Paediatric Respiratory Reviews 14 (2013) 53–60

Review

Recurrent Lower Respiratory Tract Infections in Children:A Practical Approach to Diagnosis

Maria Francesca Patria, Susanna Esposito *

Department of Maternal and Pediatric Sciences, Universita degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy

A R T I C L E I N F O

Keywords:

Bronchiectasis

lower respiratory tract infections

lung

recurrent pneumonia

recurrent respiratory tract infections

upper respiratory tract infections

S U M M A R Y

Many children are affected by recurrent lower respiratory tract infections (LRTIs), but the majority of

them do not suffer from serious lung or extrapulmonary disease. The challenge for clinicians is to

distinguish the recurrent RTIs with self-limiting or minor problems from those with underlying disease.

The aim of this review is to describe a practical approach to children with recurrent LRTIs that limits

unnecessary, expensive and time-consuming investigations. The children can be divided into three

groups on the basis of their personal and family history and clinical findings: 1) otherwise healthy

children who do not need further investigations; 2) those with risk factors for respiratory infections for

whom a wait-and-see approach can be recommended; and 3) those in whom further investigations are

mandatory. However, regardless of the origin of the recurrent LRTIs, it is important to remember that

prevention by means of vaccines against respiratory pathogens (i.e. type b Haemophilus influenzae,

pertussis, pneumococcal and influenza vaccines) can play a key role.

� 2011 Elsevier Ltd. All rights reserved.

Contents lists available at SciVerse ScienceDirect

Paediatric Respiratory Reviews

INTRODUCTION

Respiratory tract infections are common in young children.Most of them are viral upper respiratory tract infections (URTIs)that are self-limiting, and epidemiological studies indicate that upto seven episodes/year in the first three years of life and up to fiveepisodes/year after the age of three years can be considerednormal.1 By the age of 6 years, approximately 60% of children havehad at least one URTI and should not require in-depth investiga-tion.2 Lower respiratory tract infections (LRTIs), including bron-chitis, bronchiolitis and pneumonia, are less common and affectapproximately 6% of infants during the first two years oflife.3However, there is no clear definition of what recurrent ‘‘LRTI’’actually means. Wald defines recurrent pneumonia as twoepisodes of pneumonia in one year or three episodes during anytime frame, with intercritical radiographic normality;4 otherauthors use the same term when more than one LRTI occurs.5

Which definition of recurrent LRTIs is used could obviously affectthe incidence and this is in an area where the available publisheddata are already limited. A recent population-based birth cohort of900 Dutch children prospectively followed up from birth to the ageof four years included 55 (6%) who experienced �3 respiratorytract infections (RTIs)/year (from otitis to bronchitis and pneu-

* Corresponding author at: Department of Maternal and Pediatric Sciences,

Universita degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore

Policlinico, Via Commenda 9, 20122 Milano, Italy. Tel.: +39 02 55032498;

fax: +39 02 50320206.

E-mail address: susanna.esposito@unimi.it (S. Esposito).

1526-0542/$ – see front matter � 2011 Elsevier Ltd. All rights reserved.

doi:10.1016/j.prrv.2011.11.001

monia) and 715 (79%) who experienced �1/year.6 The Isle of Wightbirth cohort study (1989–1990) of 1,336 children followed up untilthey were 10 years old found that the prevalence of repeated (twoor more) LRTIs in infancy was 7.4%,7 and retrospective cohortstudies (1999–2001) of children in Germany aged 5–7 years old(28,000–30,000 cases) found 6.7–8.2% of the children had apositive history of community-acquired pneumonia (CAP), 6.9–8.2% of whom had recurrent CAP.8 Finally, data from Toronto’sHospital for Sick Children showed that 10% of more than 2,900children admitted because of CAP had experienced two or moreprevious LRTIs.9 Attending an Emergency Room (ER) because ofacute respiratory tract infection has become quite common in Italyover recent years.10 In 2010, 1,264 children with bronchitis,bronchiolitis or pneumonia were admitted to our pediatric ER and232 (18%) had experienced at least one other episode of LRTIduring their lives.10Given the number of children affected byrecurrent LRTIs, it is clear that most of them do not suffer fromserious lung or extra-pulmonary disease. The challenge for theclinician is to distinguish the children with self-limiting or minorproblems and those with underlying disease. The aim of thisreview is to describe a practical approach to children withrecurrent LRTIs with the aim of limiting unnecessary, expensiveand time-consuming investigations. Three groups of children areconsidered on the basis of their personal and family history andclinical findings: 1) otherwise healthy children who do not needfurther investigations; 2) those with risk factors for respiratoryinfections for whom a wait-and-see approach can be recom-mended; and 3) those in whom further investigations aremandatory.

