, adolescents and

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Aspirin intolerance is usually associated to nasal polyposis and asthma. It is not common in children, there are some cases
in adolescents. Treatment is based on the avoidance of the triggering agent (aspirin) and anti-IL5 monoclonal antibodies
(Mepolizumab): it is used in case of aspirin-induced asthma, asthma associated to nasal polyposis and eosinophilic severe
asthma together with high doses of corticosteroids
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some adults. In older patients with broncho-obstructive disease it is not possible to use bronchodilators because
they would not work since cells have changed their phenotype.

Another possibility is the non-eosinophilic phenotype: this is not common in children; it is a neutrophilic or
pauci-granulocytic inflammation, typical of adult patients.

 Asthma is a heterogeneous disease consisting of multiple different pathogenetic subgroups with different
cellular and molecular characteristics
 Th2-like immune response and peripheral blood and lung eosinophilia represent a consistent and dominant
subgroup
 Molecular and cellular mechanisms of non-Th2 associated asthma are poorly defined
 Allergy and IgE play a role in the pathogenesis of a majority of paediatric and approximately half of adult
patients
 Remodelling characterized by smooth muscle hypertrophy, goblet cell hyperplasia, subepithelial basement
membrane thickening and angiogenesis is a key pathogenetic feature
 Recent studies have demonstrated an essential role of permissive bronchial epithelial tight junctions and
leaky epithelium
 Small molecule mediators such as leukotrienes, adenosine, ATP that affect cellular chemotaxis, smooth
muscle relaxation and tissue inflammation play roles

Fig. 1 represents the airways in an asthmatic patient.

As in bronchiolitis, there can be a mucous plug due to
epithelial cell inflammation and necrosis; however, the
plug is not enough to completely obstruct the airways
of a child (which are larger than the ones of an infant).
At bronchoscopy with BAL, it is possible to find
inflammatory cells, as well as at endoscopic biopsy the
typical characteristics of chronic inflammation are
detected, in particular basement membrane
thickening, goblet cell metaplasia (i.e. smooth muscle
cells that have changed phenotype), thickening of
airway smooth muscle cells. Fig. 1

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Classification
Patients are classified into different disease steps according to symptoms severity during the daytime and night
time and lung function tests (spirometry – FeV1, marker of airway obstruction).
SYMPTOMS
SYMPTOMS FEV1
(NIGHT)
>80%
STEP 1: INTERMITTENT <1/week <2 episodes/month
PEF change <20%
>80%
STEP 2: MILD AND PERSISTENT >1/week, <1/day >2 episodes/month
PEF change 20-30%
STEP 3: MODERATE AND Everyday, limited physical 60-80%
>1 episode/week
PERSISTENT activity PEF change >30%
Continuous, limited <60%
STEP 4: SEVERE AND PERSISTENT Frequent
physical activity PEF change >30%
As step 4, but with persistent and uncontrolled symptoms or
STEP 5 exacerbations despite correct inhaler technique and good adherence to
treatment
Step 5 is the last step of severity: in this case biological therapy has to be considered. The cornerstone of
treatment are bronchodilators and anti-inflammatory drugs, i.e. corticosteroids and leukotrienes, but in step 5
biological drugs anti-IL5, anti-IL4 anti-IgE are added.
The classification is very important because each step has its own specific therapy: ask the patients if they
present symptoms everyday, with physical activity, at night or continuously.

Diagnosis
It should be based on:
 A history of characteristic symptom pattern
 Evidence of variable airflow limitation, from bronchodilator reversibility testing or other tests
Document evidence for the diagnosis in the patient’s notes, preferably before starting controller treatment.
It is often more difficult to confirm the diagnosis after treatment has been started.
Asthma is usually characterized by airway inflammation and airway hyperresponsiveness, but these are not
necessary or sufficient to make the diagnosis of asthma.

Typical symptoms
 Wheezing
 Dyspnea/shortness of breath
 Cough
 Chest tightness, particularly in adolescents
 Increased mucous production
 During an acute attack, there are symptoms of respiratory distress: increased ventilation and respiratory
rate, use of accessory respiratory muscles, nasal flaring, suprasternal and intercostal retraction
 Abdominal pain and vomiting
There is an increased probability that the symptoms are due to asthma if:
 More than one type of symptom
 Symptoms often worsen at night or in the early morning, which is important also for classifying the patient
according to the different steps
 Symptoms vary over time and in intensity: sometimes patients might look healthy at clinical examination
 Symptoms are triggered by viral infections, exercise, allergen exposure, changes in weather, laughter,
irritants such as car exhaust fumes or strong smells
There is a decreased probability that symptoms are due to asthma if:
 Presence of isolated cough with no other respiratory symptom
 Chronic sputum production
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  Shortness of breath associated with dizziness, light-headedness or peripheral tingling
 Chest pain
 Exercise-induced dyspnoea with noisy inspiration (stridor)

