Pediatric Lower Respiratory Infections

1 april 2015

Alessandra Scaparrotta1*, Marina Attanasi1, Sabrina Di Pillo1 and Francesco Chiarelli1

1

Department of Pediatrics, University of Chieti, Italy

Corresponding author: Alessandra Scaparrotta, Department of Pediatrics, University of Chieti, Italy

1
1.1
1.1.1
1.1.2
1.1.3
1.1.4
1.1.5
1.2
1.2.1
1.2.2
1.2.3
2
2.1
2.2
2.3
2.4
3
3.1
3.2
3.3

Acute and Chronic Bronchitis

Acute Bronchitis
Pathophysiology and Etiology
Sign and symptoms
Diagnosis
Differential Diagnosis
Therapy
Chronic Bronchitis
Differential Diagnosis
Diagnosis
Therapy
Infectious Asthmatic Bronchitis
(Wheezing/Wheeze)
Etiology
Diagnosis
Therapy
Prognosis
Bronchitis
Etiology and Pathophysiology
Clinical Symptoms
Differential diagnosis

3.4
3.5
3.6
4
4.1
4.2
4.3
4.4
4.4.1
4.4.2
4.4.3
4.4.4

Diagnosis
Therapy
Prognosis
Pneumonia
Definition
Epidemiology
Etiology
Bacterial Pneumonia
Pathophysiology
Symptoms and Signs
Diagnostic Tests
Treatment

4.4.5
4.5
4.5.1
4.5.2
4.5.3
4.5.4
4.5.5
4.6

Complications
Non-Bacterial Pneumonia
Pathophysiology
Symptoms and Signs
Diagnostic Tests
Treatment
Complications
Recurrent or Chronic Pneumonia

Lower respiratory tract infections include conditions, which may or may not involve the parenchyma [1]:

Infections not involving the parenchyma as acute bronchitis, exacerbation of chronic bronchitis, asthm
bronchitis and bronchiolitis

Infections involving the parenchyma as pneumonia.

1. Acute and Chronic Bronchitis

1.1 Acute bronchitis

Many terms are used to describe diseases characterized by cough: bronchitis, wheezy bronchitis, asthm
bronchitis, and tracheobronchitis. There is a lack of consensus regarding clinical definition of cough illnesses
nomenclature, caused by difficulty in comparing results from cough illness or bronchitis studies, with a lack
firm consensus on diagnosis and treatment [2]. Acute bronchitis is an acute or subacute cough illness lasting
than 2-3 weeks, with or without phlegm production, frequently associated to other upper respiratory tract
constitutional
symptoms
[3-5].

The cough is the most frequently mentioned symptom necessitating office evaluation; so, acute bronchitis is on
the top 10 diagnoses in ambulatory care medicine [6,7]. Physicians exhibit extensive variability in diagno
requirements and treatment, because the diagnosis is clinical, without standardized diagnostic signs and sensitiv
specific
confirmatory
laboratory
tests
[

Diagnosis of bronchitis often results in a prescription for an antimicrobial agent, reflecting the physicians belie
bacterial infection, although the term bronchitis does not imply specific etiology and it is most commonly cause
viral pathogens [2].

1.1.1 Pathophysiology and etiology: Acute bronchitis is defined as inflammation of the bronchial respira
mucosa, resulting in productive cough. For most clinicians, bronchitis is a disease clinically characterized by co
with
or
without
fever
or
sputum
production
[2].

Bronchial epithelial injury is induced by infectious or noninfectious triggers, which cause an inflammatory resp
with consequent airway hyperresponsiveness and mucus production [7,9]. International literature suggests
clinical features of uncomplicated acute bronchitis develop in sequential phases: an acute infection phase, resul
from direct inoculation by the infectious virus of the tracheobronchial epithelium, leading to cytokine release
inflammatory cell activation. In this phase there are variable constitutional symptoms, such as fever, myalgia,
malaise, that last 1 to 5 days depending on the infectious agent. The protracted phase results from hypersensitivit
the tracheobronchial epithelium and airway receptors (bronchial hyperresponsiveness), characterized primarily
cough, often accompanied by phlegm production and wheezing, and usually lasts 1 to 3 weeks. Respira
epithelial cell function plays an important role in airway inflammation, and vagal-mediated air
hyperresponsiveness has been shown to coincide with repair of the bronchial epithelial surface. Other mechanism
bronchial hyperresponsiveness may also be present, as adrenergic-cholinergic tone imbalance and IgE-medi
histamine release [5].
Selected triggers that can begin the cascade leading to acute bronchitis are [7]:

Viruses: adenovirus, coronavirus, coxsackievirus, enterovirus, influenza virus, parainfluenza v

respiratory syncytial virus, rhinovirus, human metapneumovirus.

Bacteria: Bordetella pertussis, Bordetella parapertussis, Branhamella catarrhalis, Haemophilus influen

Streptococcus pneumoniae, atypical bacteria (e.g., Mycoplasma pneumoniae, Chlamydia pneumon

Legionella species).

Yeast and fungi: Blastomyces dermatitidis, Candida albicans, Candida tropicalis, Coccidioides imm
Cryptococcus neoformans, Histoplasma capsulatum.

Noninfectious triggers: asthma, air pollutants, ammonia, cannabis, tobacco, trace metals.

Acute bronchitis is usually caused by a viral infection [10,11]: in patients younger than one year, commonly
respiratory syncytial virus, parainfluenza virus, and coronavirus; in patients one to 10 years of age predomi
parainfluenza virus, enterovirus, respiratory syncytial virus, and rhinovirus; in patients older than 10 years the m
frequent are influenza virus, respiratory syncytial virus, and adenovirus [7]. In the fall most commonly oc
parainfluenza virus, enterovirus, and rhinovirus infections, while influenza virus, respiratory syncytial virus,
coronavirus infections are most frequent in the winter and spring [7,12].

Other viral causes can be influenza A and B and human metapneumovirus, while bacterial pathogens involved ca
Bordetella pertussis, Chlamydia pneumonia and Mycoplasma pneumonia [11]. "No isolated pathogen" is al
frequent finding, probably representing viral infections for which studies did not perform appropriate analyses [5

1.1.2 Sign and symptoms: Cough is the most commonly observed symptom of acute bronchitis, beginning with
days of infection in 85% of patients, persisting in most of patients for less than 2 weeks; however, 26% are
coughing after 2 weeks, and a few cough for 6 to 8 weeks [7,13].

Other signs and symptoms may include dyspnea, wheezing, sputum production, chest pain, fever, hoarsen
malaise, rhonchi and rales, in varying degrees. Sputum may be clear, white, yellow, green, or even tinged
blood. Peroxidase released by the leukocytes in sputum causes the color changes; hence, color alone should no
considered indicative of bacterial infection [7,14,15].

1.1.3 Diagnosis: Different are the recommendations on the Gram staining use and sputum culture to drive a
bronchitis therapy; questionable is especially the usefulness of these tests in the outpatient treatment, because
often show no growth or only normal respiratory flora [7,9,12].

Chest radiography should be reserved for patients in which pneumonia is suspected or affected by heart failure,
in high risk patients with advanced age, chronic obstructive pulmonary disease, recently documented pneumo
malignancy, tuberculosis, and immunocompromised or debilitated status [7,12]. The indications for performi
chest radiograph in children with acute cough is listed in the table 1 (Table 1).
Table 1: Indications for performing a chest radiograph in a child with acute cough [28].
INDICATIONS
Uncertainty about the
diagnosis of pneumonia

FEATURES

Fever and rapid breathing in the

absence of wheeze/stridor

Localizing signs in chest

Persisting high fever or unusual

course in bronchiolitis

Cough and fever persisting

beyond 45 days

Choking episode may not have been

Possibility of an inhaled witnessed but cough of sudden onset or
foreign body
presence of asymmetrical wheeze or
hyperinflation

Pointers suggesting that

this is a presentation of
a chronic respiratory
disorder

Failure to thrive

Finger clubbing

Overinflated chest

Chest deformity

Cough is relentlessly progressive

beyond 2 3 weeks

Recurrent fever after initial

resolution

Unusual clinical course

True haemoptysis

True hemoptysis needs to be

differentiated from spitting out blood
secondary to nose bleeds, cheek biting,
pharyngeal and esophageal or gastric
bleeding.

Pulmonary function testing as spirometry are not routinely used in the acute bronchitis diagnosis, but performed
when underlying obstructive pathology is suspected or if there are repeated bronchitis episodes. Pulse oximetry
determine the severity of the illness, but results do not confirm or rule out bronchitis, asthma, pneumonia, or o
specific diagnoses [7].
1.1.4 Differential diagnosis: The differential diagnosis includes the most common causes of acute cough [11]:


Acute

Allergic
Asthma

Chronic
obstructive
pulmonary

Congestive
heart
failure

Gastroesophageal
reflux

Post-infectious

Postnasal

Viral syndrome.

bronc
rhi
disease
exacerbation
disease

exacerba

Maligna
Pneum
co

Sinu

1.1.5 Therapy: Antiviral medications against influenza may be considered during influenza season for highpatients who present within 36 hours of symptom onset [11]. Antibiotics should not be routinely used in
treatment of acute bronchitis, especially in younger patients. Although viruses cause 90% of bronchitis infecti
approximately two thirds of patients in the United States are treated with antibiotics. Antibiotics do not significa
change the course of acute bronchitis, providing only minimal benefit compared with the risk of antibiotic use it
Routine use of antibiotics is not recommend by the American College of Chest Physicians (ACCP) for patients
acute bronchitis [16], but they may be considered in certain situations: when pertussis is suspected as cough etiol
initiation of a macrolide is recommended as soon as possible to reduce transmission; however, antibiotics do
reduce duration of symptoms [11].

A very recent Cochrane concludes that there is limited evidence to support the use of antibiotics in acute bronch
they may have a modest beneficial effect in some patients with acute bronchitis, although data on subsets of pati
who may benefit more from treatment are lacking. However, the magnitude of this benefit needs to be considere
the broader context of potential side effects, medicalization for a self limiting condition, increased respira
pathogens resistance and antibiotic treatment cost [17].

The use of antibiotics in acute bronchitis may decrease the risk of subsequent pneumonia. The use of serol
markers may help to guide antibiotic use, because of the clinical uncertainty in distinguishing acute bronchitis f
pneumonia [11].

Over-the-counter (OTC) cough preparations are often as self prescribed as recommended by health practitioners
the initial treatment of cough [18]. Dextromethorphan is ineffective for cough suppression in children
bronchitis [19]. Other common therapies include antitussives, expectorants, inhaler medications, and alterna
therapies. Expectorants, which have been shown to be ineffective in the treatment of acute bronchitis, and inh
medications are not recommended for routine use in patients with bronchitis, although they are commonly used
suggested by physicians [18,20]. A Cochrane review does not suggest the routine use of beta-agonist inhaler
adults and children with acute bronchitis without airflow obstruction evidence; however, the subset of patients
wheezing during the illness responded to this therapy [20,21]. There may be some benefit only to high-d
episodic inhaled corticosteroids, but no benefit occurred with preventive therapy [22]. No data support the us
oral corticosteroids in patients with acute bronchitis without asthma [11]. Antitussives, antihistamines, antihistam
decongestants and antitussive/bronchodilator combinations were no more effective than placebo in children
acute cough; however, many studies were of low quality and very different from each other, making very diff
the evaluation of overall efficacy [18].

1.2 Chronic bronchitis

There is a lack of clarity regarding the definition of chronic bronchitis. The definition of chronic bronchitis in ad
is clear: the presence of chronic productive cough for 3 months in each of 2 successive years, in a patient u
whom other causes of chronic cough have been excluded [23]. Whether this definition can be applied to childh
chronic bronchitis remains unclear [24,25].

The diagnosis of chronic bronchitis should occur in two phases. The first is consideration and identificatio
several well-defined respiratory disorders according to a staged management protocol. The second but simultane
phase is elimination or modification of exogenous factors that produce or maintain the childs illness [24]. Howe
this diagnosis has the potential to divert the pediatrician from detecting a more specific respiratory condition [24
Despite coughing in childhood is common, there is remarkably little in the literature regarding etiology, investiga
and management of chronic cough in childhood. Recent reports have emphasized the importance of makin
specific
diagnosis
in
children
with
a
chronic
cough
(>3
weeks)
[26,27].

