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

Paediatric Respiratory Reviews 14 (2013) 53–60

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Paediatric Respiratory Reviews

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

S U M M A R Y

Keywords: Bronchiectasis lower respiratory tract infections lung recurrent pneumonia recurrent respiratory tract infections upper respiratory tract infections

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. ß 2011 Elsevier Ltd. All rights reserved.

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 up to seven episodes/year in the first three years of life and up to five episodes/year after the age of three years can be considered normal.1 By the age of 6 years, approximately 60% of children have had at least one URTI and should not require in-depth investigation.2 Lower respiratory tract infections (LRTIs), including bronchitis, bronchiolitis and pneumonia, are less common and affect approximately 6% of infants during the first two years of life.3However, there is no clear definition of what recurrent ‘‘LRTI’’ actually means. Wald defines recurrent pneumonia as two episodes of pneumonia in one year or three episodes during any time frame, with intercritical radiographic normality;4 other authors use the same term when more than one LRTI occurs.5 Which definition of recurrent LRTIs is used could obviously affect the incidence and this is in an area where the available published data are already limited. A recent population-based birth cohort of 900 Dutch children prospectively followed up from birth to the age of four years included 55 (6%) who experienced 3 respiratory tract 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: [email protected] (S. Esposito). 1526-0542/$ – see front matter ß 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 Wight birth cohort study (1989–1990) of 1,336 children followed up until they were 10 years old found that the prevalence of repeated (two or more) LRTIs in infancy was 7.4%,7 and retrospective cohort studies (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 a positive history of community-acquired pneumonia (CAP), 6.9– 8.2% of whom had recurrent CAP.8 Finally, data from Toronto’s Hospital for Sick Children showed that 10% of more than 2,900 children admitted because of CAP had experienced two or more previous LRTIs.9 Attending an Emergency Room (ER) because of acute respiratory tract infection has become quite common in Italy over recent years.10 In 2010, 1,264 children with bronchitis, bronchiolitis or pneumonia were admitted to our pediatric ER and 232 (18%) had experienced at least one other episode of LRTI during their lives.10Given the number of children affected by recurrent LRTIs, it is clear that most of them do not suffer from serious lung or extra-pulmonary disease. The challenge for the clinician is to distinguish the children with self-limiting or minor problems and those with underlying disease. The aim of this review is to describe a practical approach to children with recurrent LRTIs with the aim of limiting unnecessary, expensive and time-consuming investigations. Three groups of children are considered 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.

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OTHERWISE HEALTHY CHILDREN WHO DO NOT NEED FURTHER INVESTIGATIONS

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

Most healthy children are at risk of LRTIs: this is particularly true of those aged 2-4 years,3,10,11 as the incidence physiologically decreases 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 large number of viruses at home and in daycare centres or nursery schools. Moreover, when children first attend a daycare centre, there may be a substantial increase in the number of LRTIs, which may become recurrent. However, these children have relatively long periods of clinical well-being (at least in the summer), and most of the infections are viral and self-limiting.12 They do not have a history of risk factors for recurrent RTIs and they experience normal growth and development, show normal physical examination results, respond quickly to appropriate treatment, recover completely, and are healthy between infections. They therefore do not require any specific investigation.

Atopy

CHILDREN WITH RISK FACTORS FOR RESPIRATORY INFECTIONS FOR WHOM A WAIT-AND-SEE APPROACH CAN BE RECOMMENDED Table 1 shows the clinical and enviromental factors associated with an increased frequency of LRTIs. The mechanisms underlying the occurrence of LRTIs vary with the risk factor, but in presence of these risk factors the infections may appear earlier and be more severe than those observed in children without risk factors, and they may require hospitalisation. LRTIs mainly originate from a viral infection or bacterial colonization involving the upper respiratory tract and occur during most of the year, although there is usually an improvement in the warmer seasons and, more generally, with growth.5 The recommendation in such cases is to eliminate avoidable risk factors and adopt a wait-and-see approach. Prematurity During the first years of life, premature children (particularly those with bronchopulmonary dysplasia) experience greater respiratory morbidity and are hospitalised more frequently than children born at term.13 The most common causes of rehospitalisation in this population are LRTIs with respiratory distress,14 which have been attributed to inadequate immunity due to lower levels of maternal antibodies and pre-existing poorer lung function. More recently, it has been reported that neonatal hyperoxia might affect the response to respiratory pathogens, thus altering the innate immunoregulatory response of the lungs and contributing to viral vulnerability.15 Respiratory morbidity improves over time, especially in the children whose neonatal course was less severe. However, a recent population-based case-control study found that adults aged 18–27 years who had had a lower weight at birth were 83% more likely to Table 1 Conditions 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