M.F. Patria, S. Esposito / Paediatric Respiratory Reviews 14 (2013) 53–6054

OTHERWISE HEALTHY CHILDREN WHO DO NOT NEED FURTHERINVESTIGATIONS

Most healthy children are at risk of LRTIs: this is particularlytrue of those aged 2-4 years,3,10,11 as the incidence physiologicallydecreases during school age. The infections are typically seasonal,with a higher incidence in autumn and winter when children,especially those belonging to large families,are exposed to a largenumber of viruses at home and in daycare centres or nurseryschools. Moreover, when children first attend a daycare centre,there may be a substantial increase in the number of LRTIs, whichmay become recurrent. However, these children have relativelylong periods of clinical well-being (at least in the summer), andmost of the infections are viral and self-limiting.12 They do nothave a history of risk factors for recurrent RTIs and they experiencenormal growth and development, show normal physical examina-tion results, respond quickly to appropriate treatment, recovercompletely, and are healthy between infections. They therefore donot require any specific investigation.

CHILDREN WITH RISK FACTORS FOR RESPIRATORY INFECTIONSFOR WHOM A WAIT-AND-SEE APPROACH CAN BERECOMMENDED

Table 1 shows the clinical and enviromental factors associatedwith an increased frequency of LRTIs. The mechanisms underlyingthe occurrence of LRTIs vary with the risk factor, but in presence ofthese risk factors the infections may appear earlier and be moresevere than those observed in children without risk factors, andthey may require hospitalisation. LRTIs mainly originate from aviral infection or bacterial colonization involving the upperrespiratory tract and occur during most of the year, althoughthere is usually an improvement in the warmer seasons and, moregenerally, with growth.5 The recommendation in such cases is toeliminate avoidable risk factors and adopt a wait-and-seeapproach.

Prematurity

During the first years of life, premature children (particularlythose with bronchopulmonary dysplasia) experience greaterrespiratory morbidity and are hospitalised more frequently thanchildren born at term.13 The most common causes of re-hospitalisation in this population are LRTIs with respiratorydistress,14 which have been attributed to inadequate immunitydue to lower levels of maternal antibodies and pre-existing poorerlung function. More recently, it has been reported that neonatalhyperoxia might affect the response to respiratory pathogens, thusaltering the innate immunoregulatory response of the lungs andcontributing to viral vulnerability.15

Respiratory morbidity improves over time, especially in thechildren whose neonatal course was less severe. However, a recentpopulation-based case-control study found that adults aged 18–27years who had had a lower weight at birth were 83% more likely to

Table 1Conditions associated with an increased risk of recurrent LRTIs.

Condition

Prematurity

Atopy

Passive smoking

Indoor pollution

Outdoor pollution

Congenital abnormalities of the respiratory tract

Cardiovascular diseases

Chronic neurological diseases

be hospitalised because of asthma, respiratory infections andrespiratory failure than young adults with a normal birth weight.16

Atopy

Atopy is another risk factor for recurrent RTIs involving both theupper and lower airways. Various studies have shown that allergicchildren have more and longer-lasting RTIs than those withoutallergies.17 Allergic mucosal inflammation may predispose toupper airway infections as it induces the expression of adhesionmolecules such as intercellular adhesion molecule-1 (ICAM-1) onepithelial cells.18 ICAM-1 is the most important receptor forrhinovirus and its up-regulation may be a risk factor for this type ofviral infection.19 Moreover, epithelial cells from asthmatic patientsshow a defective innate immune response that may partiallyexplain the recurrence of LRTIs.20 Finally, interleukin(IL)-13, whichis a crucial cytokine in allergic inflammation, seems to reducemucociliary clearance, thus facilitating viral adhesion to airwayepithelial cells.21 At the same time, viral RTIs may contribute toinitiating an allergic response by increasing mucosal permeabilityor as a result of the virally-induced secretion of pro-inflammatorymediators.22

On the other hand, especially in non-English spoken commu-nities as there is no synonym for ‘‘wheeze’’ many children withbronchiolitis or asthma exacerbation are diagnosed as ‘‘pneumo-nia’’. Bronchiolitis group may be a part of children with self-limiting disease and asthmatic children may constitute a part of‘‘wait-and-see’’ group.