Juvenile chronic bronchitis with persistent endobronchial infection (recently labeled persistent bacterial bronch
has been described for many decades. Children have chronic or recurrent cough with sputum production [28].
persistent bacterial bronchitis (PBB) is, for some authors, the most common cause of a chronic cough [ 26,29
variety of diagnostic labels have been used to describe this condition: terms such as chronic suppurative lung dis
[30-32], persistent endobronchial infection [33] and PBB [29] describe the pathological process and site of infec
while terms such as chronic bronchitis [34-36] or protracted bronchitis [37,38] describe the clinical phenot
Others have suggested using the term pre-bronchiectasis [39,40] to highlight the conditions probable rol
leading to damaged airways, as evident on high-resolution computed tomography or at bronchography [

PBB is a pediatric condition characterized by the presence of an isolated moist or wet cough, lasting more th
weeks in the absence of other specific causes. It usually affects children younger than 5 years and it has b
recognized more by pediatric pulmonologists that resolves it with antibiotic treatment. The most common organ
involved in infants and children are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrh
PBB is underdiagnosed and often misdiagnosed as asthma [27,29,41,42].

1.2.1 Differential diagnosis: The term of chronic bronchitis should only be used after underlying causes h
been excluded [28,42,43]:

Asthma

Tracheobronchomalacia

Foreign body aspiration

Mechanical airway obstruction

Gastroesophageal reflux/aspiration syndromes

Cystic fibrosis

Primary ciliary disorders

Congenital malformation

Passive smoking

Environmental pollution

Pulmonary tuberculosis

Bronchiectasis

Immune deficiencies.

1.2.2 Diagnosis: Careful history - taking and physical examination, together with appropriate investigations, en
the correct diagnoses to be made for most cases of chronic cough within a reasonable time frame [43].
The diagnostic approach includes [28,42]:
1. Complete blood cell count
2. Chest x-ray examination
3. Pulse oximetry
4. Sputum for cultures
5. Mantoux
6. Sweat chloride measurement
7. Allergological evaluation
8. B-cell function (if immunological deficit is suspected)
9. High-resolution computed tomographic chest scan
10. Fiberoptic bronchoscopy with bronchoalveolar lavage and endobronchial biopsies

11. Placement of esophageal pH probe.

Therapy: The management of chronic coughing relates to first making an accurate underlying diagnosis and
applying specific treatment for that condition. Macrolide antibiotics should be early used if diagnosis of pertu
exists
[28].

PBB often resolves after a course of antibiotic such as amoxicillin - clavulanate for 2 weeks; however, some req
a longer 46 weeks antibiotic. Children with PBB should first have other underlying conditions excluded, espec
if PBB becomes recurrent or fails to respond to antibiotics and further investigations as sputum cultured are requ
to rule out the other conditions such as immunodeficiencies or other causes of chronic suppurative lung diseas
trial treatment of physiotherapy and a prolonged course (46 weeks) of appropriate antibiotics may be tried [28,4
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Infectious

Asthmatic

Bronchitis

(Wheezing

Or

Whe

Terms such as wheezy bronchitis, respiratory illness associated wheeze, and asthmatic bronchitis have been use
the past to describe episodic wheezing in infants and young children. In fact, pediatricians thought that epis
wheeze in this age group had a more benign prognosis than asthma of older children. More recently, the use of
term asthma has been promoted to describe all wheezing illness in children, allowing no distinction between vir

induced

wheeze

and

other

kind

of

asthma

[1

Approximately, one in three children has at least one episode of wheezing prior to his third birthday, wi
cumulative prevalence of wheeze almost of 50% at the age of 6 years [4-6]. Most preschool wheeze is associ
with viral upper respiratory tract infections, which frequently recur at this age

The European Respiratory Society (ERS) Task Force agrees not to use the term asthma to describe presc
wheezing illness since there is insufficient evidence showing that the pathophysiology of preschool wheezing ill
is
similar
to
the
asthmatic
one
in
older
children
and
adults

Wheezing is defined by ERS as a continuous high-pitched sound with musical quality emitting from the chest du
expiration and it is one of the forms of noisy breathing in preschool children. Parents understanding of whee
differs very much, because some think it is a sound such as whistling, squeaking or gasping; for others is a diffe
rate
or
style
of
breathing
or
the
same
as
cough
[4,7-11].

Episodic (viral) wheeze is defined as wheeze in discrete episodes, with the child being well between episodes.
phenotype appears to be most common in preschool children [4,5,12,13] and it is usually associated with clin
evidence of a viral respiratory tract infection, with repeated episodes that occur season
2.1
The most common causative agents include [4,14]:

Etio

1. Rhinovirus
2. Respiratory syncytial virus (RSV)
3. Coronavirus
4. Human metapneumovirus
5. Parainfluenza virus
6. Adenovirus

Factors underlying the frequency and severity of episodes are partially understood, but some factors as the seve
of the first episode (related to pre-existent impaired lung function and younger age), atopy, prematurity and expo
to tobacco smoke have been implicated [4,15-21].
It
2.2

is

irrelevant

whether

or

not

the

initial

episode

is

classified

as

bronchiolitis

Diagn

A careful physical examination should always be performed, which should include listening to forced expiration
nasal
examination
[

There is no evidence that microbiological investigation, with identification of the causative virus, contribute
management of the acute episode or in the long-term. There are no studies supporting the usefulness of pulmo
function tests in children with nonspecific symptoms, or in distinguishing between episodic and multiple-tri
wheeze
2.3

Ther

There is little doubt that wheezing should be treated with bronchodilators and not antibiotics, with additi
corticosteroids
if
the
wheezing
is
severe
[1].

Short-acting 2 agonists are the treatment of choice for intermittent and acute asthma episodes in very yo
children [22]. Double-blind placebo-controlled studies observed significant bronchodilatory effects and protec
effects against bronchoconstrictor agents in infants and preschool children treated with them. Oral administratio
this drug is also effective, but there are systemic side effects, while intravenous infusion use is limited to very se
acute
wheeze
in
young
children

Leukotriene receptor antagonists are suggested as treatment for viral-induced wheeze and to reduce the frequenc
exacerbations in young children aged 25 years [23,24]. Benefit has been shown in children as young as 6 month
age [22,25,26]. Daily use of montelukast over a 1-yr period had diminished the wheezing episodes rate in
children with episodic (viral) wheeze by 32% compared to placebo [4,23]. The ERS Task Force suggests
Montelukast 4 mg once daily should probably be given for the treatment of episodic (viral) wheeze, while a tria
inhaled corticosteroids may be considered in preschool children especially when episodes occur frequently or if
family
history
of
asthma
is
positive

Further studies are needed to establish the role of viral infections in precipitating obstructive airway symptoms
of
antiviral
agents
as
potential
asthma
medications
[
2.4

Prognosis

Although RSV and rhinovirus have been linked to an increased risk of persistent wheezing over time [4,27-29],
not known whether or not they play a major role in determining long-term outcome

Episodic (viral) wheeze most commonly decreases over time, disappearing by the age of 6 years, but can continu
episodic wheeze into school age, change into multiple-trigger wheeze or disappear at an older age [4,5,30].
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Horn SD, Smout RJ (2003) Effect of prematurity on respiratory syncytial virus hospital resource use
outcomes. J Pediatr 143: S133-141.

Lanner? E, Wickman M, Pershagen G, Nordvall L (2006) Maternal smoking during pregnancy increases
risk of recurrent wheezing during the first years of life (BAMSE). Respir Res 7: 3.

Mertsola J, Ziegler T, Ruuskanen O, Vanto T, Koivikko A, et al. (1991) Recurrent wheezy bronchitis
viral respiratory infections. Arch Dis Child 66: 124-129.

Rylander E, Eriksson M, Freyschuss U (1988) Risk factors for occasional and recurrent wheezing after R
infection in infancy. Acta Paediatr Scand 77: 711-715.

Simoes EA, King SJ, Lehr MV, Groothuis JR (1993) Preterm twins and triplets. A high-risk group for se
respiratory syncytial virus infection. Am J Dis Child 147: 303-306.

Bacharier LB, Boner A, Carlsen KH, Eigenmann PA, Frischer T, et al. (2008) Diagnosis and treatmen
asthma in childhood: a PRACTALL consensus report. Allergy 63: 5-34.

Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, et al. (2005) Montelukast reduces ast
exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 171: 3
322.

Bisgaard H (2003) A randomized trial of montelukast in respiratory syncytial virus post-bronchio

American Journal of Respiratory and Critical Care Medicine. 167: 379-383.

Scaparrotta A, Di Pillo S, Attanasi M, Rapino D, Cingolani A, et al. (2012) Montelukast versus inh

corticosteroids in the management of pediatric mild persistent asthma. Multidiscip Respir Med 7: 13.

3.

van Adelsberg J, Moy J, Wei LX, Tozzi CA, Knorr B, et al. (2005) Safety, tolerability, and explora
efficacy of montelukast in 6- to 24-month-old patients with asthma. Curr Med Res Opin 21: 971-979.

Bont L, Aalderen WM, Kimpen JL (2000) Long-term consequences of respiratory syncytial virus (R
bronchiolitis. Paediatr Respir Rev 1: 221-227.

Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, et al. (1999) Respiratory syncytial virus in e
life and risk of wheeze and allergy by age 13 years. Lancet 354: 541-545.

Lemanske RF Jr, Jackson DJ, Gangnon RE, Evans MD, Li Z, et al. (2005) Rhinovirus illnesses du
infancy predict subsequent childhood wheezing. J Allergy Clin Immunol 116: 571-577.

Doull IJ, Lampe FC, Smith S, Schreiber J, Freezer NJ, et al. (1997) Effect of inhaled corticosteroid
episodes of wheezing associated with viral infection in school age children: randomised double blind plac
controlled trial. BMJ 315: 858-862.

Bronchio

Bronchiolitis is the most common lower respiratory tract infection in infants aged 3 to 6 months. Infants and chil
with bronchiolitis often show upper and lower respiratory tract infection features together, including rhinitis, co
tachypnea, wheezing, crackles, nasal flaring and use of accessory muscles. It is clinically diagnosed in chil
presenting with breathing difficulties, cough, poor feeding and irritability, combined together with wheeze an
crepitations
on
auscultation
[1,2].

It is the main cause of hospitalization of infants younger than 1 year of age, with more than 80% of hospital
children younger than 6 months. Disease severity is correlated to the size and maturity of the infant; underl
medical problems (prematurity, cardiac disease or underlying respiratory disease) give more severe disease

preterm infants less than six months of age, admission rate with acute bronchiolitis is 6.9% with more freq
admission
to
intensive
care
[1,

In most infants the disease is self limiting, lasting typically between 3 and 7 days. Home managing is frequent, w
admission to hospital is generally to receive supportive care such as nasal suction, supplemental oxygen
nasogastric
tube
feeding

The risk of death for a healthy infant with bronchiolitis is less than 0.5%, but the risk is much higher for chil
with congenital heart disease (3.5%) and chronic lung disease (3.45%) (3); in a UK study, the respiratory sync
virus -attributed death rate (measured in infants aged one to 12 months) was 8.4 per 100,000 population [1,5]. 2
of infants with bronchiolitis (40-50% of those hospitalized) proceed to a persistent cough and recurrent viral-indu
wheeze, probably related to continuing inflammation and temporary cilial dysfunction [1,
3.1

Etiology

and

pathophysio

A consensus definition of bronchiolitis is a seasonal viral illness characterized by fever, nasal discharge, and
wheezy cough, with fine inspiratory crackles and/or high-pitched expiratory wheeze on examination [1,8].
American Academy of Pediatrics (AAP) guideline defined bronchiolitis as a constellation of clinical symptoms
signs including a viral upper respiratory prodrome, followed by increased respiratory effort and wheezing in chil
less
than
2
years
of
age
[9

The viral infection begins through the upper respiratory tract and extents in lower within a few days, cau
inflammation of the bronchiolar epithelium, with peribronchial infiltration of white blood cell types, mo
mononuclear cells, and edema of the submucosa and adventitia. Consequently, there is total or partial obstructio
airflow caused by necrotic epithelium and fibrin in the airways. There is also an air trapping distal to obstru
areas, caused by a ball-valve mechanism, with subsequent absorption, atelectasis, and a mismatch of pulmo
ventilation and perfusion with consequent hypoxemia. Smooth-muscle constriction seems to have little role in
pathologic process, explaining the limited benefit of bronchodilators observed in clinical studies

Bronchiolitis is associated with viral infections: respiratory syncytial virus (RSV) is responsible for 70%-75%
bronchiolitis, rising to 80% to 100% in winter epidemics; around 70% of all infants will be infected with RSV
their
first
year
of
life
and
22%
develop
symptomatic
disease
[1,3,11].