Atopy is another risk factor for recurrent RTIs involving both the upper and lower airways. Various studies have shown that allergic children have more and longer-lasting RTIs than those without allergies.17 Allergic mucosal inflammation may predispose to upper airway infections as it induces the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on epithelial cells.18 ICAM-1 is the most important receptor for rhinovirus and its up-regulation may be a risk factor for this type of viral infection.19 Moreover, epithelial cells from asthmatic patients show a defective innate immune response that may partially explain the recurrence of LRTIs.20 Finally, interleukin(IL)-13, which is a crucial cytokine in allergic inflammation, seems to reduce mucociliary clearance, thus facilitating viral adhesion to airway epithelial cells.21 At the same time, viral RTIs may contribute to initiating an allergic response by increasing mucosal permeability or as a result of the virally-induced secretion of pro-inflammatory mediators.22 On the other hand, especially in non-English spoken communities as there is no synonym for ‘‘wheeze’’ many children with bronchiolitis or asthma exacerbation are diagnosed as ‘‘pneumonia’’. Bronchiolitis group may be a part of children with selflimiting disease and asthmatic children may constitute a part of ‘‘wait-and-see’’ group. Passive smoking It has been shown that prenatal exposure to maternal smoking is a major risk factor for lower lung volume, poor lung function, and increased susceptibility to LRTIs.23 Tobacco smoke acts on developmental lung defects directly (fetal hypoxia and ischemia) and indirectly on the growing fetus, thus predisposing newborns to increased respiratory morbidity.24 In the first two years of life, passive smoking has been associated with a higher dose-dependent incidence of LRTIs and hospitalisation.25,26 This may be due to a direct effect of cigarette smoke on host defences because it has been shown that smoking reduces the production of oxygen radicals by neutrophils and monocytes/macrophage cells, and suppresses their phagocytic activity.27 Furthermore, the children of smoking mothers have an impaired neonatal tolllike receptor-mediated immune response.28 Finally, passive smoking increases bacterial adherence and the risk of inflammation as well as further respiratory infections.29 It is very important to improve education with simple material showing to the general population risks associated with smoking, even when passive. Indoor pollution Air pollutants increase the frequency and the severity of LRTIs by causing inflammation of the lung airways and alveoli. In addition to tobacco smoke, the most important indoor pollutants are particulate matter, smoke from household solid fuels, nitrogen dioxide from cooking stoves, carbon monoxide, volatile organic compounds and biological allergens (i.e. mites, moulds and pet allergens).30 Infants and young children are particularly susceptible to these pollutants because of the immaturity of their respiratory defence mechanisms and the anatomy of their airways.31 Indoor exposure to mould and dampness is also frequently associated with asthma symptoms, with the highest risk being associated with mould and dampness in the living room or the child’s bedroom.32 Moulds may induce recurrent respiratory