Passive smoking

It has been shown that prenatal exposure to maternalsmoking is a major risk factor for lower lung volume, poor lungfunction, and increased susceptibility to LRTIs.23 Tobacco smokeacts on developmental lung defects directly (fetal hypoxia andischemia) and indirectly on the growing fetus, thus predisposingnewborns to increased respiratory morbidity.24 In the first twoyears of life, passive smoking has been associated with a higherdose-dependent incidence of LRTIs and hospitalisation.25,26 Thismay be due to a direct effect of cigarette smoke on host defencesbecause it has been shown that smoking reduces the productionof oxygen radicals by neutrophils and monocytes/macrophagecells, and suppresses their phagocytic activity.27 Furthermore,the children of smoking mothers have an impaired neonatal toll-like receptor-mediated immune response.28 Finally, passivesmoking increases bacterial adherence and the risk of inflam-mation as well as further respiratory infections.29 It is veryimportant to improve education with simple material showingto the general population risks associated with smoking, evenwhen passive.

Indoor pollution

Air pollutants increase the frequency and the severity of LRTIsby causing inflammation of the lung airways and alveoli. Inaddition to tobacco smoke, the most important indoor pollutantsare particulate matter, smoke from household solid fuels, nitrogendioxide from cooking stoves, carbon monoxide, volatile organiccompounds and biological allergens (i.e. mites, moulds and petallergens).30 Infants and young children are particularly suscep-tible to these pollutants because of the immaturity of theirrespiratory defence mechanisms and the anatomy of theirairways.31 Indoor exposure to mould and dampness is alsofrequently associated with asthma symptoms, with the highestrisk being associated with mould and dampness in the living roomor the child’s bedroom.32 Moulds may induce recurrent respiratory

Table 2Underlying causes of recurrent LRTIs.

LRTIs affecting a single lobe or

area of the lung

LRTIs affecting multiple

areas/lobes of the lung

Intraluminal obstruction

- inhaled foreign body

- endobronchial tumour

Rhinosinusitis and post-nasal drip

Extraluminal compression

– enlarged lymph nodes (infection,

tumour, sarcoidosis)

- enlarged or aberrant vessels

Immunodeficiency

Structural abnormalities of airways

or lung parenchyma

GERD

Middle lobe syndrome Primary ciliary dyskinesia

Bronchiectasis Cystic fibrosis

GERD, gastro-esophageal reflux.

M.F. Patria, S. Esposito / Paediatric Respiratory Reviews 14 (2013) 53–60 55

disorders as result of IgE-mediated hypersensitivity. A recent studyof more than 58,000 children aged 6-12 years in Russia, NorthAmerica and Europe found a positive association betweenexposure to moulds and the children’s respiratory health (anodds ratio of 1.38 for bronchitis, with 95% confidence intervals of1.29-1.47).33

Outdoor pollution

Outdoor air pollution also significantly increases the inci-dence of LRTIs.34 The risk depends on the type and concentrationof the pollutant and the duration of the exposure. Children areparticularly susceptible, and may be more exposed than adultsbecause of their higher ventilation rates and their tendency tospend more time outside. It has also been shown that there is asignificant association between the level of outdoor pollutantsand ER admissions because of respiratory diseases. The authorsof a recent Italian pediatric study found that the increasednumber of ER visits due to respiratory diseases among childrenaged <15 years of age was related to PM10 and NO2 levels,35 andit has also been found that ER visits due to wheezing in childrenaged 0-2 years were most closely associated with CO, followedby SO2.36

Even in this case, as for passive smoking, education of thepopulation on risks associated with outdoor pollution and onimportance of reducing exposure of children to these environ-mental risk factors.