RSV is an enveloped, non-segmented, negative-stranded RNA virus, member of the Paramyxoviridae fam
subtype A usually causes more severe disease. The dominant strains shift each year, causing frequent reinfecti
The incubation period ranges from 2 to 8 days; viral shedding ranges from 3 to 8 days, although it may continue
up to 4 weeks in young infants. An RSV infection begins with replication of the virus in the nasopharynx
following spread to the small bronchiolar epithelium lining the small airways within the lungs [11-1

RSV infection causes inflammation and necrosis of the bronchiolar epithelial cells with a lymphoc
peribronchiolar infiltration and submucosal edema at the first. Cytokines and chemokines as interfero
interleukin-4, interleukin-8 and interleukin-9, released by infected respiratory epithelial cells, amplify the imm
response by increasing cellular recruitment into the infected airways. Edema of the airway wall obstructs bronch
lumina, associated with an increased mucus secretion, sloughed epithelium and cellular debris [15

The other viruses involved, recognized thanks to availability of sensitive diagnostic tests that use molec

amplification techniques, are: adenovirus, parainfluenza 13 and influenza A and B virus, human metapneumov
(HMPV), bocavirus, rhinovirus and coronavirus [9,16-18]. The HMPV has been estimated to account for 3% to
of bronchiolitis cases [19,20], with a clinical course similar of RSV. Molecular diagnostic techniques have
revealed rates of co-infection ranged from 10% to 30% in hospitalized children, most commonly with RSV
either HMPV or rhinovirus [21]. HMPV accounts for 3% to 19% of bronchiolitis cases, with clinical courses sim
to RSV-caused bronchiolitis; there is a subset of children that develops bronchiolitis, even if very frequent is
infection during annual widespread wintertime epidemics. The role of rhinoviruses in triggering exacerbation
wheezing among older children with reactive airway disease or asthma is well documented, but remains unclea
bronchiolitis
[9,223.2

Clinical

symptoms

Clinical is the diagnosis of bronchiolitis, based on typical history and findings on physical examination. Clin
signs and symptoms of bronchiolitis consist of rhinorrhea, cough, wheezing, tachypnea, and increased respira
effort manifested as grunting, nasal flaring, and intercostal and/or subcostal retractions. A coryzal phase for 2
days precedes the onset of other symptoms. Clinical conditions may deteriorate suddenly in the first 72 hours of
illness [10,25,26]. Clinical features of bronchiolitis are listed in the table 1 (Table 1).
Table 1: Clinical features of bronchiolitis [1].

Clinical Features of Bronchiolitis

Fever may be present, but high fever is uncommon and the absence
of fever should not preclude the diagnosis.

Rhinorrhea often precedes other symptoms such as cough,

tachypnea, respiratory distress and feeding difficulties.

A dry, wheezy cough is another earliest symptom.

Increased respiratory rate is an important symptom.

Frequent is the feeding difficulties due to dyspnea.

Dyspnea and subcostal, intercostal and supraclavicular recessions

are commonly features, with the chest visibly hyperinflated in
bronchiolitis.

Fine inspiratory crackles in all lung fields are a common (but not
universal).

High-pitched expiratory wheeze is a common, but not always

observed.

Apnea can be the presenting feature of bronchiolitis, especially in

the very young and in premature or low birth weight infants.

Decisions to admit or discharge from hospital must take into consideration risk factors and clinical features
severe disease, taking also account of the stage of the illness (early and perhaps worsening stage), of geograph
factors,
transport
difficulties
and
social
factors

Risk factors for severe disease include [10]: age less than 6-12 weeks; history of prematurity (less than 37 wee
underlying cardiopulmonary disease; immunodeficiency; chronic lung disease (bronchopulmonary dysplasia, cy
fibrosis,
congenital
anom

Any of the indications listed in table 2 (Table 2) should prompt hospital referral and pediatric assessment in an in
with
acute
bronchiolitis
or
suspected
acute
bronchiolitis
Table 2: Clinical features for severe respiratory disease in patients with acute bronchiolitis [1].

Clinical Features for Severe Respiratory Disease

Poor feeding (<50% of usual fluid intake in preceding 24

hours)

Lethargy

Apnea

Respiratory rate > 70/min

Presence of nasal flaring and/or grunting

Severe chest wall recession

Cyanosis

Oxygen saturation = 94%

Uncertainty regarding diagnosis.

Indications for intensive care unit consultation include [1]: failure to maintain oxygen saturations of greater
92% with increasing oxygen therapy; deteriorating respiratory status with signs of increasing respiratory dist
and/or
exhaustion;
recurrent
apnea.
3.3
Differential
diagn

The differential diagnosis with other diseases that can mimic acute bronchiolitis comprehends [1,9
1) Pulmonary causes:

Pneumonia (Mycoplasma, Chlamydia)

Tuberculosis

Congenital lung disease

Cystic fibrosis

Inhaled foreign body

Pertussis

Laryngotracheomalacia

Bronchogenic cyst
2) Non-pulmonary causes:

Congenital heart disease

Sepsis

Severe metabolic acidosis

Gastroesophageal reflux

Vascular ring

Allergic reaction

Mediastinal mass

Tracheoesophageal fistula.

3.4 Diagnosis Acute bronchiolitis is a clinical diagnosis, but clinicians may perform investigations such as oxy
saturation recording, blood gas analysis, chest X-ray, virological or bacteriological testing, hematology
biochemistry to make management decisions and when diagnostic uncertainty exists [1]

As stated in the AAP guideline, results of evidence-based reviews have not supported a role for any diagnostic
in
the
management
of
routine
cases
of
bronchiolitis
[9-

Pulse oximetry should be performed in every child who attends hospital with acute bronchiolitis: infants
oxygen saturation = 92% require inpatient care; when oxygen saturations is between 92% and 94% hospitaliza
decision depends on: clinical assessment; phase of the illness; social and geographical factors. Oxygen saturatio
94% in room air may be considered for discharge [1]. The AAP recommends that if the childs clinical co
improves, continuous measurement of SpO2 is not routinely needed. Premature infants and those with a kn
history of significant heart or lung disease require close monitoring as the oxygen is being weaned [1

The use of chest radiography for diagnosis and management of bronchiolitis is not recommended routinely by
AAP. After reviewing the radiographs, clinicians were more likely to treat with antibiotics, although the findings
not
support
treatment
[9,10].

Blood gas analysis (capillary or arterial) is not usually indicated in acute bronchiolitis, but it is important in inf
with severe respiratory distress or respiratory failure, because knowledge of arterialized carbon dioxide values
guide
referral
to
intensive
care
[1].

Rapid testing for RSV is recommended in infants who require admission to hospital with acute bronchiolitis, in o
to
guide
cohort
arrangem

Rapid viral antigen tests have variable sensitivity and specificity depending on the test and if used during
respiratory season [27], with a good predictive value during the peak viral season that decreases considerabl

times of low prevalence. Most viruses have similar clinical courses, so the value of identifying the specific a
varies if the patients are managed as outpatient (virus identification may have little impact on management) or in
hospital setting, in which specific viral testing has been used as part of successful interventions to reduce nosoco
infections
[9,28

Routine bacteriological testing (of blood and urine) is not indicated in infants with typical acute bronchiolitis, b
should be considered in febrile infants less than 60 days old. Full blood count and measurement of urea
electrolytes are not indicated in assessment and management of infants with typical acute bronchiolitis, but the
ones should be considered in those with severe disease. Existing retrospective studies do not provide suffic
evidence
to
recommend
C-reactive
protein
(CRP)
measurement
[1].
3.5

Ther

The AAP recommends the following therapeutic strategy in infants with bronchiolitis [10]:

Antibacterial medications should be used only in children with bronchiolitis who have specific indication
the coexistence of a bacterial infection. When present, bacterial infection should be treated in the s
manner as in the absence of bronchiolitis.

A carefully monitored trial of a-adrenergic or -adrenergic medication is an option. Inhaled bronchodila

should be continued only if there is a documented positive clinical response.

Clinicians should assess hydration and ability to take fluids orally.

Supplemental oxygen is indicated if oxyhemoglobin saturation (SpO2) falls persistently below 90%
previously healthy infants. If the SpO2 does persistently fall below 90%, adequate supplemental oxy
should be used to maintain SpO2 at or above 90%. Oxygen may be discontinued if SpO2 is at or above
and the infant is feeding well and has minimal respiratory distress.

Infants with a known history of hemodynamically significant heart or lung disease and premature inf
require close monitoring as the oxygen is being weaned.

Pavilizumab prophylaxis is recommended in selected infants and children with CLD or a history
prematurity (less than 35 weeks gestation) or with congenital heart disease; when given, prophylaxis

palivizumab should be given in 5 monthly doses, usually beginning in November or December, at a dos
15 mg/kg per dose administered intramuscularly.

The routinely use of bronchodilators is not recommended.

The routinely use of corticosteroid medication is not recommended.

The routinely use of ribavirin is not recommended.

The routinely use of chest physiotherapy is not recommended.

Continuous measurement of SpO2 is not routinely needed, if the childs clinical course improves.

Supplemental oxygen by nasal cannule or facemask is required in infants with oxygen saturation levels = 92%
who
have
severe
respiratory
distress
or
cyanosis
[1].

In synthesis, bronchodilators use not improve in duration of illness or hospitalization, so the routine use is
recommended, but it may improve short-term clinical score in a subset of children, so the use is allowed only a
proven benefit. Corticosteroids and leukotriene receptor antagonist not improve in duration of illness
hospitalization, so routine use is not recommended for the first, while the use is not recommended for the sec
ones. There are not recommendations about nebulized hypertonic saline, which however may reduce lengt
inpatients
hospitalization
3.6

Progn

Around half of infants without comorbidity are asymptomatic by 2 weeks after an acute bronchiolitis, but th
small proportion will still have symptoms after 4 weeks. Following acute bronchiolitis, cilial damage persists for
17
weeks
[1].

In some children, intermittent symptoms may continue for several years, particularly with subsequent v
infections, and treatment is difficult, because no studies have shown efficacy of inhaled steroids; one random
controlled trial found that the leukotriene receptor antagonist montelukast may give short term, minor symptom
benefit after acute bronchiolitis, but widespread treatment with montelukast in this setting cannot be recommen
[30,31].

An obliterative bronchiolitis, a rare complication in viral infections, may occur in infants with acute adenov
bronchiolitis, in which there is a disease of the small and large airways associated with bronchiectasis. Symptom
tachypnea, chronic cough, wheeze, chronic sputum productions may persist over the years, with a prolonged oxy
dependency. No effective specific treatment can be recommended: bronchiectasis is treated conventionally
chest
physiotherapy
and
antibiotics
[31].

The relation between RSV infection and subsequent asthma is hotly debated [32,33]. The best evidence is that R
does not cause asthma; however, pre-existing atopy may be a marker for more severe bronchiolitis [34] and a
itself predisposes to asthma. The separation of different phenotypes for preschool wheeze can be very difficult [3
References
1

Scottish Intercollegiate Guidelines Network (SIGN) (2006) Bronchiolitis in children. A national clin
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Worrall G (2008) Bronchiolitis. Can Fam Physician 54: 742-743.

Deshpande SA, Northern V (2003) The clinical and health economic burden of respiratory syncytial v
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Fleming DM, Pannell RS, Cross KW (2005) Mortality in children from influenza and respiratory sync
virus. J Epidemiol Community Health 59: 586-590.

Hall CB (2001) Respiratory syncytial virus and parainfluenza virus. N Engl J Med 344: 1917-1928.

Wong JY, Rutman A, O'Callaghan C (2005) Recovery of the ciliated epithelium following acute bronchio
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Zorc JJ, Hall CB (2010) Bronchiolitis: recent evidence on diagnosis and management. Pediatrics 125:
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Dawson-Caswell M, Muncie HL Jr (2011) Respiratory syncytial virus infection in children. Am

Physician 83: 141-146.

Papadopoulos NG, Gourgiotis D, Javadyan A, Bossios A, Kallergi K, et al. (2004) Does respiratory sync
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Gilca R, De Serres G, Tremblay M, Vachon ML, Leblanc E, et al. (2006) Distribution and clinical impa
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Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS (eds.). Red Book: 2
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Leung AK, Kellner JD, Davies HD (2005) Respiratory syncytial virus bronchiolitis. J Natl Med Assoc
1708-1713.

Stempel HE, Martin ET, Kuypers J, Englund JA, Zerr DM (2009) Multiple viral respiratory pathogen
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Antunes H, Rodrigues H, Silva N, Ferreira C, Carvalho F, et al. (2010) Etiology of bronchiolitis

hospitalized pediatric population: prospective multicenter study. J Clin Virol 48: 134-136.

Jartti T, Korppi M (2011) Rhinovirus-induced bronchiolitis and asthma development. Pediatr All
Immunol 22: 350-355.

Kahn JS (2006) Epidemiology of human metapneumovirus. Clin Microbiol Rev 19: 546-557.

van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, et al. (2001) A newly discovered hu
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Paranhos-Baccal? G, Komurian-Pradel F, Richard N, Vernet G, Lina B, et al. (2008) Mixed respiratory v

infections. J Clin Virol 43: 407-410.