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disorders as result of IgE-mediated hypersensitivity. A recent study of more than 58,000 children aged 6-12 years in Russia, North America and Europe found a positive association between exposure to moulds and the children’s respiratory health (an odds ratio of 1.38 for bronchitis, with 95% confidence intervals of 1.29-1.47).33 Outdoor pollution Outdoor air pollution also significantly increases the incidence of LRTIs.34 The risk depends on the type and concentration of the pollutant and the duration of the exposure. Children are particularly susceptible, and may be more exposed than adults because of their higher ventilation rates and their tendency to spend more time outside. It has also been shown that there is a significant association between the level of outdoor pollutants and ER admissions because of respiratory diseases. The authors of a recent Italian pediatric study found that the increased number of ER visits due to respiratory diseases among children aged <15 years of age was related to PM10 and NO2 levels,35 and it has also been found that ER visits due to wheezing in children aged 0-2 years were most closely associated with CO, followed by SO2.36 Even in this case, as for passive smoking, education of the population on risks associated with outdoor pollution and on importance of reducing exposure of children to these environmental risk factors. Congenital respiratory tract abnormalities, cardiovascular diseases, and chronic neurological diseases Recurrent LRTIs are frequent in children with congenital abnormalities of the respiratory tract. Repeated episodes of pneumonia are often presenting features of pulmonary sequestration and cystic adenomatoid malformation of the lung,37 and recurrent LRTIs, bronchitis and aspiration pneumonia are common in children with esophageal atresia with or without fistula, especially in the early years of life.38,39 Many factors may contribute to recurrent respiratory symptoms: epithelial abnormalities in the major airways (which impair the mucociliary clearance of secretions), and the presence of gastroesophageal reflux disease (GERD) and esophageal dysmotility causing recurrent aspiration episodes.40 However, even in these patients, the prevalence and severity of recurrent LRTIs tend to decrease with age.41Congenital heart diseases with left-to-right shunts are also risk factors for recurrent LRTIs due to increased pulmonary blood flow.42,43 Among the various shunt lesions that present in infancy, ventricular septal defect is the most common.44 Other defects include atrial septal defect, patent ductus arteriosus, and atrioventricular septal defect.42–44 In these diseases, the blood is shunted through an abnormal opening from the left side of the heart to the right side of the heart. Pulmonary blood flow increases because of the extra volume in the right side. There is a ‘‘step-up’’ O2 saturation in the right side of the heart because of the addition of more highly saturated blood. Physiologic effects include increased pulmonary blood flow and increased cardiac workload (including ventricular strain, dilation, and hypertrophy). A left-to-right shunt can adversely affect lung function, and superimposed lower respiratory tract infections cause additional compromise and might lead to respiratory failure, necessitating mechanical ventilation.42–44Neurologically impaired children are particularly vulnerable to recurrent LRTIs because of increased mucous secretion due to anti-epileptic drugs, poor mucociliary clearance due to hypotonia, the presence of GERD, uncoordinated swallowing and an impaired cough reflex.45–47

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CHILDREN WHO SHOULD UNDERGO FURTHER INVESTIGATIONS Underlying serious structural or systemic diseases can predispose many children to recurrent LRTIs. The characteristics suggesting an underlying disease are a history of serious recurrent infections involving multiple sites or caused by opportunistic organisms; a history of recurrent pneumonia affecting the same lobe; a history of prolonged interstitial pneumonia with no infective cause; a history of chronic URTIs (i.e. rhinosinusitis, otitis media) from the first months of age; the presence of a chronic productive cough (lasting >4 weeks) with purulent sputum; the persistence of abnormal thoracic examination findings with lung crackles on auscultation or the persistence of radiological abnormalities for more than eight weeks; physical signs of malabsorption or digital clubbing; and a family history of severe infections or early death.4,5,48,49 In the presence of at least one of these features, further investigations are necessary because it is important to recognise the underlying disease early, before any significant organ damage occurs. Table 2 shows the underlying causes of recurrent LRTIs and the sites involved. Recurrent LRTIs affecting a single lobe or area of the lung Pneumonia recurring in the same area of the lung suggests a focal pathology that requires bronchoscopy and chest highresolution computed tomography (HRCT). Intraluminal obstruction Foreign body aspiration is a relatively common cause of recurrent LRTIs as it is involved in the etiology of 4-18% of the cases of pediatric bronchiectasis.50,51 It should be suspected in the presence of sudden-onset cough, dyspnea, and recurrent pneumonia with a history of choking episodes. However, there may be no definite history and this can lead to long delays in diagnosis that increase the risk of long-term complications such as bronchiectasis.52,53 A physical examination may reveal respiratory distress, localised pulmonary hypoventilation, wheezing, ronchi and metallic sounds. Radiography may show atelectasis or areas of hyperinflation, although the findings are normal in about 20-40% of children with foreign body inhalation confirmed by bronchoscopy.48 Although rare in childhood, endobronchial tumours may also cause intraluminal obstruction. These may be low-grade malignant neoplasms such as bronchial carcinoid and mucoepidermoid tumours, or benign endobronchial tumours such as hemangiomas, papillomas, leiomyomas and mucous gland tumours.54 Also endobronchial tuberculosis may be a cause of intraluminal obstruction.55 Table 2 Underlying 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 Extraluminal compression – enlarged lymph nodes (infection, tumour, sarcoidosis) - enlarged or aberrant vessels Structural abnormalities of airways or lung parenchyma