Congenital respiratory tract abnormalities, cardiovascular diseases,

and chronic neurological diseases

Recurrent LRTIs are frequent in children with congenitalabnormalities of the respiratory tract. Repeated episodes ofpneumonia are often presenting features of pulmonary seques-tration and cystic adenomatoid malformation of the lung,37 andrecurrent LRTIs, bronchitis and aspiration pneumonia arecommon in children with esophageal atresia with or withoutfistula, especially in the early years of life.38,39 Many factors maycontribute to recurrent respiratory symptoms: epithelialabnormalities in the major airways (which impair the muco-ciliary clearance of secretions), and the presence of gastro-esophageal reflux disease (GERD) and esophageal dysmotilitycausing recurrent aspiration episodes.40 However, even in thesepatients, the prevalence and severity of recurrent LRTIs tend todecrease with age.41Congenital heart diseases with left-to-rightshunts are also risk factors for recurrent LRTIs due to increasedpulmonary blood flow.42,43 Among the various shunt lesions thatpresent in infancy, ventricular septal defect is the mostcommon.44 Other defects include atrial septal defect, patentductus arteriosus, and atrioventricular septal defect.42–44 Inthese diseases, the blood is shunted through an abnormalopening from the left side of the heart to the right side of theheart. Pulmonary blood flow increases because of the extravolume in the right side. There is a ‘‘step-up’’ O2 saturation inthe right side of the heart because of the addition of more highlysaturated blood. Physiologic effects include increased pulmon-ary blood flow and increased cardiac workload (includingventricular strain, dilation, and hypertrophy). A left-to-rightshunt can adversely affect lung function, and superimposedlower respiratory tract infections cause additional compromiseand might lead to respiratory failure, necessitating mechanicalventilation.42–44Neurologically impaired children are particu-larly vulnerable to recurrent LRTIs because of increased mucoussecretion due to anti-epileptic drugs, poor mucociliary clearancedue to hypotonia, the presence of GERD, uncoordinatedswallowing and an impaired cough reflex.45–47

CHILDREN WHO SHOULD UNDERGO FURTHER INVESTIGATIONS

Underlying serious structural or systemic diseases can predis-pose many children to recurrent LRTIs. The characteristicssuggesting an underlying disease are a history of serious recurrentinfections involving multiple sites or caused by opportunisticorganisms; a history of recurrent pneumonia affecting the samelobe; a history of prolonged interstitial pneumonia with noinfective cause; a history of chronic URTIs (i.e. rhinosinusitis, otitismedia) from the first months of age; the presence of a chronicproductive cough (lasting >4 weeks) with purulent sputum; thepersistence of abnormal thoracic examination findings with lungcrackles on auscultation or the persistence of radiologicalabnormalities for more than eight weeks; physical signs ofmalabsorption or digital clubbing; and a family history of severeinfections or early death.4,5,48,49

In the presence of at least one of these features, furtherinvestigations are necessary because it is important to recognisethe underlying disease early, before any significant organ damageoccurs. Table 2 shows the underlying causes of recurrent LRTIs andthe sites involved.

Recurrent LRTIs affecting a single lobe or area of the lung

Pneumonia recurring in the same area of the lung suggests afocal pathology that requires bronchoscopy and chest high-resolution computed tomography (HRCT).

Intraluminal obstruction

Foreign body aspiration is a relatively common cause ofrecurrent LRTIs as it is involved in the etiology of 4-18% of thecases of pediatric bronchiectasis.50,51 It should be suspected in thepresence of sudden-onset cough, dyspnea, and recurrent pneu-monia with a history of choking episodes. However, there may beno definite history and this can lead to long delays in diagnosis thatincrease the risk of long-term complications such as bronchiec-tasis.52,53 A physical examination may reveal respiratory distress,localised pulmonary hypoventilation, wheezing, ronchi andmetallic sounds. Radiography may show atelectasis or areas ofhyperinflation, although the findings are normal in about 20-40%of children with foreign body inhalation confirmed by broncho-scopy.48

Although rare in childhood, endobronchial tumours may alsocause intraluminal obstruction. These may be low-grade malig-nant neoplasms such as bronchial carcinoid and mucoepidermoidtumours, or benign endobronchial tumours such as hemangiomas,papillomas, leiomyomas and mucous gland tumours.54 Alsoendobronchial tuberculosis may be a cause of intraluminalobstruction.55

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Extraluminal compression and structural abnormalities of the airways

or lung parenchyma

Extrinsic compression of the airways is usually due to enlargedlymph nodes, which may be caused by infections, tumours orsarcoidosis.56–59 Tuberculosis is one of the most common causes ofextraluminal compression of the airways associated with recurrentlung infections, mainly in developing countries.59 Vascular ringscan also cause extraluminal compression.60 Children usuallypresent with localised wheezing or recurrent pulmonary infectionduring the first years of life. Recurrent pneumonia due tocongenital airway malformations (i.e. tracheo-bronchomalacia orbronchial stenosis) or anatomical abnormalities of the lung are alsorare causes of recurrent localised LRTIs, which typically presentwith symptoms in early childhood.