Miller EK, Lu X, Erdman DD, Poehling KA, Zhu Y, et al. (2007) Rhinovirus-associated hospitalization
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Peltola V, Waris M, Osterback R, Susi P, Hyypi? T, et al. (2008) Clinical effects of rhinovirus infection
Clin Virol 43: 411-414.

Korppi M, Kotaniemi-Syrj?nen A, Waris M, Vainionp?? R, Reijonen TM (2004) Rhinovirus-associ

wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis. Pediatr Infect Dis J 23: 9
999.

Viswanathan M, King VJ, Bordley C, et al (2003) Management of bronchiolitis in infants and child
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Paediatric Society of New Zealand (2005) Wheeze and chest infection in infants under 1 year. The Soc
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Henrickson KJ, Hall CB (2007) Diagnostic assays for respiratory syncytial virus disease. Pediatr Infect D
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Ralston S, Hill V (2009) Incidence of apnea in infants hospitalized with respiratory syncytial v
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Willwerth BM, Harper MB, Greenes DS (2006) Identifying hospitalized infants who have bronchiolitis
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Bisgaard H (2003) Study Group on Montelukast and Respiratory Syncytial Virus. A randomized tria
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Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, et al. (1999) Respiratory syncytial virus in e
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4.
4.1

Pneum
Definition

Pneumonia can be defined as an acute inflammation of the parenchyma of the lower respiratory tract, but
definition varies according to the organization, institution or health care setting. The World Health Organiza
(WHO) guidelines include a standardized definition of pneumonia based on clinical signs. The WHO definitio
clinical pneumonia captures a broad spectrum of different pediatric respiratory diseases. The WHO criteria for n
severe pneumonia included: a history of cough and/or difficult breathing of less than 3 weeks duration, with
increased respiratory rate (Rate = 60/min if age <2 months, = 50/ min if age 211 months and = 40/min if age 12
months); (b) lower chest wall in drawing (severe pneumonia); or (c) cyanosis and/or inability to feed or drink (
severe pneumonia). The pneumonia can be divided into community-acquired pneumonia (CAP) and hosp
associated pneumonia. The CAP was defined as pneumonia with onset prior to or less than 72 hours follow
admission to hospital, while the hospital-associated pneumonia was defined as pneumonia with onset 48 hours a
admission
[1,2].

4.2

Epidemio

Pneumonia contributes significantly to global childhood morbidity and mortality. According to a UNICEF-W
report from 2006, over 2 million children die from pneumonia each year, accounting for almost one in five und
deaths worldwide [3]. This is more than the number of deaths associated with any other disease in the wo
including acquired immune deficiency syndrome (AIDS), tuberculosis (TB), or malaria [4]. In 2010, pneumonia
ranked in the United States as the sixth leading cause of death for children one to 4 years of age and the 10th lead
cause of death in adolescents [5]. Globally, the estimated incidence of clinical pneumonia in children aged < 5 y
in developing countries is 0.28 episodes per child-year, whereas in developed countries it is 0.05 episodes per ch
year [6,7]. Thus, ? 155 million episodes of clinical pneumonia occur in children <5 years of age annually, with 11
million
of
these
needing
hospital
admission

The WHO region with the highest number of pneumonia deaths was the African region (with 569,940 post-neon
pneumonia deaths), whereas the regions with the highest percentage of post-neonatal pneumonia deaths were
East Mediterranean and South East Asian regions (with 30.69% and 31.45% of all post-neonatal de
respectively). The countries with the highest number of pneumonia deaths were India, Nigeria, Democratic Repu
of the Congo, Pakistan, Afghanistan and Ethiopia and these accounted for more than 55% of total pneumonia de
[9].

National estimates of absolute and relative pneumonia mortality for post-neonatal children are presented in Figur
and
Figure 1: National estimates of number of pneumonia deaths for children 159 months [9]

Figure 2: National estimates of % pneumonia deaths for children 159 months [9].

When comparing the number of estimated child pneumonia deaths between the years 20002003 [10] and 200
reduction in pneumonia mortality (27 %) is observed. This reduction may be explained by a general decrease in
overall child mortality in developing countries. In particular, in the years 20002003 the average annual
number of child deaths under five years old was 10.4 M, whereas it was 8.8 M deaths in 2008 [11], with a declin
15%.

This reduction in pneumonia mortality is likely due in part to general socio-economic development (fert
maternal education and empowerment) and in part due to development of general health services infrastructure
specific
health
programs
[9].

Recently the introduction of effective new vaccines against bacterial pneumonia, such as Haemophilus influe
type B (Hib) vaccine and pneumococcal conjugate vaccines (PCVs), performed mainly in countries of lo
mortality, had an impact on global pneumonia mortality estimates [12]. Risk factors for CAP are shown in Tab
(Table 1).

Medical Factors

Prematurity
Age < 1 year
Immunosuppression
Malnutrition

4.3

Environmental Factors

Passive tobacco smoke exposure

Winter season
Overcrowding and inadequate housing
Indoor fuel exposure

Etio

Rational treatment for pneumonia depends on knowing the most likely pathogens in each community, as the rela
frequency of different agents may vary from one geographical region to another. However, identifying the ca

pathogen, particularly bacteria, in children with lower respiratory tract infections is particularly difficult and
not establish causality. Conventional or experimental diagnostic tests identified pathogens in 42% to 85% of chil
with community-acquired pneumonia [13-15]. Mixed viral-bacterial infection is found in 23-33% of CAP cases [

Viruses, atypical and typical bacteria cause the vast majority of childhood pneumonia [17,18]. The distributio
pathogens varies with age and clinical setting (Table 2).

Bacteria

Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Mycobacterium tuberculosis

Viruses

Respiratory syncytial virus

Human metapneumovirus
Parainfluenza virus types 1 and 3
Adenovirus
Influenza A or B
Rhinovirus
Human bocavirus

Atypical bacteria

Mycoplasma pneumoniae
Chlamydia pneumoniae

The predominant pathogens vary for children of different age groups:

We
4.4

< 2 months: Gram-negative bacteria, Group B streptococcus, S. aureus, C. trachomatis,

viruses (VRS, Adenovirus, Influenza e Parainfluenza);

2 months - 5 years: S. pneumoniae, H. influenzae, S. aureus, viruses.

> 5 years: similar pathogens as 2 mounths - 5 years age group; in addition M. pneumoniae,
C. pneumonia

describe

below

pneumonia

caused
Bacterial

by

bacterial

and

non-bacterial

cau

Pneum

Bacteria are the major cause of pneumonia mortality in both HIV-uninfected and HIV-infected children [19,
Streptococcus pneumoniae is the commonest cause of bacterial pneumonia in children of all ages and is found in
40 % of cases as a single or co-pathogen [21]. Group A streptococcal pneumonia is much less common an
contributes 1-7 % of cases. Although Staphylococcus aureus is not a common cause of pediatric pneumonia, it
been increasingly encountered in communities where methicillin-resistant Staphylococcus aureus (MRSA
prevalent. Haemophilus influenza type b has almost disappeared because of vaccination. The overall incidenc
pneumonia decreases with age, but it has been reported that the proportion of cases from atypical bacterial pathog
may increase among older children. Mycoplasma pneumoniae and Chlamydophila pneumoniae are more com
causes of pneumonia among school-age children, [21,22]; in fact Mycoplasma infections have been common f

the

age

of

years

and

Chlamydophila

infections

from

the

age

of

10

years

onwards

The difference between the CAP and the hospital-associated pneumonia is in the causing organism: the patho
causing hospital-associated pneumsonia are characteristically different from those causing CAP, with gre
representation of gram-negative bacteria such as Klebsiella pneumoniae and Pseudomonas aeruginosa [

Culture-confirmed Mycobacterium tuberculosis has been identified in 8 % of HIV-infected and HIV-uninfe

children
hospitalized
for
acute
pneumonia
[25

Among bacteria, newly other microbes have been discovered. Simkania negevensis, identified in early 1990s, i
intracellular bacterium that shares many characteristics with Chlamydophila species, such as the growth cy
genomic identity (8087%) and antibiotic spectrum (susceptible to macrolides, tetracyclins and m
fluoroquinolones but resistant to penicillins and cephalosporins). Primary infection seems to happen in e
childhood; 30% of <2-year-old children are seropositive to S. negevensis, compared with only 2% to C. pneumo
[27].

4.4.1 Pathophysiology: The pulmonary host defense is complex and includes mechanical barriers, hum
immunity, phagocytic cells and cell-mediated immunity [28,29].

Mechanical barriers are hairs from the nostrils that filter particles larger than 10 microns, mucoci
clearance, and sharp-angle branching of the central airways that helps the 5- to 10-micron particle
become impacted in the mucosa.

Humoral immunity is represented by mucosal immunoglobulin A (IgA), alveolar immunoglobulin M (Ig

and immunoglobulin G (IgG) present in transudates from the blood.

Phagocytic cells consist of polymorphonuclear (PMN) cells; alveolar, interstitial, and intravasc
macrophages; and respiratory dendritic cells. Alveolar macrophages provide the first defense involve
internalizing and degrading the viral pathogens. They act as antigen-presenting and opsonin-producing ce

Respiratory dendritic cells undergo maturation, activation, and early migration into the regional lymph n
after the viral exposure. They act as antigen-presenting cells and are involved in the activation
differentiation of CD8+ T cells.

Cell-mediated immunity is the most important defense mechanism against the intracellular viral pathog
This immunity is involved in antibody production, cytotoxic activity, and cytokine production. C
memory or effector T cells tend to dominate the lymphocyte component of the virus-induced inflamma

component.

Pneumonia is characterized by inflammation of the alveoli and terminal airspaces in response to invasion by
infectious agent [30]. In non-hospitalized children, bacteria reach the lung by one of four routes [30]:

1. Inhalation of microorganisms that have been released into the air when an infected individual cough
sneezes.
2. Aspiration of bacteria from the upper airways.
3. Spread from contiguous infected sites.
4. Hematogenous spread.

The activated inflammatory response often results in targeted migration of phagocytes, with the release of t
substances from granules and the initiation of poorly regulated cascades (e.g., complement, coagulation, cytokin
These cascades may directly injure host tissues and adversely alter endothelial and epithelial integrity, vasom
tone, intravascular hemostasis, and the activation state of fixed and migratory phagocytes at the inflammatory fo
[31]. Pulmonary injuries are caused directly and/or indirectly by invading microorganisms [29,30

Direct injury by the invading agent usually results from synthesis and secretion of microbial enzymes, proteins, t
lipids, and toxins that disrupt host cell membranes, metabolic machinery, and the extracellular matrix that usu
inhibits
microbial
migration
[29

Indirect injury is mediated by structural or secreted molecules, such as endotoxin, leukocidin, and toxic sh
syndrome toxin-1 (TSST-1), which may alter local vasomotor tone and integrity, change the characteristics of
tissue perfused, and generally interfere with the delivery of oxygen and nutrients and removal of waste prod
from local tissues [32]. On a macroscopic level, the invading agents and the host defenses both tend to incr
airway smooth muscle tone and resistance, mucus secretion, and the presence of inflammatory cells and debr
these secretions. These materials may further increase airway resistance and obstruct the airways, partially or tot
causing
air
trapping,
atelectasis,
and
ventilatory
dead
space
[30].

Four stages of lobar pneumonia have been described. In the first stage, which occurs within 24 hours of infect
the lung is characterized microscopically by vascular congestion and alveolar edema. Many bacteria and
neutrophils are present. The stage of red hepatization, so called because of its similarity to the consistency of live
characterized by the presence of many erythrocytes, neutrophils, desquamated epithelial cells, and fibrin within
alveoli. In the stage of gray hepatization, the lung is gray-brown to yellow because of fibrinopurulent exud
disintegration of RBCs, and hemosiderin. The final stage of resolution is characterized by resorption and restora
of the pulmonary architecture. Fibrinous inflammation may lead to resolution or to organization and ple
adhesions
[33].