Rhinosinusitis and post-nasal drip

Middle lobe syndrome Bronchiectasis

Primary ciliary dyskinesia Cystic fibrosis

GERD, gastro-esophageal reflux.

Immunodeficiency

GERD

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Extraluminal compression and structural abnormalities of the airways or lung parenchyma Extrinsic compression of the airways is usually due to enlarged lymph nodes, which may be caused by infections, tumours or sarcoidosis.56–59 Tuberculosis is one of the most common causes of extraluminal compression of the airways associated with recurrent lung infections, mainly in developing countries.59 Vascular rings can also cause extraluminal compression.60 Children usually present with localised wheezing or recurrent pulmonary infection during the first years of life. Recurrent pneumonia due to congenital airway malformations (i.e. tracheo-bronchomalacia or bronchial stenosis) or anatomical abnormalities of the lung are also rare causes of recurrent localised LRTIs, which typically present with symptoms in early childhood. Middle lobe syndrome and bronchiectasis Middle lobe syndrome is a distinct clinical and radiological entity characterised by a spectrum of diseases that range from recurrent atelectasis and asthma or pneumonitis to bronchiectasis of the middle lobe.61 Anatomical characteristics such as a lobar bronchus with a narrow diameter, an acute angle originating from the bronchus intermedius, and the proximity of the right middle lobe to the hilar lymph nodes make it particularly vulnerable to transient obstruction. In addition, its relative anatomical isolation from the other lobes and poor collateral ventilation decrease the chance of reinflation once atelectasis has been established. Bronchiectasis forms part of a persistent and often evolving condition that is characterised by dilated and thickened bronchi. It may be congenital and can occur in a localised region of the lung, or may be acquired as a focal disease or be widespread depending on many disease processes.62 The most commonly acquired cause of bronchiectasis is post-infectious disease. Frequent associations have been found with severe bacterial CAP as well as with Mycoplasma pneumoniae or viral infections (particularly those due to adenovirus, influenza or respiratory syncytial virus).63 Children with bronchiectasis typically have recurrent LRTIs, but bronchiectasis can also occur after a single severe infection. In the case of the incomplete resolution of a severe LRTI, persistent inflammation may damage the muscular and elastic components of the bronchial wall. Retrospective studies of different pediatric populations have found that the prevalence of bronchiectasis after pneumonia varies from 11% to 85%.50,64 Cystic fibrosis, immunological disorders, aspiration, and primary ciliary dyskinesia are other potential etiologies, although no underlying cause may be found in up to 40% of patients.63 The most important functional effect of bronchial dilation is severely impaired secretion clearance from the bronchial tree, which can further exacerbate a vicious pathological circle as the clinical hallmarks of bronchiectasis are recurrent chest infections, chronic purulent cough, dyspnea and wheezing.50 Recurrent LRTIs affecting multiple lobes of the lung Many underlying conditions are associated with recurrent pneumonia in multiple lung areas. Such cases may require a broader range of investigations than those recommended when recurrent LRTIs affect a single lobe. The choice of the investigations depends on the patient’s history and clinical findings. Immunodeficiencies Recurrent URTIs and LRTIs leading to chronic suppurative lung diseases are common characteristics of primary immunodeficiencies (PIDs).65 These may be caused by multiple defects, but the most frequent are antibody deficiencies (i.e. from severe deficiencies of all immunoglobulin isotypes to milder deficiencies of specific antibodies or IgG subclasses in patients with normal