Middle lobe syndrome and bronchiectasis

Middle lobe syndrome is a distinct clinical and radiologicalentity characterised by a spectrum of diseases that range fromrecurrent atelectasis and asthma or pneumonitis to bronchiectasisof the middle lobe.61 Anatomical characteristics such as a lobarbronchus with a narrow diameter, an acute angle originating fromthe bronchus intermedius, and the proximity of the right middlelobe to the hilar lymph nodes make it particularly vulnerable totransient obstruction. In addition, its relative anatomical isolationfrom the other lobes and poor collateral ventilation decrease thechance of reinflation once atelectasis has been established.

Bronchiectasis forms part of a persistent and often evolvingcondition that is characterised by dilated and thickened bronchi. Itmay be congenital and can occur in a localised region of the lung, ormay be acquired as a focal disease or be widespread depending onmany disease processes.62 The most commonly acquired cause ofbronchiectasis is post-infectious disease. Frequent associationshave been found with severe bacterial CAP as well as withMycoplasma pneumoniae or viral infections (particularly those dueto adenovirus, influenza or respiratory syncytial virus).63

Children with bronchiectasis typically have recurrent LRTIs, butbronchiectasis can also occur after a single severe infection. In thecase of the incomplete resolution of a severe LRTI, persistentinflammation may damage the muscular and elastic componentsof the bronchial wall. Retrospective studies of different pediatricpopulations have found that the prevalence of bronchiectasis afterpneumonia varies from 11% to 85%.50,64 Cystic fibrosis, immuno-logical disorders, aspiration, and primary ciliary dyskinesia areother potential etiologies, although no underlying cause may befound in up to 40% of patients.63 The most important functionaleffect of bronchial dilation is severely impaired secretion clearancefrom the bronchial tree, which can further exacerbate a viciouspathological circle as the clinical hallmarks of bronchiectasis arerecurrent chest infections, chronic purulent cough, dyspnea andwheezing.50

Recurrent LRTIs affecting multiple lobes of the lung

Many underlying conditions are associated with recurrentpneumonia in multiple lung areas. Such cases may require abroader range of investigations than those recommended whenrecurrent LRTIs affect a single lobe. The choice of the investigationsdepends on the patient’s history and clinical findings.

Immunodeficiencies

Recurrent URTIs and LRTIs leading to chronic suppurative lungdiseases are common characteristics of primary immunodeficien-cies (PIDs).65 These may be caused by multiple defects, but themost frequent are antibody deficiencies (i.e. from severe defi-ciencies of all immunoglobulin isotypes to milder deficiencies ofspecific antibodies or IgG subclasses in patients with normal

immunoglobulin concentrations). In a recent series of 67 pediatricpatients affected by recurrent LRTIs, 55% showed antibody defects(IgA deficiency in 31%, IgG2 deficiency in 18%, IgG3 deficiency in15%, and IgM defects in 6%).66 In common variable immunode-ficiency (CVID), the prevalence of recurrent CAP before startingprophylactic immunoglobulin replacement treatment varies from63% to 84%.67,68

Children with immune defects usually present with highlyrecurrent and/or severe bacterial infections of the respiratory tractwithout any seasonality, recurrent gastrointestinal infections andrecurrent skin infections.65 Lymphadenopathy and a failure tothrive are also common features. The family history is oftencharacterised by recurrent infections and early deaths becausemany immunodeficiencies are inherited.65 In general, age at thetime of the presentation of recurrent LRTIs can help identify thetype of immunodeficiency. A neonatal onset suggests DiGeorgesyndrome; onset at an age of 6-12 months is indicative of severecombined immunodeficiency (SCID), X-linked agammaglobuline-mia (XLA), chronic mucocutaneous candidiasis, and chronicgranulomatous disease; and onset at an age of >5 years supportsa diagnosis of CVID, specific antibody deficiency and complementdisorders.69 The type of organism can also suggest the underlyingcondition. Interstitial pneumonia due to cytomegalovirus orPneumocystis jiroveci is typical of T cell defects; recurrent bacterialinfections (particularly in males aged >6 months) suggest ahumoral immunodeficiency; staphylococcal lung infections arecommon in hyper-IgE syndrome; and fungal pneumonia iscommon in chronic granulomatous disease.70