When a bacterial infection is established, the diseases process varies according to the causative organ
Pneumococcal pneumonia remains the most common type of bacterial pneumonia and its pathophysiology has b

extensively studied. The initial step in the development of this disease is the attachment of S. pneumoniae to cell
the nasopharynx and subsequent colonization. Colonization alone, however, does not cause clinical manifestation
illness because perfectly healthy people can harbor the microbe without evidence of infection. Factors that pe
pneumococci to spread beyond the nasopharynx include the virulence of the strain, impaired host def
mechanisms, and viral infections of the respiratory tract. Viruses can damage respiratory tract lining cells, enha
bacterial adherence, and increase the production of mucus, which protects pneumococci from phagocytosis. In
alveoli, pneumococci infect type II alveolar cells and adhere to alveolar walls, causing an outpouring of fluid,
and white blood cells, and fibrin from the circulation, which, in turn, results in consolidation of the lung. Fluid in
lower airways creates a medium for further multiplication of bacteria and aids in the spread of infection thro
pores
of
Kohn
into
adjacent
regions
of
the
lung
[

Instead the pathogenicity of M. pneumoniae is linked to the 2 properties. The first is a selective affinity
respiratory epithelial cells, and the second is the ability to produce hydrogen peroxide, which is responsible for m
of the initial cell disruption in the respiratory tract and for damage to erythrocyte membranes. M. pneumoniae h
notable motility and specialized filamentous tips end that allows it to burrow between cilia within the respira
epithelium,
eventually
causing
sloughing
of
the
respiratory
epithelial
cells
[

4.4.2 Symptoms and signs: The clinical presentation of bacterial pneumonia varies from a mildly ill, ambula
patient to a critically ill patient with respiratory failure or septic shock. The symptoms of pneumonia may
nonspecific, especially in infants and younger children. The sudden onset of symptoms with rapid progression of
illness is typical of bacterial pneumonia. A thorough past medical history and history of potential exposures
usually obtained. If the patient has been healthy previously, the cause of pneumonia is usually Mycoplasma
gram-positive microbe. However, if the patient has been hospitalized, gram-negative microbes are suspec
Although not diagnostic of a particular causative agent, characteristics of the sputum may suggest a partic
pathogen. Pneumococci may cause bloody or rust-colored sputum. Patients with Pseudomonas, Haemophilus
pneumococcal infections are known to expectorate green sputum. Klebsiella and type 3 pneumococci cause
production
of
thick,
dark
red
sputum
[36].

In general, respiratory distress (tachypnea, nasal flaring, decreased breath sounds, cough, and rales) and fever are
prominent
symptoms
associated
with
pneumonia
(Table
3)
(
Table 3: Criteria for Respiratory Distress in Children with Pneumonia [22]

Signs of Respiratory Distress

1.Tachypnea, respiratory rate, breaths/min*

Age 02 months: > 60

Age 212 months: > 50

Age 15 Years:

> 40

Age > 5 Years:

> 20

2. Dyspnea

3. Retractions (suprasternal, intercostals, or subcostal)

4. Grunting

5. Nasal flaring

6. Apnea

7. Altered mental status

8. Pulse oximetry measurement < 90% on room air

*Adapted from World Health Organization criteria.

Infants and children with mild to moderate infection most commonly have a temperature < 38C and a respira
rate < 50 breaths per minute (bpm). Children with severe CAP commonly present with a temperature > 38C, fla
of nostrils, grunting with breathing, tachypnea, tachycardia, and cyanosis. Although respiratory rate is a valu
clinical sign, the work of breathing (as evidenced by nasal flaring, breathlessness, cough, or wheeze) required by
infant
or
child
may
be
more
indicative
of
pneumonia
[37].

Rigors or severe shaking chills may be observed with any infectious process. However, and for reasons that are
clear, the presence of rigors suggests pneumococcal pneumonia more often than pneumonia caused by o
bacterial pathogens. A significant persistent cough may predominate in pneumonia caused by M. pneumoniae [3

Patients may complain of non-specific symptoms that include headache, malaise, nausea, vomiting, and diarr
myalgia, shortness of breath, abdominal pain, loss of appetite and unintentional weight loss. Sharp or stabbing c
pain worsened by deep breathing or coughing and secondary to pleuritis is a common symptom of pneumoco
infection,
but
may
also
occur
with
other
types
of
pneumonia
[

Pneumonia by typical respiratory bacterial pathogens have the greatest inflammation and disease severity
evidenced by high temperature (> 38.4C) within 72 hours after admission, association with pleural effusions,
percentage of band forms, elevated levels of procalcitonin, prolonged hospitalization, and a relatively
proportion of patients requiring assisted ventilation and readmission to hospital [40]

Leukocytosis (> 15.000 white blood cells/mm3) with a shift to the left and a predominance of neutrophils in
circulation may be observed with any bacterial infection. However, its absence, particularly in patients who
debilitated should not cause the clinician to discount the possibility of a bacterial infection. Leukopenia
threatening sign of impending sepsis. An assessment of the arterial blood gases is essential to determine if hos
admission or oxygen supplementation is indicated and may reveal hypoxemia and respiratory acidosis. A p
oximetric
finding
that
is
<
90%
indicates
significant
hypoxemia
[39].

Physical signs suggesting consolidation include dullness to percussion, increased tactile fremitus, reduced no
vesicular breath sounds and increased bronchial breath sounds, all of which can be difficult to detect in yo
children. Fine end-inspiratory crackles are typical for pneumonia in children [23]. Furthermore, the presenc
wheezing should suggest the possibility that radiographic changes may be due to atelectasis and mucous plug
from
asthma
or
bronchiolitis
rather
than
pneumonia.

Finally, signs of an effusion are dullness to percussion, decreased tactile fremitus, and decreased or absent br
sounds,
associated
with,
in
some
cases,
signs
of
dehydration
and/or
sepsis
[

4.4.3 Diagnostic tests: The etiology of pneumonia is difficult to determine in children because few children s
bacteremia, and most cannot provide a sputum sample. If adequate sputum is available, it should be sent for G
staining and subsequent culture [42]. Culture of pleural fluid is suggested if it can be sampled. Additional invasiv
molecular testing should be pursued if the child fails to improve or worsens on ther

Specimens for culture from the lower respiratory tract can be obtained using sputum induction [43], endotrac
aspiration in intubated children and bronchoalveolar lavage (BAL). The isolation of bacteria from these sam
may, however, represent contamination with bacteria that normally colonize the nasopharynx. A gram stain
expectorated sputum helps to distinguish bacterial from viral pneumonia and gram-negative from gram-pos
microbes
[42].

Blood culture may be useful to identify bacterial pathogens and their antimicrobial sensitivity, but only about 5%
blood cultures are positive in HIV-uninfected children with bacterial CAP. The sensitivity of blood cultures is gre
in HIV-infected children, in whom approximately 18% of cultures are positive [44]

Blood cultures should not be routinely performed in nontoxic, fully immunized children with CAP managed in
outpatient setting. Blood cultures should be obtained in children who fail to demonstrate clinical improvement an
those who have progressive symptoms or clinical deterioration after initiation of antibiotic therapy. Blood cult
are not necessary repeated in children with clear clinical improvement to document resolution of pneumoco
bacteremia
[22].

Urinary antigen detection tests are not recommended for the diagnosis of pneumococcal pneumonia in chil
because
false-positive
tests
are
common
[22].

General tests of infection including acute phase reactants [erythrocyte sedimentation rate (ESR), C-reactive pro

(CRP)], white cell count (WBC), neutrophil count and procalcitonin may not differentiate between bacterial
viral pneumonia [45-47]. In patients with more serious disease, such as those requiring hospitalization or those
pneumonia-associated complications, acute-phase reactants may be used in conjunction with clinical finding
assess
response
to
therapy
[22].

Pulse oximetry is performed in all children with pneumonia and suspected hypoxemia. The presence of hypoxe
guides
decisions
regarding
site
of
care
and
further
diagnostic
testing
[

Serological tests are performed for Chlamydia and Mycoplasma. The presence of Mycoplasma and Chlam
immunoglobulin M and G antibodies contributes to the diagnosis; acute infection of Chlamydia is indicated b
IgM titer = 1:16 or by a = 4-fold rise in IgG titer, while an acute infection of Mycoplasma is indicated by an
titer
=
1:10
or
by
a
=
4-fold
rise
in
IgG
titer
[48,49].

Tuberculin skin testing (Mantoux method) and induced sputum or gastric lavage are indicated when TB is suspe
[50]. A Chest radiographs (CXRs) may be useful for confirming the presence of pneumonia and detec
complications such as a lung abscess or empyema. CXRs are however less useful for discriminating betw
causative pathogens and cannot accurately discriminate between viral and bacterial pneumonia [51
CXRs reveal white shadows in the involved area indicative of an alveolar inflammatory process and may
indicate the following [39]:

A segmental or lobar opacity is observed with S. pneumonia.

Cavitary lesions and bulging lung fissures are caused by K. pneumoniae and S. aureus.

Cavitation and pleural effusions are caused by S. aureus and gram negative infections.

Focal infiltrates are caused by atypical pathogens, M. pneumoniae or C. pneumonia.

Routine chest radiographs are not necessary for the confirmation of suspected CAP in patients well enough t
treated
in
the
outpatient
setting
[

Indications for CXR include: clinical pneumonia unresponsive to standard ambulatory management; suspe
pulmonary TB; suspected foreign body aspiration; hospitalized children to detect complications. CXRs may als
considered in children presenting with high fever, leukocytosis and no obvious focus of infections, s
approximately 26% of such children may have radiographic evidence of pneumonia [22

Follow-up films after acute uncomplicated pneumonia are of no value where the patient is asymptomatic [53
follow-up CXR is performed: in children with lobar collapse; to document resolution of a round pneumonia (as
may mimic the appearance of a Ghon focus); and in those with ongoing respiratory symptoms [2

Bronchoscopic or blind protected specimen brush sampling, bronchoalveolar lavage (BAL), percutaneous
aspiration, or open lung biopsy are reserved for the immunocompetent child with severe CAP if initial diagno
tests
are
not
positive
[22].

4.4.4 Treatment: The choice of antibiotics is influenced by the epidemiology of the infecting organisms in the a
prevalence of drug resistance, HIV prevalence and available resources. As it is difficult to distinguish betw
pneumonia caused by bacteria and that caused by viral infection, and because of the frequency of mixed bacte
viral infections [54], children with pneumonia require an antibiotic. Antimicrobial therapy is not routinely requ
for preschool-aged children with CAP, because viral pathogens are responsible for the great majority of clin
disease. For patients with a suspected bacterial pathogen, start empiric antibiotic therapy as soon as possible (Tab
and 5). Most bacterial pneumonia is responsive to amoxicillin, making it the antibiotic of choice. Amoxicillin sh
be used as first-line therapy for previously healthy, appropriately immunized infants and preschool children
mild to moderate CAP suspected to be of bacterial origin. Amoxicillin provides appropriate coverage
Streptococcus
pneumoniae,
the
most
prominent
invasive
bacterial
pathogen
[22,55].

Table 4: Guidelines for empirical antimicrobial therapy for previously healthy children three months to 17 year
age with community-acquired radiologically proven pneumonia of suspected bacterial etiology [132].

Step 1: assess severity and features of pneumonia:

A. Most cases of nonsevere pneumonia ? high-dose amoxicillin oral or ampicillin IV
B. Non-severe pneumonia with primary features of atypical pneumonia (subacute onset, prominent
cough, minimal leukocytosis and a non-lobar infiltrate, usually in a school-age child) ?
clarithromycin oral or azithromycin oral
C. Severe pneumonia ? ceftriaxone IM/IV or cefotaxime IV plus clarithromycin oral or azithromycin
oral/IV

Step 2: assess whether child has proven or clinically suspected influenza plus evidence of secondary
bacterial infection, consider adding an antiviral for influenza and use the following instead of the
antibiotics from step 1:
A. Non-severe pneumonia ? amoxicillin/clavulanate oral or cefuroxime IV
B. Severe pneumonia ? ceftriaxone IM/IV or cefotaxime IV plus clarithromycin oral or azithromycin
oral/IV. Some experts advise also adding cloxacillin IV

Step 3: If the child also has a pleural effusion:

A. Small effusion ? follow carefully for clinical deterioration and use antibiotics as directed in steps 1
and 2
B. Moderate to large effusion ? consider pleural tap. Treat with ceftriaxone or cefotaxime instead of
antibiotics in steps 1 and 2. Some experts recommend adding clindamycin

Step 4: If the child has features that indicate pneumonia could be due to methicillin-resistant
Staphylococcus aureus, add vancomycin or linezolid to the antibiotics chosen after steps 1, 2 and 3.