immunoglobulin concentrations). In a recent series of 67 pediatric patients affected by recurrent LRTIs, 55% showed antibody defects (IgA deficiency in 31%, IgG2 deficiency in 18%, IgG3 deficiency in 15%, and IgM defects in 6%).66 In common variable immunodeficiency (CVID), the prevalence of recurrent CAP before starting prophylactic immunoglobulin replacement treatment varies from 63% to 84%.67,68 Children with immune defects usually present with highly recurrent and/or severe bacterial infections of the respiratory tract without any seasonality, recurrent gastrointestinal infections and recurrent skin infections.65 Lymphadenopathy and a failure to thrive are also common features. The family history is often characterised by recurrent infections and early deaths because many immunodeficiencies are inherited.65 In general, age at the time of the presentation of recurrent LRTIs can help identify the type of immunodeficiency. A neonatal onset suggests DiGeorge syndrome; onset at an age of 6-12 months is indicative of severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), chronic mucocutaneous candidiasis, and chronic granulomatous disease; and onset at an age of >5 years supports a diagnosis of CVID, specific antibody deficiency and complement disorders.69 The type of organism can also suggest the underlying condition. Interstitial pneumonia due to cytomegalovirus or Pneumocystis jiroveci is typical of T cell defects; recurrent bacterial infections (particularly in males aged >6 months) suggest a humoral immunodeficiency; staphylococcal lung infections are common in hyper-IgE syndrome; and fungal pneumonia is common in chronic granulomatous disease.70 Immunoglobulin replacement therapy has significantly reduced the frequency and severity of acute bacterial infections in PIDs, although long-term pulmonary complications such as chronic lung disease do occur. A study conducted some years ago found that even after the introduction of intravenous immunoglobulin replacement therapy, about 20% of patients still had additional episodes of pneumonia,67 possibly because the administered immunoglobulins do not reach the mucosal surface. GERD Many pulmonary diseases, such as chronic cough, asthma, apnea, recurrent URTIs and LRTIs, and interstitial pneumonia, are potential consequences of GERD,71 possibly because of the aspiration of gastric contents or vagally mediated bronchoconstriction. Although some studies have not documented a clear causal effect between GERD and lung diseases,72 GERD should always be considered a possible cause of recurrent LRTIs when children complain of typical symptoms (i.e. heartburn, regurgitation and dysphagia). Furthermore, some patients with chronic cough and asthma may also have clinically silent GERD.73 Twenty-four hour esophageal pH monitoring is currently the gold standard diagnostic test for GERD in the presence of recurrent LRTIs, but it is not very sensitive and many refluxes may be missed as they are not acid or slightly alkaline. Moreover, children have a much greater proportion of non-acid than acid reflux. A recent study of 51 children with refractory respiratory symptoms documented it by overnight scintigraphy, and pulmonary aspiration in about 50% of cases; but only 24% had concomitant pathological pH.74 As only a few children with respiratory symptoms have pathological gastroesophageal acid reflux, normal intra-esophageal pH findings do not rule out GERD.74 Multichannel intraluminal impedance and pH monitoring improve diagnostic capacity as they are able to detect both the anterograde and retrograde passage of acid and non-acid material.75 Primary ciliary dyskinesia (PCD) PCD is an autosomal recessive disease characterised by chronic sino-pulmonary infections caused by impaired ciliary motility.

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

Age at onset Growth Course of infections Involvement of other organ systems Recurrence in the same site Pathogens Well-being between episodes Family history

Healthy children

Children with chronic underlying disease

>1 year Normal Not serious No No Mainly viruses Prolonged (i.e. at least 3 months) Negative for primary immunodeficiencies or early death

First months of life Slow Serious, requiring hospitalisation Yes Yes Uncommon Short periods or absent Positive for primary immunodeficiencies or early death