Immunoglobulin replacement therapy has significantlyreduced the frequency and severity of acute bacterial infectionsin PIDs, although long-term pulmonary complications such aschronic lung disease do occur. A study conducted some years agofound that even after the introduction of intravenous immuno-globulin replacement therapy, about 20% of patients still hadadditional episodes of pneumonia,67 possibly because the admi-nistered immunoglobulins do not reach the mucosal surface.

GERD

Many pulmonary diseases, such as chronic cough, asthma,apnea, recurrent URTIs and LRTIs, and interstitial pneumonia, arepotential consequences of GERD,71 possibly because of theaspiration of gastric contents or vagally mediated bronchocon-striction. Although some studies have not documented a clearcausal effect between GERD and lung diseases,72 GERD shouldalways be considered a possible cause of recurrent LRTIs whenchildren complain of typical symptoms (i.e. heartburn, regurgita-tion and dysphagia). Furthermore, some patients with chroniccough and asthma may also have clinically silent GERD.73

Twenty-four hour esophageal pH monitoring is currently thegold standard diagnostic test for GERD in the presence of recurrentLRTIs, but it is not very sensitive and many refluxes may be missedas they are not acid or slightly alkaline. Moreover, children have amuch greater proportion of non-acid than acid reflux. A recentstudy of 51 children with refractory respiratory symptomsdocumented it by overnight scintigraphy, and pulmonary aspira-tion in about 50% of cases; but only 24% had concomitantpathological pH.74 As only a few children with respiratorysymptoms have pathological gastroesophageal acid reflux, normalintra-esophageal pH findings do not rule out GERD.74 Multi-channel intraluminal impedance and pH monitoring improvediagnostic capacity as they are able to detect both the anterogradeand retrograde passage of acid and non-acid material.75

Primary ciliary dyskinesia (PCD)

PCD is an autosomal recessive disease characterised by chronicsino-pulmonary infections caused by impaired ciliary motility.

Table 3Clinical characteristics to be evaluated in children with recurrent LRTIs.

Healthy children Children with chronic underlying disease

Age at onset >1 year First months of life

Growth Normal Slow

Course of infections Not serious Serious, requiring hospitalisation

Involvement of other organ systems No Yes

Recurrence in the same site No Yes

Pathogens Mainly viruses Uncommon

Well-being between episodes Prolonged (i.e. at least 3 months) Short periods or absent

Family history Negative for primary immunodeficiencies or early death Positive for primary immunodeficiencies or early death

M.F. Patria, S. Esposito / Paediatric Respiratory Reviews 14 (2013) 53–60 57

Nearly 50% of cases show situs inversus viscerum, but only 23% ofpatients with situs inversus have PCD.76 The triad of situs inversus

viscerum, rhinosinusitis and bronchiectasis is consistent withKartagener’s syndrome. Clinical symptoms of PCD may appear inthe neonatal period with unexplained tachypnea and/or respira-tory distress, neonatal pneumonia or persistent rhinitis, whereasdaily productive rhinitis, severe rhinosinusitis, recurrent otitis,chronic purulent cough and recurrent pneumonia are common inchildhood. The prevalence of PCD as a cause of pediatricbronchiectasis is 1-15%.50,51 Patients with PCD may also haveextra-respiratory manifestations, such as congenital heart disease,polycystic kidney, liver disease, biliary atresia and retinaldegeneration (including retinitis pigmentosa).77

The diagnosis is frequently delayed because of the overlappingsymptoms of recurrent URTIs (which are more common in youngchildren) or the technical expertise required for ciliary ultra-structural analysis. In one review of 55 children, median age atdiagnosis was 4.4 years despite the presence of typical symptomsearly in life.78 Screening tests for PCD include nasal nitric oxide(abnormally low in PCD) and in vivo tests of ciliar motility.79 Aspecific diagnosis requires cilia examination by means of light andelectronic microscopy and, more recently, a genetic test has alsobeen proposed.80

Cystic fibrosis (CF)

CF is the most common life-limiting genetic condition inCaucasians.81 The primary defect is abnormal ion and watertransport across epithelial cells, which leads to abnormally thickmucus in the lung that predisposes to chronic airway infectionsand inflammation. A history of neonatal jaundice, poor weightgain, steatorrhea and highly recurrent pneumonia may suggestcystic fibrosis, although atypical cases may present with recurrentpneumonia alone, in the absence of malabsorption.