Differential diagnosis
Asthma can be mimicked by several
conditions: in the paediatric field, it is
important to remember all asthma’s
differential diagnoses, particularly in
severe or difficult to treat asthma.
For example, wheezing can be the
clinical sign lower respiratory tract
conditions, such as bronchopulmonary
dysplasia, also in older children. Acute
attacks are usually present in children
with chronic respiratory conditions and
bronchiectasis (cystic fibrosis, primary
ciliary dyskinesia; immunodeficiency,
in particular common variable
immunodeficiency might present with respiratory symptoms); bronchiectasis is usually due to recurrent
pneumonia. Interstitial lung diseases, like neuroendocrine interstitial disease, might manifest in infants and
young children with an asthma picture, as well as allergic rhinitis.
Other disease affecting the upper and middle respiratory tract enter in differential diagnosis, such as
laryngomalacia and laryngotracheobronchomalacia which manifest with wheezing. Remember also, foreign
body aspiration; airways obstruction depends on the size of the foreign body: foreign bodies obstruct the upper
airways and might be lethal, whereas little foreign bodies can cause an incomplete obstruction8.
Remember that when there is no response to asthma treatment, particularly in children, then think about
another possible diagnosis explaining the symptoms.

Physical examination
Physical examination in patients with asthma is often normal in wellness. At auscultation, the most common
finding is wheezing, especially on forced expiration.
There are some red flags to remember, especially during acute attacks:
 Wheezing may be absent during quit respiration and during severe asthma exacerbation (“silent chest”):
it is a sign of the impending – first phase of respiratory failure.
 Wheezing is not a pathognomonic sign of asthma; it can be found in respiratory infections (bronchiolitis),
COPD, endobronchial obstruction, inhaled foreign body.

Lung function test

Asthma diagnosis is clinical, but it is usually supported by lung function tests. Spirometry is performed to
confirm airflow obstruction in children who are > 5-6 years old; if they are younger, it is difficult for them to
collaborate to perform the test. There are also new tests, for example nitric oxide test: NO is measured in
exhaled breath, and it is high (> 20 part per million, ppm) in children with eosinophilic inflammation; therefore,
NO is the biomarker of eosinophilic inflammation. Another possibility is bronchoprovocation with methacholine
or exercise challenge test, performed when bronchodilation on spirometry is negative despite a clinical
presentation suggestive for asthma; methacholine test is usually carried out in adolescents, whereas exercise
challenge test can be performed when the child is > 6 years old, if he is collaborating.

8
The professor reports the case of a child presenting with recurrent wheezing unresponsive to treatment; since asthma
usually responds to treatment, then it is the case to think about other possible diagnoses. This child had inhaled a piece of
peanut which obstructed the small bronchi.
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Spirometry
It is necessary to confirm the presence of airflow limitation: obstruction is present when FeV1/FVC < 80% of the
predicted value.
Since airflow obstruction is usually partially reversible, a bronchodilation test is carried out with the use of β2
agonists (salbutamol 400 microg); then a second spirometry is performed, which shows:
 Increase in FeV1 ≥ 12% or 200 ml from baseline
 Excessive diurnal variability from 1-2 weeks twice-daily PEF monitoring
 Significant increase in FeV1 or PEF after 4 weeks of controller treatment
In this case the test is positive, so the test confirms the diagnosis of asthma.
For patients with normal lung function, a negative bronchoprovocation test during exercise or with
methacholine may be useful in ruling out asthma.
Spirometry is reliable in children > 6 years old because they are more compliant.
Is possible to measure the variability of obstruction by peak expiratory flow (PEF), but it is not routinely used
nowadays.

The curves in Fig. 2 represent the results of

spirometry: the green one is normal. In case
of asthma, there is an obstruction (red) curve
which is typical for every asthma patient.
When a second spirometry is performed 20
minutes after bronchodilation test, the curve
changes shape, and this can be measured in
ml.

Fig. 2
Allergy tests
The other examinations that can corroborate the diagnosis of asthma are allergy tests: they are usually skin
prick tests and measurement o serum IgE, in particular serum-specific IgE for molds, pollen, house dust mites,
cat or dog epithelium. It is a mandatory step in diagnosis in children, because most of them have allergic asthma.