Ceftriaxone or cefotaxime may offer better coverage than amoxicillin or ampicillin for penicillin-resis

pneumococcus (although this remains controversial), and offer improved coverage for Haemophilus influenzae
Moraxella catarrhalis, but these are rare causes of pneumonia in healthy, immunized children. Clarithromycin
azithromycin do not always cover pneumococcus, so they should be reserved for children with suspected atyp
pneumonia. Additionally, in patients who fail to improve after 48 h of therapy with a beta lactam alone (penic
such as ampicillin or cephalosporins), one should first rule out an empyema and then consider adding clarithrom
or azithromycin for atypical pneumonia.
Table 5: Doses of antimicrobials for suspected or proven bacterial pneumonia [132]

Antibiotic

Route

Regimen

Amoxicillin

PO

75100 mg/kg/day divided tid* - Maximum 1 g tid

Amoxicillin clavulanate

PO

75100 mg/kg/day of amoxicillin component divided tid

Maximum 500 mg tid

Ampicillin

IV

200 mg/kg/day divided q6h - Maximum 2 g q6h

Azithromycin

IV/PO

10 mg/kg day 1; 5 mg/kg days 25

Maximum 500 mg day 1; 250 mg days 25

Cefprozil

PO

30 mg/kg/day divided bid - Maximum 500 mg bid

Cefotaxime

IV

200 mg/kg/day divided q6h -Maximum 1500 mg to 2 g q6h

Ceftriaxone

IV

75100 mg/kg/day divided q12h or q24h

Maximum 2 g daily

Cefuroxime axetile

PO

30 mg/kg/day divided tid - Maximum 500 mg tid

Cefuroxime

IV

150 mg/kg/day divided q8h - Maximum 1.5 g q8h

Clarithromycin

PO

15 mg/kg/day divided bid - Maximum 500 mg bid

Clindamycin

PO

3040 mg/kg/day divided tid - Maximum 450 mg tid

Clindamycin

IV

40 mg/kg/day divided q8h - Maximum 600 mg q8h

Linezolid

Vancomycin

IV/PO

IV

<40 kg: 30 mg/kg/day divided tid

12 years of age or older 600 mg bid

40 mg/kg/day divided qid - Maximum 500 mg qid

*Although twice daily (bid) dosing is adequate for otitis media, three times daily (tid) dosing is recommended
pneumonia; Alternatively, one could supplement 50 mg/kg/day of amoxicillin-clavulanate with 25 mg/kg/day t
mg/kg/day of amoxicillin to reduce the risk of diarrhea with use of amoxicillin-clavulanate alone. Higher d
may be indicated for highly resistant strains of methicillin-resistant Staphylococcus aureus. IV Intravenously;
Orally; q6h Every 6 h; q8h Every 8 h; q12h Every 12 h; q24h Every 24 h; qid Four times daily.

If atypical pathogens are suspected, then macrolide antibiotics become the antibiotic drug class of choice,
azithromycin
being
the
preferred
first-line
agent
[22,56-

When the previous penicillin allergic reaction is suspected, all beta-lactams should be avoided. For children
non-severe pneumonia treated as outpatients, clarithromycin and azithromycin are reasonable choices, while kee
in
mind
that
pneumococcal
resistance
to
antimicrobials
is
increasingly
common
[

The guidelines strongly recommend hospitalization for infants and children with respiratory distress or hypoxe
(oxygen saturation <90%); for suspicion of infection caused by community-acquired methicillin-resis
Staphylococcus aureus or any pathogen with high virulence; for infants 3 to 6 months old; or for family unabl
provide
appropriate
care
[22].

Treat with parenteral antibiotics to provide reliable blood and tissue concentrations [55]. Ampicillin or penicilli
may be given to fully immunized infants and school-aged child admitted to a hospital; however, take into acc
the local resistance pattern of S. pneumoniae to drugs within the penicillin class. For hospitalized children who
not yet fully immunized, who have life-threatening infections, or who are in a facility with a documented high
of penicillin resistance, administer a third-generation parenteral cephalosporin such as ceftriaxone or cefotax
empirically [59]. In monotherapy treatment of pneumococcal pneumonia, non-beta-lactam agents such
vancomycin have not been shown to be more effective than the third-generation cephalosporins. If S. aureus is
suspected microorganism or is confirmed with clinical, laboratory, or imaging characteristics, give vancomyci
clindamycin with a beta-lactam agent [60,61]. When atypical pathogens such as M. pneumoniae or C. pneumonia
suspected, empiric therapy start with an oral or parenteral macrolide in combination with a beta-lactam [

Once a pathogen has been identified, adjust antimicrobial therapy as needed to target the specific microbe, to l
empiric antibiotic exposure, and to help limit the potential for antibiotic resistance. The recommended duratio
treatment for CAP is 10 days, supported by clinical data and the practice guidelines [22,62-64]. Shorter treatm
courses may be effective, especially in mild cases or outpatient treatment (5 days). Specific pathogens, suc
MRSA, may need to be treated longer, exactly for 7-21 days [65]. Vancomycin has been the drug of choice
MRSA infections for many years. Recent data suggest that linezolid may be superior to vancomycin in the treatm
of MRSA nosocomial pneumonia, but prospective, randomized studies are needed before linezolid is recommen
as the preferred first-line therapy. Other approved agents for nosocomial MRSA infections, such
quinupristin/dalfopristin and daptomycin, should not be used in the treatment of MRSA pneumonia, as they w
inferior in clinical trials. Tigecycline has excellent activity against MRSA in vitro, but should not be routinely
for the treatment of MRSA pneumonia, as clinical data are lacking [66]. If a patient is receiving intraven
antibiotics it is possible to switch to an oral agent when the clinical condition are improved to decrease risks f
parenteral administration and to plan for the earliest possible discharge from the hospital. Hospital discharge ma
considered when a child is clinically stable (improved appetite and activity level, afebrile for 24 hours, thor
objectivity improved), mental status is back to baseline or stable, and the pulse oximetry level is > 90% on room
for at least 24 hours. Children receiving adequate therapy regimens should demonstrate both clinical and labora
signs of improvement within 48 to 72 hours [22]. If improvement does not occur, further investigations shoul
carried, such as additional cultures to identify whether the original pathogen persists or it has developed resistanc
the agent used, laboratory tests, and imaging evaluation to assess the extent and progression of the pneumoni
parapneumonic
process.

In addition to antibiotics, careful supportive management is required for children with CAP. Oxygen therapy is u
when there is: central cyanosis; lower chest in drawing; grunting; restlessness; inability to drink or feed;
respiratory rate > 70 breaths per minute [67-71]. Children with uncomplicated pneumonia should receive nor
maintenance fluids. Appropriate rehydration is required in children who are dehydrated [22

Children with pneumonia require a minimum of 50-60 kcal/kg/day, that needs to be considerably increase
malnutrition exist or following several days of poor nutrition. Vitamin A is not given to children with a
pneumonia unless this is measles associated [72-73]. There is no evidence that vitamin A improves outcome in
measles pneumonia [72]. Therefore zinc is considered for use in children hospitalized with pneumonia, particul
if
there
is
coexisting
malnutrition
[74].

Specific preventive strategies may reduce the incidence and the severity of pneumonia. All children should
immunized with vaccines for bacterial pathogens, including S. pneumoniae, Haemophilus influenza type b,
Pertussis to prevent CAP [22]. Parents and caretakers of infants, 6 months of age, including pregnant adolesce
should be immunized with vaccines for influenza virus and pertussis to protect the infants from expos
Pneumococcal CAP after influenza virus infection is decreased by immunization against influenza virus [

Chest physiotherapy (CPT) is an important adjuvant in the treatment of most respiratory illnesses in chil
compared to adults. In general, it is accepted that application of manual techniques in patients with consolidation
no beneficial effect; however, the wider role that physiotherapy may play should be considered in term
positioning to optimize ventilation and perfusion. Once the consolidatory phase begins to resolve, c
physiotherapy techniques might have some benefit in mobilizing and clearing secretions, especially in the wea
uncooperative
child
[

Chest physiotherapy is an airway clearance technique that consists of manual percussion of the chest wall by
caregiver, strategic positioning of the patient for mucus drainage with cough and breathing techniques. It is us
for individuals with copious mucus or thick secretions, those with weak respiratory mechanics or those
ineffective
cough
[76].

CPT consists of various manipulative procedures like postural drainage, chest percussion, vibration, thor
squeezing and cough stimulation. Breathing exercise is an integral part of chest physiotherapy. It plays a signifi
role in airway clearance and parenchymal expansion by improving the efficiency of respiratory muscles. Post
drainage prevents the accumulation and enhances mobilization of bronchial secretion from the airway utili
gravity to facilitate drainage. CPT should be done 1-4 times a day, preferably half an hour before meals or one
half hour after meals. The total duration should not exceed 30 minutes with 3-6 minutes in each position [7

4.4.5 Complications: Complications of pneumonia are usually a consequence of direct spread of bacterial infec
in the chest cavity (empyema, pleural effusion) or bacteremia with hematogenous spread (Table 6). Mening
suppurative arthritis and osteomyelitis are rare complications of hematogenous spread of infection by S. Pneumo
[77] or by H. Influenzae. Complications of bacterial pneumonia in children include pleural effusion, empyema,
abscess,
pneumatocele
and
necrotizing
pneumo

Empyema is associated with 3% of all pneumonia hospitalizations [78] and up to one third of pneumoco
pneumonia hospitalizations [79]. Empyema causes significant morbidity, with prolonged hospitalizations [80]
multiple invasive procedures. Occasionally, the infectious agent invades the pleura to cause pediatric paraneum
empyema characterized by the presence of pus [81]. Empyema is a term derived from the Greek verb empyein
suppurate) and literally refers to frank pus in the pleural space. Empyema and parapneumonic effusion complica
pneumonia has increased dramatically in children in the UK over the last decade [82-83]. Empyema and com
parapneumonic effusion represent parts of a spectrum of disease, with three stages of progression (exuda
fibropurulent, organizational). Streptococcus pneumoniae has been found to be the principal pathogen in childh
empyema in the USA, with serotype 1 accounting for 2450% of culture positive cases between 1993 and 2000
85]. The treatment options for parapneumonic effusions range from non-invasive antibiotic therapy and observa
to semi-invasive techniques such as therapeutic aspiration, tube thoracostomy and intrapleural fibrinolytics
invasive
interventions
such
as
thoracoscopy,
thoracotomy
or
open
drainage
[86].
4.5

Non-Bacterial

Pneum

Viruses may act as sole pathogens in pediatric CAP or predispose to bacterial pneumonia [87-89]. Viral pathog
are more common causes of CAP in children younger than 2 years, accounting for 80% of cases [22]. V
etiologies vary by geography, season, and the age of patients studied, but Respiratory Syncytial Virus (RSV), Hu
Rhinovirus (hRV), Adenovirus, Human Bocavirus (hBoV), Human Metapneumovirus (hMPV), and Parainflu
Viruses (PIV) are described consistently as the most common viruses associated with CAP in children. Vir
usually circulate in winter (e.g., RSV, influenza, PIV and hMPV) and as a sole cause of pneumonia are less com
in
older
children
with
the
exception
of
influenza
[90].

RSV is the commonest cause of viral CAP, especially in the first 3 years of life. RSV causes significant mort
and morbidity in both HIV-infected and uninfected children, especially in children born prematurely and who
less than 6 months of age at the onset of the RSV season. HIV-infected children with RSV are more likely to dev
pneumonia
rather
than
bronchiolitis
compared
with
HIV-uninfected
children
[

PIV is a common virus that infects most persons during childhood. PIV is second in importance to only RSV
causing lower respiratory tract disease in children and pneumonia and bronchiolitis in infants younger than 6 mo
[91]. Adenovirus accounts for 10% of pneumonias in children and can occur at any time of the ye

hMPV is a relatively newly discovered respiratory pathogen. It was recognized 10 years ago [92] and shares m
properties with RSV, including human beings as the only hosts, a similar seasonality and nearly identical clinical
laboratory features [93-94]. hMPV is in the Paramyxoviridae family (like RSV and PIV) and is a pleomorp
shaped virus surrounded by surface protein projections. Children aged <5 are susceptible to hMPV infection,
infants aged <2 with primary infection are at risk of severe infection [94-95]. hMPV and hBoV are found in 8-1
and
?
5%,
respectively
[16].

The fungal pneumonia in children is a rare condition, and is often seen in individuals with compromised imm
system like AIDS. The most common fungal agents that cause pneumonia in children are Histoplasma capsulat
Cryptococcus neoformans, Pneumocystis jiroveci, Blastomyces and Coccidioides immitis [96]. Pneumoc
jiroveci (previously P. carinii) pneumonia (PCP) is a common, serious infection among HIV-infected children an
associated with high mortality. Infants aged 6 weeks 6 months are at highest risk for infection; PCP is
predominant cause of pneumonia mortality in HIV-infected children less than 6 months of age [97]. PCP has
been described in malnourished children and in young HIV-exposed uninfected infants

4.5.1 Pathophysiology: After contamination, most respiratory viruses tend to multiply in the epithelium of the u
airway and secondarily infect the lung by means of airway secretions or hematogenous spread. Severe pneumo
may result in extensive consolidation of the lungs with varying degrees of hemorrhage. Some patients sho
bloody
effusions
and
diffuse
alveolar
damage
[98].

