Частые ОРЗ у детей. Системный подход. Статья февраль 2009 (англ.)

[Наталья П.]

Pediatric Clinics of North America, Volume 56, Issue 1, February 2009
пдф 347 кб

System Based Approach
Recurrent Respiratory Infections
Andrew Bush MBBS (Hons), MA, MD, FRCP, FRCPCH,

Imperial School of Medicine at National Heart and Lung Institute, London, UK
Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK


Available online 8 January 2009.

The child who has recurrent infections poses one of the most difficult diagnostic challenges in pediatrics. The clinician faces a two-fold challenge in determining first whether the child is normal or has a serious disease, and then, in the latter case, how to confirm or exclude the diagnosis with the minimum number of the least invasive tests. It is hoped that, in the absence of good-quality evidence for most clinical scenarios, the experience-based approach described in this article may prove a useful guide to the clinician.

Keywords: Pneumonia; Croup; Otitis media; Immunodeficiency; Cystic fibrosis; Primary ciliary dyskinesia; Human immunodeficiency virus; Gastro-esophageal reflux

Article Outline

Clinical scenarios: upper airway
Recurrent Viral Colds
Recommendations
Rhinitis
Recommendations
Recurrent Tonsillitis and Pharyngitis
Recommendations
Sinusitis
Recommendations
Recurrent Acute and Chronic Otitis Media with Effusion
Recommendations
Croup and other Causes of Acute Upper Airway Obstruction
Recommendations
Further investigations in upper airway obstruction
Recommendations for further investigations

Clinical scenarios: lower airway
Chronic, Usually Productive Cough
Recommendations
Recurrent Wheezing Lower Respiratory Tract Infection
Airway sounds that are not true wheeze
Episodic (viral) wheeze
Multi-trigger wheeze
Recommendations
Recurrent Radiologic Shadowing
Recurrent radiologic shadowing in the same place
Recommendations
Other recurrent focal abnormalities in a single site
Recommendations
Recurrent multifocal radiologic shadowing
Recommendations

Diagnosing specific conditions presenting as chronic or recurrent acute on chronic productive cough
Cystic Fibrosis
Recommendations
Primary Ciliary Dyskinesia
Recommendations
Idiopathic Bronchiectasis
Recommendations
The Special Problems of Congenital and Acquired Immunodeficiency
Tuberculosis

Summary
References

[Наталья П.]

This article begins with a symptom-based approach to the diagnosis of the child who has recurrent infections of the upper or lower respiratory tract, or of both. Because the differential diagnosis is huge, it is summarized in tables, but no attempt is made to describe in detail every conceivable condition that can present (eg, multifocal consolidation). The second section discusses the presentation of a few specific respiratory conditions that may present as recurrent upper and/or lower respiratory tract infection (eg, cystic fibrosis [CF]). For reasons of space, this article does not discuss the details of specific therapies for these conditions. The problem in trying to provide an evidence-based review of this topic is that there is very little, if any, evidence to review. The methodology required would be to recruit prospectively a large cohort of children presenting with a particular condition (eg, multifocal consolidation), to investigate them in detail, to generate predictive indices for particular conditions or indices that would exclude the need for certain tests, and to validate these indices in at least one other population. Although a systematic approach has been described for cough,1 it has not been validated in a second population, and in most cases there is not even a discovery population.

Most children experience one or more acute respiratory infections. The challenge is first to decide when the time has come to move from symptomatic therapy to performing diagnostic testing, then to determine which tests need to be done and when testing should be discontinued, and finally to institute specific therapies for the child's underlying condition.

The key decision, whether or not to investigate, is always made on the basis of clinical judgment and experience. Factors to be considered vary with the different specific conditions and are discussed later. General pointers are listed in Box1, Box2 and Box3.

[Наталья П.]

Box 1. Pointers that suggest early investigation of a child with recurrent infection may be indicated


The acronym “SPUR” (Severe, Persistent, Unusual, Recurrent) may be a useful mnemonic.

Respiratory infection plus extrapulmonary infections or other disease (eg, arthropathy)

Positive family history: unexplained death, infections or multisystem disease

Severe infection

Persistent infection and failure of expected recovery

Unusual organisms (eg, Pneumocystis jiroveci)

Recurrent infection




Box 2. Pointers in the history of a child presenting with respiratory symptoms that should lead to further investigation


Is the child/family in fact describing true wheeze?

Marked chronic upper airway symptoms: snoring, rhinitis, sinusitis

Symptoms from the first day of life

Very sudden onset of symptoms

Chronic moist cough/sputum production (differentiate from recurrent acute symptoms)

More severe symptoms (or irritability) after feeds and when the child is lying down (vomiting and choking on feeds suggests gastroesophageal reflux or aspiration syndrome)

Any feature of a systemic immunodeficiency

Continuous, unremitting, or worsening symptoms




Box 3. Pointers in the physical examination of a child presenting with respiratory symptoms that should lead to further investigation


Digital clubbing, signs of weight loss, failure to thrive

Upper airway disease: enlarged tonsils and adenoids, prominent rhinitis, nasal polyps

Unusually severe chest deformity (Harrison's sulcus, barrel chest)

Fixed monophonic wheeze

Stridor (monophasic or biphasic)

Asymmetric wheeze

Signs of cardiac or systemic disease





Unless otherwise stated in this article, the level of evidence should be assumed to be low, based on informal consensus and case reports or series.