Asthma control
It is defined as the degree to which manifestations of the disease are reduced or removed by therapy: if therapy
works, the patient has a good control of the disease, and he can move in the steps of asthma classification and,
consequently, in the steps of therapy. Therefore, the therapeutic management of asthma is dynamic.
Control can be assessed in several phases of patient’s management: he is usually monitored in the outpatient
clinic every 3 months even if he is well.
 Optimal asthma control is the goal of asthma management
 Optimal asthma control consists of current (day to day) control and reduced future risk
 Asthma control and asthma severity are not synonymous
 Asthma control can be achieved in the majority of patients
 The most common reason for poor control is lack of adherence of medications
 There are several validated questionnaires to measure asthma control in research studies

The picture represents the management circle:

the first phase is the initial assessment, when the
diagnosis is performed, and therapy is prescribed.
The next assessment is useful in order to adjust
the treatment, if it does not work or if the patient
has a bad asthma control. Lastly, it is important to
review response.

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Treatment
First of all, it is crucial to assess severity, according to which it is possible to categorise the patients in:
 Mild asthma: well-controlled with steps 1 or 2
 Moderate asthma: well-controlled with step 3
 Severe asthma: requires step 4-5, or uncontrolled despite treatment
Severity assessment is essential before starting the treatment: it depends on the level of therapy required to
control symptoms and exacerbations. Remember to re-assess asthma severity in patients under controller
treatment.

Stepwise management in children > 6 years

In case of intermittent asthma, it is possible to prescribe just a reliever or low-dose inhaled corticosteroids.
When patient’s asthma is not controlled by this therapy, it is possible to step up to step 2 (mild persistent
asthma) treatment, which consists of low-dose inhaled corticosteroids. In step 3, an anti-inflammatory drug
(like leukotriene receptor antagonist or LABA: long-acting β2 agonist, like salmeterol, formoterol, vilanterol) is
added to low- dose corticosteroid. Stepping up again to step 4, the treatment of choice is based on
medium/high-dose inhaled corticosteroids in association with LABA. In step 5, all of the previous drugs are used
together with a high dose of oral corticosteroids in continuative therapy, together with an add-on anti-IgE or
another biological agent.

The goal of treatment is to control the disease and to reduce

acute attacks; control is usually achieved with several
medications, and it is possible to act with three types of
agents:
 Bronchodilators, to treat obstruction and relax airways
smooth muscle
 Corticosteroids or leukotriene antagonists, to treat
inflammation
 Anti-IgE, to block IgE in severe allergic asthma

Bronchodilators
β-agonists and anticholinergic are the most commonly used categories of bronchodilators.

β-agonists
 Short-acting (SABA), ex. salbutamol: usually employed only in acute phase of asthma, it is not a chronic
therapy. Albuterol (Aerosol: 150 μg/kg (max 5 mg) x 3-4/die; Spray: 200-400 μg/kg (2-4 puff) x 4-6/die)
 Long-acting (LABA): used in association with medium/high-dose inhaled corticosteroids. Salmeterol is only
used in children > 4 years old. Salmeterol (Diskus 50 μg/kg x 2/die)

Anticholinergic
 Ipratropium bromide: rarely used in children, but it can be added to therapy in case of acute severe attack,
when there is no response to salbutamol. It is a sort of second-line therapy in patients with intolerance to
all β-agonists, severe asthma attacks or asthma attacks induced by β-blockers.
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Theophylline
Usually it is added to step 4 treatment, when there is no response with high-dose steroids and LABA: the patient
is still inflamed and obstructed, so it is possible to open the airways with theophylline.
It has different mechanisms of action: it is a competitive non-selective phosphodiesterase inhibitor which
increases intracellular cAMP and activates PKA, inhibits leukotrienes synthesis and β-TGF; it is also a non-
selective adenosine receptor antagonist, causing cardiac side effects.
However, it is difficult to use because the ECG and drug levels in blood must be monitored, so patients have to
come to the hospital several days a week. It can also cause severe adverse effects, therefore it is not usually
employed in children; the side effects include low therapeutic index with may drug interactions (cimetidine,
phenytoin), cardiac effects (arrhythmias, increased HR), gastroenteric (nausea, diarrhoea), CNS (headache,
irritability, seizures).