The mechanism of damage to tissues depends on the virus involved. Viral infections are characterized by
accumulation of mononuclear cells in the submucosa and perivascular space, resulting in partial obstruction of
airway. Some viruses are mainly cytopathic, directly affecting the pneumocytes or the bronchial cells. With oth
over exuberant inflammation from the immune response is the mainstay of the pathogenic process. Imm
responses can be categorized according to patterns of cytokine production. Type 1 cytokines promote cell-medi
immunity,
while
type
2
cytokines
mediate
allergic
responses
[

In addition to humoral responses, cell-mediated immunity appears to be important for recovery from cer
respiratory viral infections. Impaired type 1 response may explain why immunocompromised patients have m
severe viral pneumonias. Respiratory viruses damage the respiratory tract and stimulate the host to release mul
humoral factors, including histamine, leukotriene C4, and virus-specific immunoglobulin E in RSV infection
bradykinin, interleukin 1, interleukin 6, and interleukin 8 in rhinovirus infections. RSV infections can also
bacterial colonization patterns, increase bacterial adherence to respiratory epithelium, reduce mucociliary cleara
and
alter
bacterial
phagocytosis
by
host
cells.

The mechanism of viral transmission varies with the type of virus. Routes include large-droplet spread over s
distances (<1 m), hand contact with contaminated skin and subsequent inoculation onto the nasal mucos
conjunctiva (e. g., rhinovirus, RSV), and small-particle aerosol spread (e. g., influenza, adenovirus). Some vir
are extremely fastidious, whereas others have the capability of surviving on environmental surfaces for as long
hours,
on
gloves
for
2
hours,
and
on
hands
for
30
minu

4.5.2 Signs and symptoms: The clinical manifestations of viral pneumonia vary because of the number of div

etiologic agents. The common constitutional symptoms of all viral pneumonias are fever, chills, nonproduc
cough, rhinitis, myalgias, headaches, and fatigue. Symptoms of viral pneumonia are similar to that of bact
pneumonia, although studies have shown a lower probability of having chest pain and rigors in viral pneumo
[100]. Most patients have cough. Ascertaining immunization status, travel history, and possible exposur
important. During outbreaks with the usual respiratory viruses, the signs and symptoms can suggest the cor
diagnosis
in
most
ca

The typical infection with influenza virus consists of a sudden onset of fever, chills, myalgia, arthralgia, cough,
throat, and rhinorrhea. The incubation period is 1-2 days, and symptoms normally last 3-5 days. These symptoms
common to other respiratory viral infections but are highly suggestive of influenza virus infection when an outb
is occurring in the community. Influenza is usually seen in epidemics and pandemics in late winter and early spr

Peak attack rates for RSV occur in the winter in infants younger than 6 months. PIV infection most often occur
the late fall or winter, although PIV-3 pneumonia is especially common in the spring [1

Pneumonia caused by PCP is frequently (20-40 %) the initial presenting feature of AIDS in HIV-infected chil
not taking cotrimoxazole prophylaxis [102-103]. Although PCP may present with a tetrad of features compri
tachypnea, dyspnea, fever and cough, these are not specific for pneumonia caused by P. jiroveci. Hypoxia ma
prominent and rapidly progressive. Other stigmata of AIDS such as hepatosplenomegaly and general
lymphadenopathy are not always present and adventitious sounds in the chest may be absent despite clinical sign
severe
respiratory
dist

4.5.3 Diagnostic tests: The currently validated methods to define the etiology of viral infection are serology, cul
cytological evaluation, rapid detection of antigens, and gene amplification techniques, even though they are
widely
available
and
are
often
co

Virtually all viruses can be diagnosed through serology. However, it is necessary to collect paired blood sam
(acute/convalescent phases), as a four-fold titer increase in relation to the first sampling is necessary to confirm
diagnosis. Therefore, serology is not routinely used, as it has been shown to be of little use in the acute phase of
disease, because titers rarely increase at this stage [22]. Serology is available for many of the community respira
viruses
such
as
Adenovirus,
RSV,
and
seasonal
Influe

Viral culture can also be employed for most of the respiratory viruses, with the long time necessary to obtain
results being a disadvantage, as well as the need for specific culture mediums. To perform the cultures, ti
samples from the upper and/or lower airways, sputum, and nasopharyngeal and bronchoalveolar lavage can be u
The cytopathic effects of the viruses are observed in cell cultures, such as the formation of syncytial collection
multinucleated giant cells, or evidence of viral growth. The subsequent identification of specific viruses in
cultures may be accomplished by immunofluorescence techniques (direct or indirect), or nucleic acid probes. O
disadvantages of this method are high cost, low availability in clinical practice, and also the low yield for s
specific
agents
such
as
RSV,
hMPV,
and
Coronavirus
[

Cytological assessment use samples from respiratory tissues and also secretions such as nasal and bronchoalve
lavage. The technique aims at identifying nuclear (virus DNA) or cytoplasmic (virus RNA) inclusions, which
normally present in infected cells. The identification of the presence of such inclusions confirms the diagnosis [

These are rapid tests performed in easily obtainable specimens, such as nasal swab or wash. The enzyme-lin

immunosorbent assay (ELISA) test is available for most pathogenic respiratory viruses; it is capable of detec
viral
antigens,
whereas
the
immunofluorescence
requires
intact
infected
cells
[22].

The polymerase chain reaction (PCR) or reverse transcriptase-polymerase chain reaction (RT-PCR) techniques
extremely sensitive and specific to detect virus presence. It is the examination of choice for most respiratory vir
and, if available, should be employed together with the aforementioned diagnostic methods. The cur
development of this technique has allowed the knowledge of new causative agents of bronchiolitis and pneumon
both pediatric and adult populations. This method can be applied to samples of nasopharyngeal or bronc
secretion swabs, and has the advantage that it can be performed in other body fluids [

A new molecular technique called multiplex reverse transcriptase polymerase chain reaction (MRT-PCR) allows
the rapid detection of several respiratory viruses such as influenza A and B; RSV A and B; HPIV 1, 2, and 3; hM
and
adenovirus
[1

Radiological confirmation is required whenever possible to support the clinical diagnosis and if the child h
worsening of the clinical condition. Poorly defined nodules and patchy areas of opacity with variable hyperinfla
and without effusion are more indicative of a viral etiology [105], but some features are characteristic of indivi
viruses.

Radiographic findings in Influenza pneumonia are nonspecific and can be seen as perihilar and peribronc
opacities, consolidations, and diffuse bilateral interstitial opacities, especially in more severe forms of the dise
RSV pneumonia typically presents with patchy bilateral alveolar infiltrates and interstitial changes (simila
influenza)
[1

In PIV pneumonia chest radiographs may reveal findings ranging from focal infection to diffuse interstitial infiltr
or diffuse mixed alveolar-interstitial infiltrates consistent with acute lung injury. Adenovirus pneumonia usu
presents with diffuse, bilateral and patchy, ground-glass infiltrates with a preference for lower lobes, although it
present with lobar consolidation [106]. Common, but no specific radiographic finding of severe PCP is diffus
scattered
ground-glass
opacification
[107].

4.5.4 Treatment: Children less than 2 years of age are commonly infected with viral pathogens. Those with
cases of viral CAP do not require anti-microbial therapy. For children with moderate-to-severe CAP consistent
influenza infection, administer influenza antiviral therapy as soon as possible, especially during a widespread l
circulation of influenza viruses (Table 7) [22]. Some influenza A strains will be susceptible to antiviral therapy, e
though genetic variability is high each year. Early antiviral treatment has been shown to provide maximal ben
therefore treatment should not be delayed until confirmation of positive influenza test results. Negative result
influenza diagnostic tests do not conclusively exclude influenza disease. Treatment after 48 hours of symptom
infection may still provide clinical benefit to those with more severe disease [
Table 7: Influenza antiviral therapy in pediatric patients [22]

Drug (Brand name)

Formulation

Dosing

Oseltamivir (Tamiflu)

75 mg capsule;

4-8 mo: 6 mg/kg/d in 2 doses

60 mg/5 mL suspension

9-23 mo: 7 mg/kg/d in 2 doses

>24 mo: -4 mg/kg/d in 2 doses, for 5 days
Si 5 kg: 60 mg/d in 2 divided doses
>15-23 kg: 90 mg/d in 2 divided doses
>23-40 kg: 120 mg/d in 2 divided doses
>40 kg: 150 mg/d in 2 divided doses

Zanamivir (Relenza)

5 mg per inhalation, using a >7 y: 2 inhalations (10 mg total per dose),

Diskhaler
twice daily for 5 days

Amantadine (Symmetrel)

100 mg tablet;
50 mg/5 mL suspension

1-9 y: 5-8 mg/kg/d as single daily dose or in 2

doses; not to exceed 150 mg/d
9-12 y: 200 mg/d in 2 doses
(not studied as a single dose)

Rimantadine (Flumadine)

100 mg tablet;
50 mg/5 mL suspension

Not FDA approved for treatment in children,

but published data exist on safety and efficacy
in children
Suspension: 1-9 y: 6.6 mg/kg/d (max 150
mg/kg/d) in 2 doses; >10 y: 200 mg/d, as
single daily dose or in 2 doses

Children with chronic pulmonary, cardiovascular or immunosuppressive disease or those on aspirin should
vaccinated annually at the start of the influenza season. Children between 6 months and 9 years of age who have
been vaccinated previously require 2 immunizations of a single dose given 1 month apart; children who are o
than 9 years or those who have been immunized previously require only a single immunization. Immune prophyl
with RSV specific monoclonal antibody is also considered for premature infants or those with bronchopulmo
dysplasia, congenital heart disease, or immunodeficiency, to decrease the risk of severe pneumonia
hospitalization
[

At last, the use of HAART to reconstitute immunity is very effective for decreasing the incidence of pneumonia
opportunistic
infections
in
HIV-infected
children
[

4.5.5 Complications: Prompt diagnosis and treatment of lung infections are necessary to prevent complicat
(Table 6). The complications of viral pneumonia in children are: focal necrosis and airway plugging, atelect
bronchospasm, apnea spells, respiratory failure, bronchiectasis, bronchiolitis obliterans and pulmonary fibr
[108].
Table 6: Complications associated with Community-Acquired Pneumonia [22]

Pulmonary

Pleural effusion or empyema

Pneumothorax

Lung abscess

Bronchopleural fistula

Necrotizing pneumonia

Acute respiratory failure

Metastatic

Meningitis

Central nervous system abscess

Pericarditis

Endocarditis

Osteomyelitis

Septic arthritis

Systemic

4.6

Systemic inflammatory response syndrome or sepsis

Hemolytic uremic syndrome

Recurrent

or

Chronic

Pneum

Recurrent pneumonia is defined as 2 episodes of pneumonia in a single year, or 3 episodes over any time period,
it is reported in 7-9% of children with pneumonia. The chest radiograph should show resolution of radiol
changes between episodes. It is common practice to investigate the immune and respiratory systems in children
recurrent pneumonia [109,110]. A rationale approaches to this problem first requires a clear definition conc
recurrent and persistent pneumonia. Unfortunately there is little uniformity among investigators. Although the c
radiographs are not universally obtained in all pediatric patients with suspected pneumonia, the presenc
abnormal radiographic results must be considering as a crucial criterion for defining an episode of pneumonia
child
with
recurrent
or
persistent
lower
respiratory
infections
[1

Given the relatively common occurrence of recurrent pneumonia in children, it is suggestive that only
retrospective studies evaluate its causes [112-115]. An underlying cause was identified in more than 80% of patie
with large differences between studies as regards the prevalence of the most common cause

It is useful to assess the etiology of recurrent or chronic pneumonia to classify the process according to the anato
distribution in the lungs:
1. Pneumonias affecting a single anatomic region.
2. Pneumonias affecting multiple anatomic regions.

In general, pneumonias affecting a single lobe are caused by obstruction of the lumen of the affected lobe. This
be caused by intraluminal obstruction, extraluminal compression and structural abnormalities of the airway an
the
lung
parenchy

Aspiration of foreign bodies into the lung represents the most common cause of intraluminal airway obstructio
the pediatric population. Retained foreign bodies occur most commonly in the 6 months to 3 years age group. M
of the foreign bodies are localized in the right bronchus because it is slightly wider and originates at a less a
angle from the trachea. Symptoms of a bronchial foreign body include wheeze, cough, dyspnea, and occasion
hemoptysis. Physical signs vary in relation to the localization, size, composition, number of foreign bodies an

relation to the degree of resulting obstruction. Chest radiographs may be useful to diagnose the presence of inh
foreign
bodies.
Sometimes,
local
atelectasis
or
air
trapping
may
be
shown
[1

Other causes of intraluminal obstruction are far less frequent in children, such as the active disease caused
Mycobacterium tuberculosis that it may appear with persistent focal infiltrates or atelectasis resulted by air
granulomas
or
bronchial
adenomas
[116]
and
endobronchial
lipomas
[1

Enlarged lymph nodes are the most common causes of extraluminal airway compression. Infect
lymphadenopathy that causes airway compression is commonly caused by infection with M. tubercul
Lymphadenopathy caused by histoplasmosis and coccidiomycosis, in certain geographic areas where these fu
species may be endemic, causes similar symptoms, including compression and recurrent infectious pneumo
[118].