Nearly 50% of cases show situs inversus viscerum, but only 23% of patients with situs inversus have PCD.76 The triad of situs inversus viscerum, rhinosinusitis and bronchiectasis is consistent with Kartagener’s syndrome. Clinical symptoms of PCD may appear in the neonatal period with unexplained tachypnea and/or respiratory distress, neonatal pneumonia or persistent rhinitis, whereas daily productive rhinitis, severe rhinosinusitis, recurrent otitis, chronic purulent cough and recurrent pneumonia are common in childhood. The prevalence of PCD as a cause of pediatric bronchiectasis is 1-15%.50,51 Patients with PCD may also have extra-respiratory manifestations, such as congenital heart disease, polycystic kidney, liver disease, biliary atresia and retinal degeneration (including retinitis pigmentosa).77 The diagnosis is frequently delayed because of the overlapping symptoms of recurrent URTIs (which are more common in young children) or the technical expertise required for ciliary ultrastructural analysis. In one review of 55 children, median age at diagnosis was 4.4 years despite the presence of typical symptoms early in life.78 Screening tests for PCD include nasal nitric oxide (abnormally low in PCD) and in vivo tests of ciliar motility.79 A specific diagnosis requires cilia examination by means of light and electronic microscopy and, more recently, a genetic test has also been proposed.80 Cystic fibrosis (CF) CF is the most common life-limiting genetic condition in Caucasians.81 The primary defect is abnormal ion and water transport across epithelial cells, which leads to abnormally thick mucus in the lung that predisposes to chronic airway infections and inflammation. A history of neonatal jaundice, poor weight gain, steatorrhea and highly recurrent pneumonia may suggest cystic fibrosis, although atypical cases may present with recurrent pneumonia alone, in the absence of malabsorption. It is important to remember that the screening of newborns is not very specific but it is sensitive.82 A positive sweat test confirms the diagnosis, but the findings may be normal in patients with atypical CF.83 Genetic screening for CF transmembrane regulator (CFTR) mutation is also used to confirm the diagnosis, and can provide information concerning genotype/phenotype correlations.81 Some studies of adults with idiopathic bronchiectasis have found an increased frequency of heterozygous mutation and polymorphisms of the CFTR gene whose meaning is still unclear.84 Rhinosinusitis and post-nasal drip Rhinosinusitis is characterised by inflammatory edema of the sinus mucosa, obstruction of the sinus ostia, and ineffective mucociliary activity.85–87 It is very common in pediatric patients because of the anatomical features of the paranasal sinuses of children. Adenoidal hypertrophy may predispose to recurrent rhinosinusitis by causing mechanical obstruction and the pooling of secretions; at the same time, it can act as a reservoir for pathogenic bacteria.88 If untreated, a thicker, viscous, purulent post-nasal drip can flow into the respiratory organs when the host is asleep, and may lead to LRTIs.88,89

Rhinosinusitis with post-nasal drip is clinically characterised by a purulent nasal discharge, throat clearing and productive cough, especially when a child lies down or wakes up. However, children frequently have few or no URTI symptoms and present only with a chronic productive cough.90 The diagnosis of rhinosinusitis should only be based on clinical criteria. Paranasal sinus computed tomography, magnetic resonance and optical fibre rhinoscopy are useful in recurrent or severe cases that do not respond to antibiotic therapy and may require surgery.85–87 PRACTICAL DIAGNOSTIC APPROACH TO RECURRENT LRTIS When evaluating a child with recurrent LRTIs, the first step is to distinguish otherwise healthy subjects from those with an underlying chronic disease that require further investigations. Table 3 shows the clinical characteristics of a patient’s medical history that should be assessed. A few, detailed questions are usually sufficient to exclude or raise the suspicion of an underlying disease. Otherwise healthy children start to experience respiratory symptoms after the age of one year, generally when they begin attending a daycare centre. Their respiratory infections have a normal course, and the children do not require hospitalisation and respond to the usual treatments; growth is normal, and there are generally long periods of well-being between episodes. However, if LRTIs appear in the first months of life, are severe, and are accompanied by systemic involvement and/or sustained by unusual pathogens, further investigations are essential. What remains is a ‘‘grey area’’ represented by children with early respiratory symptoms, an occasional need for hospitalisation, and short periods of well-being between episodes, without any focal involvement. In this case, the presence of the risk factors mentioned above (i.e. prematurity, atopy, passive smoking, exposure to indoor and/or outdoor pollution) may justify a wait-and-see approach for 6-12 months. If the number and the characteristics of the LRTIs do not change during the follow-up period despite the elimination of avoidable risk factors, further investigations should be made. Figure 1 summarises the investigations required in relation to clinical history. Once the patients needing further attention have been identified, the second step is to select the most appropriate investigations on the basis of clinical history and a physical examination. Figure 2 shows the investigations recommended in children with recurrent LRTI and a suspected underlying disease. If the recurrent infections affect a single area of the lungs, or if localised pathological sounds (i.e. rhonchi and rales) are detectable even in the intercritical intervals, the first recommendation is a bronchoscopic examination to exclude the presence of foreign bodies, mucus plugs, intraluminal obstructions, extrinsic compression and tracheo-bronchial malacia. If the endoscopic result is normal or inconclusive, it should be followed by HRCT, which enables the better delineation of any extrinsic compression (i.e. mediastinal lymph nodes, abnormal vessels) and highlights the bronchial lumen beyond the limits of endoscopic resolution (i.e. the sub-segmental bronchi).