It is important to remember that the screening of newborns isnot very specific but it is sensitive.82 A positive sweat test confirmsthe diagnosis, but the findings may be normal in patients withatypical CF.83 Genetic screening for CF transmembrane regulator(CFTR) mutation is also used to confirm the diagnosis, and canprovide information concerning genotype/phenotype correla-tions.81 Some studies of adults with idiopathic bronchiectasishave found an increased frequency of heterozygous mutation andpolymorphisms of the CFTR gene whose meaning is still unclear.84

Rhinosinusitis and post-nasal drip

Rhinosinusitis is characterised by inflammatory edema of thesinus mucosa, obstruction of the sinus ostia, and ineffectivemucociliary activity.85–87 It is very common in pediatric patientsbecause of the anatomical features of the paranasal sinuses ofchildren. Adenoidal hypertrophy may predispose to recurrentrhinosinusitis by causing mechanical obstruction and the poolingof secretions; at the same time, it can act as a reservoir forpathogenic bacteria.88 If untreated, a thicker, viscous, purulentpost-nasal drip can flow into the respiratory organs when the hostis asleep, and may lead to LRTIs.88,89

Rhinosinusitis with post-nasal drip is clinically characterised bya purulent nasal discharge, throat clearing and productive cough,especially when a child lies down or wakes up. However, childrenfrequently have few or no URTI symptoms and present only with achronic productive cough.90 The diagnosis of rhinosinusitis shouldonly be based on clinical criteria. Paranasal sinus computedtomography, magnetic resonance and optical fibre rhinoscopy areuseful in recurrent or severe cases that do not respond to antibiotictherapy and may require surgery.85–87

PRACTICAL DIAGNOSTIC APPROACH TO RECURRENT LRTIS

When evaluating a child with recurrent LRTIs, the first step is todistinguish otherwise healthy subjects from those with anunderlying chronic disease that require further investigations.Table 3 shows the clinical characteristics of a patient’s medicalhistory that should be assessed. A few, detailed questions areusually sufficient to exclude or raise the suspicion of an underlyingdisease. Otherwise healthy children start to experience respiratorysymptoms after the age of one year, generally when they beginattending a daycare centre. Their respiratory infections have anormal course, and the children do not require hospitalisation andrespond to the usual treatments; growth is normal, and there aregenerally long periods of well-being between episodes. However, ifLRTIs appear in the first months of life, are severe, and areaccompanied by systemic involvement and/or sustained byunusual pathogens, further investigations are essential. Whatremains is a ‘‘grey area’’ represented by children with earlyrespiratory symptoms, an occasional need for hospitalisation, andshort periods of well-being between episodes, without any focalinvolvement. In this case, the presence of the risk factorsmentioned above (i.e. prematurity, atopy, passive smoking,exposure to indoor and/or outdoor pollution) may justify await-and-see approach for 6-12 months. If the number and thecharacteristics of the LRTIs do not change during the follow-upperiod despite the elimination of avoidable risk factors, furtherinvestigations should be made. Figure 1 summarises the investiga-tions required in relation to clinical history.

Once the patients needing further attention have beenidentified, the second step is to select the most appropriateinvestigations on the basis of clinical history and a physicalexamination. Figure 2 shows the investigations recommended inchildren with recurrent LRTI and a suspected underlying disease.

If the recurrent infections affect a single area of the lungs, or iflocalised pathological sounds (i.e. rhonchi and rales) are detectableeven in the intercritical intervals, the first recommendation is abronchoscopic examination to exclude the presence of foreignbodies, mucus plugs, intraluminal obstructions, extrinsic compres-sion and tracheo-bronchial malacia. If the endoscopic result isnormal or inconclusive, it should be followed by HRCT, whichenables the better delineation of any extrinsic compression (i.e.mediastinal lymph nodes, abnormal vessels) and highlights thebronchial lumen beyond the limits of endoscopic resolution (i.e.the sub-segmental bronchi).