Non-infectious causes of pulmonary lymph nodes enlargement are less common and may also lead to extri
airway compression. Sarcoidosis is a rare multisystem disorder of unknown etiology that causes chronic, n
caseating, granulomatous lesions, in particular in lymphoid tissue of the mediastinal nodes [119]. Medias
malignancies
may
also
occasionally
lead
extraluminal
airway
compression
[1

Congenital anomalies of heart and great vessels may also cause extrinsic compression of the airway [110]. Vasc
rings and slings are a heterogeneous group of anomalies that result from abnormal development of the aortic a
Anomalies include double aortic arch, vascular rings consisting of right aortic arch, anomalous origin of the
subclavian artery, and ligamentum arteriousus, innominate artery compression and pulmonary artery slings. Do
aortic arch is the most common of these. Symptoms usually begin in early infancy and are characterized by whe
stridor,
cough
and
infectious
complications
[1

Bronchoscopy may define a focal area of large airway compression, suggesting the presence of a congenital vasc
anomaly, but the definitive diagnosis requires using several imaging techniques such as chest computed tomogra
(CT), magnetic resonance imaging (MRI) with contrast, echocardiography and angiography [1

Bronchial abnormalities may predispose to recurrent pneumonias, such as tracheal bronchus, bronchial sten
bronchomalacia and bronchiectasis. Tracheal bronchus is an extra or aberrant bronchus that usually originates in
right lateral wall of the trachea [110]. Congenital bronchomalacia is a rare cause of recurrent pneumonias that aff
premature
infants
and
children
with
Trisomia
21
[110].

Bronchiectasis is irreversible focal or generalized abnormal dilatation of the bronchial segments that occur
congenital or acquired lesion caused by destruction of muscle and elastic tissue. Most cases of focal bronchiec
occur after severe bacterial infection of the lung, which leads to localized airway damage. Measles virus, adenov
Bordetella pertussis and M. tuberculosis are often involved in the developmental of bronchiectasis. Haemoph
influenza and Staphylococcus aureus may contribute to the progression of the airway damage [1

Bronchiectasis are divided into cylindric and saccular; in cylindric bronchiectasis the damage involves only
elastic and muscular supporting tissues of the airways, sparing the cartilage, while in the saccular bronchiectasis
damage extends to the cartilaginous structures of the airways. Another cause of focal recurrent atelectasi
pneumonia in children is the right middle lobe syndrome. The right middle lobe bronchus has a small diameter
a pliable wall and originates from the right brainstem bronchus with acute angle. These factors may contribute to
compression
or
collapse
[1

Pulmonary sequestrations, congenital cystic adenomatoid malformations and bronchogenic cysts are pulmo
lesions that may cause recurrent pneumonia. A wide variety of anatomic, immunologic and neurologic disorders
cause recurrent pneumonias affecting multiple lobes of the lung [110]. In one large study conducted on 238 chil
with recurrent pneumonia, Owayed and co-workers [112] have found that the oropharyngeal incoordination
aspiration syndrome is the commonest cause (48%), followed by immune disorders (10%), congenital heart dis
(9%)
and
pulmonary
abnormalities
(8

Aspiration pneumonia develops after the inhalation of oropharyngeal contents into the lungs. It may be an acut
chronic event and it has multiple etiologies. The degree of pulmonary compromise caused by aspiration depend
the volume of aspirated material, the pH level of the material, and the type of material aspirated [1

Impaired swallowing may be caused by central nervous system disorders, neuromuscular disease or anato
abnormalities of the oropharynx. Drugs such as anesthetic agents and sedatives cause acute aspiration events bec
they may depress consciousness, the gag reflex and swallowing function. Aspiration may occur chronicall
association with seizures in children with severe mental retardation and cerebral palsy [1

Children with neuromuscular disorders, such as muscular and myotonic dystrophy, have a decreased or absent co
and gag reflexes and they produce a large amount of secretions, resulting in abnormalities of autonomic con
therefore they have abnormal swallowing mechanisms [110]. Although uncommon, some congenital or acqu
anatomic lesions of the upper airway can be associated with recurrent pneumonia. Laryngeal and pa
abnormalities including cleft palate, laryngeal clefts and submucosal clefts are associated with uncoordin
swallowing
reflexes
[1

On the other hand, recurrent pneumonia may be a complication of gastroesophageal reflux disease (GERD) du
aspiration of gastric juice [121]. GERD should always be considered a possible cause of recurrent pneumonia w
children complain of typical symptoms (heartburn, regurgitation and dysphagia) [122-123]. However, the lac
gold standard diagnostic tests for both GERD and aspiration makes it difficult to clarify the contribution of GER
recurrent pneumonia. Therefore markers of aspiration are needed for clinical practice to prove the causal relation
between
gastroesophageal
reflux
and
chronic
aspiration
[1

Although asthma has been reported as a common and important underlying cause of recurrent pneumonia [
110,122], data from the recent literature do not support this [125-127]; this is likely due to the diagnostic confu
between asthma and recurrent pneumonia. Therefore, it seems probably that very unusual and complicated c
of
asthma
may
be
considered
a
cause
of
recurrent
pneumonia
in
children
[1

In order, asthma is a differential diagnostic consideration, and not an underlying cause of recurrent pneumonia [1
There are several immunodeficiency disorders in which pneumonia occur as a main feature [128]. Most of t
involve abnormalities of B-lymphocyte function, with associated abnormalities of immune globulin production
function. Patients with global deficiencies of immunoglobulin A (IgA) or IgG have increased susceptibilit
bacterial pulmonary infections. Levels of IgG subclasses should also be evaluated because there are some pati
who have normal levels of total IgG and decreased levels of IgG2 and/or IgG4 subclasses [110

Patients with deficiencies of the complement pathway (C3, C4, properdin) or those with deficient number
function of phagocytic cells (Chediak-Higashi syndrome, Jobs syndrome or hyperimmunoglobulinemia E)
experience
recurrent
pneumonia
[110].

Disorders of mucociliary function commonly present with recurrent pneumonia, sinusitis, otitis media and m
infertility. Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease, caused by specific prim
structural and/or functional abnormalities of the motile cilia with prevalence about 1/15.000 to 1/30.000 [1
Approximately one half of the patients with PCD have situs inversus. Those patients having PCD with situs inve
are
known
to
have
Kartageners
Syndro

Cystic fibrosis is caused by a mutation in a gene that encodes cystic fibrosis transmembrane conductance regul
(CFTR) protein, which is expressed in many epithelial cells and blood cells. Cystic fibrosis is most commo
populations of northern European descent, among whom the disease occurs in approximately 1 in 3.000 births [1
and it presents with recurrent pneumonia, chronic sinusitis, steatorrhea and failure to thriv

Other causes of recurrent pneumonia in childhood are congenital heart disease, bronchopulmonary dyspl
toxicity by smoke inhalation, chronic ingestion of lipids and hypersensitivity pneumonitis (HP). The HP is a rare
heterogeneous group of conditions characterized by an allergic response to numerous environmental or occupati
agents
and
it
may
occurs
as
an
acute,
subacute
or
chronic
condition
[1

The initial clinical evaluation of a patient with chronic or recurrent pulmonary infections will provide the physi
with information necessary to guide the choice of the laboratory investigations. A careful review of the patie
history and physical examination will enable the clinician to proceed with appropriate diagnostic tools [11

In case of suspected recurrent or chronic pneumonia, there are a number of aspects in the history that mus
considered such as the frequency, duration and severity of all episodes of supposed pneumonia. Associ
symptoms such as recurrent fever, weight loss, cough, wheeze, systemic illness, upper airway noises and lab
breathing are important. Neonatal history and information about any serious infections, illnesses or surg
procedures
are
necessary
for
a
correct
diagnosis
[110].

The timing and nature of onset of illness may provide valuable clues. A family history of early or unexplained de
or chronic respiratory problems may suggest a diagnosis of immunodeficiency, or other diseases with gen
component. Important aspects of the social history are occupational exposure to potential hypersensitivity-indu
antigens, daycare attendance and the presence of siblings with similar problems [1

The general examination should take into account of the dysmorphic features, which may be associated
structural airway abnormalities (trisomy 21) or immune disorders. Growth and development are important becau
normal growth is a reassuring sign. The vital signs should be documented (oxyhemoglobin saturation) and
presence of eczema is often in association with asthma. Examination of the head and neck may document
presence of the signs of the chronic otitis or sinusitis. Periodontal disease and abnormal dentition may be indica
of
phagocytic
cell
dysfunction
and
hyper
IgE
syndrome,
respectively
[110].

Examination of the respiratory system consists of a careful evaluation of the mechanics of breathing with attentio
symptoms such as shortness of breath, retractions, accessory muscle use, scoliosis and chest-wall deformit
asymmetry
[1

A careful cardiac examination can document undiagnosed cardiac lesions. Extremities should be carefully exam
for signs of cyanosis and clubbing which may be seen in patients with cystic fibrosis, bronchiectasis and cyan
heart disease. Chest radiograph is an important tool as laboratory evaluations that should be required in all case

suspected recurrent pneumonia. All previous chest radiographes should review because this approach allows
physician to make a difference between recurrent and persistent pneumonia. The patients clinical status is
important to determine the urgency of the initial visit. If the patient is ill the priority is to establish adequac
oxygenation and ventilation. Oxygen saturation is measured easily using pulse oximetry, while the method use
evaluate the ventilation is an arterial blood gas. If there is cough with sputum production should be collect a sam
to
be
sent
for
gram
stain
and
culture
[1

Bronchoscopy, chest CT, MRI or angiography should be performed to rule out foreign bodies or anato
abnormalities in children with recurrent or persistent focal abnormalities on chest radiograph. Also a tubercu
skin
test
(PPD)
should
be
performed
in
any
child
with
focal
changes
[1

Neurologic dysfunction and swallowing difficulty or vomiting should be evaluated n children with abnormalitie
diffuse or variable regions of the lungs on chest radiograph. In these cases a barium swallow should be require
assess the adequacy of the swallowing mechanism; it is also important to check for GERD. A 24-hour PH p
study may be the gold standard method of testing of GERD. Spirometry should be obtained before and a
administration of an inhaled bronchodilator to evaluate if there is reversible airway obstruction. In patients
clinical history suggestive of asthma bronchial provocation tests (methacholine, mannitol, exercise, cold
inhalation) may also prove useful. In patients with signs and symptoms suggestive of cystic fibrosis a sweat
should be obtained. Immunologic function evaluation is also indicated by the clinical and radiographic his
Ciliary biopsy should be performed for children with recurrent sinusitis and otitis. A complete blood count
differential can provide important clues; anemia may suggest hemoglobinopathy or chonic disease
thrombocytopenia can be present in malignancy or Wiskott-Aldrich syndrome. The neutrophil number and func
should be assessed in patients with recurrent abscesses of the skin or infections of the gums serial blood counts
T-lymphocyte function should be evaluated in patients with recurrent fungal infections or abnormal response to v
infections. A history of recurrent pyogenic infections requires a quantitative evaluation of immune globu
including IgG subclasses, and an assessment of the classic complement pathways (total emolytic complement
and
C4
titers)
[1

Therapy of recurrent or persistent pneumonia includes nutritional support, exercise, chest physiotherapy
avoiding exposure to smoke or allergens, important factors implicated in the resolution of disease. The active c
of breathing techniques used together with exercise training in clinically stable young cystic fibrosis pati
increases thoracic mobility and the physical fitness parameters such as muscle endurance, strength, flexibility
speed
[131].

In particular, the standard treatment for X-linked agammaglobulinemia (XLA) is intravenous immunoglob
(IVIG). Despite apparently adequate treatment with IVIG, however, many patients still develop pansinusitis or p
infectious chronic lung diseases, most commonly bronchiectasis. Rotating antibiotics in treatment doses are
needed in addition to monthly IVIG infusions [127]. Surgical intervention is used for patients with conge
anatomic abnormalities or acquired focal disease involving a single lobe or segment of lung. In most cases, a car
analysis of the etiology of recurrent or persistent pneumonia will direct the clinician to a correct therape
approach [110].
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