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Onset > 1 year Normal course of LRTI No hospitalisation Normal growth Prolonged well-being

No further investigations

Improvement

Wait-and-see for 6-12 months, then reassess

Yes Is there any risk factor for recurrent LRTIs?

Early onset (< 1 year), Occasional hospitalisation Short periods of well-being No focal involvement

No improvement

No

Early onset (< 1 year), Severe course, Systemic involvement Focal involvement Unusual pathogen

Immediate further investigations

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

Pneumonia in the same area or localised ronchi and rales in the intercritical period

Pneumonia in different areas

Chest HRCT

Bronchoscopy

If normal Normal

Pathological

Chest HRCT Reconsider the diagnosis of recurrent LRTI

Investigations for immunodeficiency Nasal fiberoptic endoscopy Sweat test 24-hour esophageal pH monitoring Nasal FeNo and nasal brushing Cardiologic evaluation Tuberculosis screening If normal

Bronchoscopy

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

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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 the need for further investigations. On the contrary, if the findings show pathological changes (i.e. bronchiectasis, atelectasis, airtrapping, ground-glass lesions), further investigations are essential. All patients with abnormal HRCT findings should undergo a blood test to assess their immune status (i.e. blood cell counts, serum immunoglobulins, total IgE, IgG sub-classes, lymphocyte sub-populations, C3, C4, CH50). They should also undergo an otorhinolaryngologic examination, including a nasal fiberoptic examination, a sweat test, 24-hour esophageal pH monitoring, and the study of ciliary motility by means of nasal fractional exhaled nitric oxide (FeNo) analysis and ciliary brushing. We recommend all of these investigations because it is not uncommon to encounter the presence of an underlying disease in the absence of an indicative history (i.e. post-nasal drip without rhinorrhea, GERD without subjective symptoms of pyrosis and heartburn). It is also important to undertake a complete cardiological examination, not in order to diagnose congenital heart disease (which is usually done in utero or in early life) but to ensure that the impaired lung does not give rise to pulmonary hypertension, which may contribute 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 LRTIs persist, we recommend bronchoscopy with a bronchoalveolar lavage in order to identify a possibly untreated pathogen, taking a ciliary sample from the tracheo-bronchial tree (in cases in which nasal cilia brushing is not possible), and assess the lipid burden in alveolar macrophages (an indirect sign of pulmonary aspiration).91 If all of these tests, only a negligible proportion of causes of recurrent LRTIs will remain undetermined.92 CONCLUSIONS A significant number of children experience recurrent episodes of LRTIs in the first years of life. When evaluating children with recurrent LRTIs, the first step is to distinguish otherwise healthy subjects from those with an underlying chronic disease that requires further investigations. The aim of this paper is to suggest a practical approach to selecting the patients that should be further evaluated, and to indicate a diagnostic path for reaching a precise clinical diagnosis and preventing chronic lung disease and the loss of lung function. 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 by reducing the risk of LRTIs due to common pathogens.93–96 As pediatricians, we should ensure the adequate use of these vaccines because of the impact they can have on public and personal health. DISCLOSURE STATEMENT None of the authors has any commercial or other association that might pose a conflict of interest. Acknowledgements This study was supported in part by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2007). References 1. Griffin MR, Walker FJ, Iwane MK, et al. Epidemiology of respiratory infections in young children. Pediatr Infect Dis J 2004;23:188–92.

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