Onset > 1 yearNormal course of LRTINo hospit alisationNormal growthProlonged well-bein g

No further investigations

Ear ly onset (< 1 year), Occ asional hosp ital isat ionShort periods of wel l-beingNo focal inv olv ement

Early onset (< 1 year), Severe course, Systemic in volvemen t Focal involvementUnusual pathogen

Imm ediate further investigations

Is thereany risk factorfor recurrentLRTIs ?

Yes

No

Wait-a nd-see for 6-12 months , then reassess

Improvement

No improvement

Figure 1. Relationship between clinical history and the need of further investigations in children with recurrent LRTIs.

Pneumonia in the same areaor

localised ronch i and rales in the inte rcritical period

Bronchos copy

Chest HRCT

Pneumonia in different areas

Chest HRCT

Norma l Pathological

Rec onsi derthe diagnosisof recurr entLRTI

Investigations forimm unodeficiencyNasal fiberoptic endoscopySwea t test24-hour e soph ageal pH monitori ngNasa l FeNo and nasal brush ingCardiologic evaluati onTuberculosis screening

Bronchoscop y

If norma l

If norma l

Figure 2. Investigations recommended in children with recurrent LRTIs and suspected underlying disease.

M.F. Patria, S. Esposito / Paediatric Respiratory Reviews 14 (2013) 53–6058

M.F. Patria, S. Esposito / Paediatric Respiratory Reviews 14 (2013) 53–60 59

If a recurrent LRTI seems to involve different areas of the lung,the first choice is HRCT and, if the findings are completely normal,it is important to reconsider a diagnosis of recurrent LRTI and theneed for further investigations. On the contrary, if the findingsshow pathological changes (i.e. bronchiectasis, atelectasis, air-trapping, ground-glass lesions), further investigations are essen-tial. All patients with abnormal HRCT findings should undergo ablood test to assess their immune status (i.e. blood cell counts,serum immunoglobulins, total IgE, IgG sub-classes, lymphocytesub-populations, C3, C4, CH50). They should also undergo anotorhinolaryngologic examination, including a nasal fiberopticexamination, a sweat test, 24-hour esophageal pH monitoring, andthe study of ciliary motility by means of nasal fractional exhalednitric oxide (FeNo) analysis and ciliary brushing. We recommendall of these investigations because it is not uncommon to encounterthe presence of an underlying disease in the absence of anindicative history (i.e. post-nasal drip without rhinorrhea, GERDwithout subjective symptoms of pyrosis and heartburn). It is alsoimportant to undertake a complete cardiological examination, notin order to diagnose congenital heart disease (which is usuallydone in utero or in early life) but to ensure that the impaired lungdoes not give rise to pulmonary hypertension, which maycontribute to worsening the respiratory failure. In addition,tuberculosis screening should be performed for suspicious cases.

If all of the investigations are negative but the recurrent LRTIspersist, we recommend bronchoscopy with a bronchoalveolarlavage in order to identify a possibly untreated pathogen, taking aciliary sample from the tracheo-bronchial tree (in cases in whichnasal cilia brushing is not possible), and assess the lipid burden inalveolar macrophages (an indirect sign of pulmonary aspiration).91

If all of these tests, only a negligible proportion of causes ofrecurrent LRTIs will remain undetermined.92

CONCLUSIONS

A significant number of children experience recurrent episodesof LRTIs in the first years of life. When evaluating children withrecurrent LRTIs, the first step is to distinguish otherwise healthysubjects from those with an underlying chronic disease thatrequires further investigations. The aim of this paper is to suggest apractical approach to selecting the patients that should be furtherevaluated, and to indicate a diagnostic path for reaching a preciseclinical diagnosis and preventing chronic lung disease and the lossof lung function. However, regardless of the origin of the recurrentLRTIs, it is important to remember that prevention by means ofvaccines against respiratory pathogens (i.e. type b Haemophilus

influenzae, pertussis, pneumococcal and influenza vaccines) canplay a key role by reducing the risk of LRTIs due to commonpathogens.93–96 As pediatricians, we should ensure the adequateuse of these vaccines because of the impact they can have on publicand personal health.

DISCLOSURE STATEMENT

None of the authors has any commercial or other associationthat might pose a conflict of interest.

Acknowledgements

This study was supported in part by a grant from the ItalianMinistry of Health (Bando Giovani Ricercatori 2007).

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