Anti-inflammatory drugs
Inhaled corticosteroids
Cornerstone of asthma therapy: they reduce airway inflammation and bronchial hyperresponsiveness; they can
prevent acute attacks, exacerbations and the progressive decline in lung function typical of severe patients.
They are able to improve lung function and quality of life in all ages. However, they can have adverse effect,
particularly oral candidiasis, sore throat and dysphonia; high-dose inhaled corticosteroids may also affect
children growth, even though all studies performed resulted in a decreased growth of 1cm/year of therapy,
therefore it does not have such a big impact. Other possible adverse effects include cataracts, bone mass loss
and glaucoma (in adults).

The following tables represent the low, medium and high dose inhaled corticosteroids in adults and adolescents
(> 12 years old) VS children 6-11 years.
Several molecules can be used: the most effective are fluticasone propionate, budesonide and beclometasone.
Usually start with a low dose, and if it does not work then increase to the medium and high dose. These
molecules are not equivalent, but they have comparable effects.

Oral steroids
The usually employed ones are prednisolone and prednisone during exacerbations and acute attacks of asthma,
for a short time. The first choice is oral administration, but it is possible to use a systemic intravenous steroid
like methylprednisolone or hydrocortisone, but they are reserved to sever attacks and administered only in the
hospital. PDN: 1-2 mg/Kg/day for 3-5 days

Leukotriene modifiers
The anti-inflammatory effect of corticosteroids might be enhanced by other anti-inflammatory drugs like anti-
leukotrienes (leukotriene modifiers).
 Montelukast, Zafirlukast: it is the most commonly used one in children, it is the only rug approved in Italy
for patients > 6 months old who present with recurrent wheezing and asthma. It is a cysteinyl-leukotriene
receptor antagonist (LTRA).
 Zileuton: 5-lipoxygenase antagonist
They are an alternative treatment for mild persistent asthma; they do not present relevant side effects, except
for Zileuton hepatotoxicity.

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Cromoglycates
Cromolyn and Nedocromil, provide limited long-term control of asthma and no additive benefit in combination
with corticosteroids. They are administered orally.

Anti-IgE monoclonal antibody: Omalizumab

It has been intriduced 10 years ago for the
treatment of severe asthma. This monoclonal
antibody reduces circulating IgE and down
regulates IgE receptor on immune cells
surface. It binds to free serum IgE, not to IgE
already bound to high affinity receptors on
mast cells, basophils or other inflammatory
cells. This contact with the monoclonal
antibody prevents the binding of IgE with
receptors, in turn preventing activation of
inflammatory cells: therefore, there is a
decrease in inflammatory mediators released
by mast cells, basophils and eosinophils (all of which express the high affinity receptor for IgE). The final result
is a decrease in allergic inflammation, and clinically there is a decrease in the rate of asthma attacks, adding to
the corticosteroid effect: this allows to decrease the dose of inhaled corticosteroids when anti-IgE are added.
The administration is subcutaneous, every 2-4 weeks and the dose depends on the level of free serum IgE, age
and weight; therefore, this drug can only be amdinistered in the hospital.
It is indicated in children > 6 years old with moderate and severe persistent allergic asthma that does not
responds to high dose treatment with other drugs (LABA, inhaled corticosteroids and leukotriene modifiers).
Omalizumab is able to reduce the frequency of exacerbations, although long-term effects on airway remodelling
have not yet been established.

Reviewing response and adjusting treatment

Response to therapy should be reviewed asking for sympotms, control and therapy.
The patient should be assessed every 3 months (1-3 months after treatment is started), or longer if the disease
is well controlled (every 3-12 months). Duing pregnancy, women should be assessed every 4-6 weeks, and
afteran exacerbation the patient should be seen within 1 week.
It is possible to move up and down according to sympotms: if they worsen, step up the treatment, if asthma
control is achieved, then step down. Asthma management is dynamic, and the correct treatment is crucial
because when there are episodes of acute asthma, particularly in children, then there is a high risk of a decline
in lung function or of severe attacks that have to be treated in ICU.

Stepping up asthma treatment:

 Sustained step-up, for atf least 2-3 months if asthma is poorly controlled. First check for common causes
of symptoms not due to asthma, incorrect inhaler technique, poor adherence to therapy
 Short-term step-up, for 1-2 weeks, ex. with viral infection or allergen. It may be initiated by the patient
with a written asthma action plan
 Day-to-day adjustment: for patients with prescribed low-dose inhaled corticosteroids/formoterol
maintainance and reliever regimen

Stepping down asthma treatment:

 Consider stepping down after a good control maintained for 3 months
 Find each patient’s minimum effective dose that controls both symptoms and exacerbations

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