[Наталья П.]

Clinical scenarios: upper airway
Most children presenting with recurrent upper airway infection are normal. Immunodeficiency, however, can present with upper airway problems.[2] and [3] Particular triggers for further investigation include:4

Eight or more new ear infections within a year

Two or more serious sinus infections (eg, requiring intravenous antibiotic treatment) within a year

Persistent oral or cutaneous candidiasis

Two or more months of continuous antibiotics with no effect

The need for intravenous antibiotics to clear infections

Associated systemic features including recurrent deep-seated or skin abscesses or infections, recurrent pneumonia, failure to thrive, positive family history of immunodeficiency

Recurrent Viral Colds
A large, community-based study documented that in childhood the median number of viral colds is five per year, but more than 10% of children have 10 or more colds per year.[5] and [6] A viral cold usually is a trivial illness. The mean duration of symptoms is around 8 days, but the normal range extends beyond 2 weeks.6 Symptoms are nasal congestion, rhinorrhea, cough, sore throat, and fever. Thus a normal child may have symptoms of the common cold for nearly 6 months in the year. The misinterpretation of common symptoms as “wheeze”[7], [8], [9] and [10] may lead to an incorrect diagnosis of asthma. Not unexpectedly, attendance in child day care facilities early in life increases the risk of viral colds.11 The frequency and duration of colds may come as a surprise, particularly to first-time parents, and misconceptions about the need for treatment are common.12 The issue of virally induced wheezing is discussed under in the section devoted to the lower airway.

Recommendations
In the absence of any other worrying features on history and examination (Boxes 2 and 3), isolated recurrent viral colds do not require further investigation unless the frequency is more than 15 per year, and the duration habitually is more than 15 days per episode. Level of evidence: low.

[Наталья П.]

Rhinitis
Intermittent acute rhinitis must be distinguished from chronic rhinitis, which has a wider differential diagnosis. The definitions of acute and persistent rhinitis are variably defined; one group defined persistent rhinitis as occurring at least 4 days a week for at least 4 weeks;13 another group holds that acute rhinitis may last as long as 12 weeks.14 The evidence base on the timing and nature of appropriate investigations in persistent rhinitis is scanty; however, recent combined adult and pediatric guidelines have listed potential investigations that may be useful.14 The two common causes are infective and allergic rhinitis, and skin prick testing may be indicated. Unilateral rhinitis should lead to consideration of anatomic abnormalities such as unilateral choanal stenosis or the presence of a foreign body. The combination of persistent rhinitis and lower respiratory tract symptoms should prompt diagnostic consideration of allergic rhinitis and asthma (the most common cause); primary ciliary dyskinesia (PCD), especially with neonatal onset of rhinitis; CF (especially if there are nasal polyps); and Wegener's granulomatosis (seen in 21 of 25 patients in one series).15

Recommendations
Persistent rhinitis usually does not require detailed investigations. Evidence of allergic sensitization may be sought, and empiric therapeutic trials are reasonable, unless there is evidence that rhinitis is part of a more generalized disease. Level of evidence: low.

[Наталья П.]

Recurrent Tonsillitis and Pharyngitis
In childhood, significant tonsillar disease manifests commonly as either obstructive sleep apnea (not discussed here) or recurrent acute tonsillitis. Children are considered to have an episode of significant tonsillitis if they satisfy at least one of the following criteria: (1) an oral temperature of at least 38.3°C; (2) cervical lymphadenopathy (enlarged by > 2 cm or tender cervical nodes); (3) tonsillar or pharyngeal exudate; and (4) a positive culture for group A β-hemolytic streptococcus. Conventionally, tonsillectomy is indicated if there have been seven or more documented episodes in the preceding year, five or more in each of the 2 preceding years, or three or more in each of the preceding 3 years.16 The other indication for tonsillectomy is obstructive sleep apnea. One study has suggested tonsillectomy is a cost-effective strategy for treating obstructive sleep apnea,17 but in a randomized, controlled trial the risks of surgery were thought to outweigh any benefits.18 Furthermore, about two thirds of operations are performed for less stringent and thus even less evidence-based criteria.19 Usually no other investigations are performed for isolated recurrent tonsillitis in the absence of features listed in Boxes 2 and 3, but there is no good-quality evidence to inform the decision making about the need for further investigation.

Recommendations
Isolated recurrent tonsillitis and pharyngitis do not require further investigation in the absence of any other worrying features (see Boxes 2 and 3). Level of evidence: low.

[Наталья П.]

Sinusitis
Acute sinusitis in children is common and usually a self-limiting disease that requires no investigation. Further investigation, usually in collaboration with an ear, nose, and throat surgeon, should be considered in children who have recurrent acute or severe chronic sinusitis. The differential diagnosis includes respiratory allergy, CF (particularly if nasal polyps or other features of this condition are present), PCD (nasal polyps are said to be common in this condition, but this has not been the author's experience), and systemic immunodeficiency.14 Mechanical obstruction of the ostia should be considered; the most common isolated cause is an antrachoanal polyp. Gastroesophageal reflux also enters the differential diagnosis or may be a significant comorbidity.20 Of note: laryngopharyngeal reflux disease may differ from the more usual patterns of reflux, being more common when the patient is upright, and extending into the hypopharynx.21 Many patients are unaware of the extent of this problem.22

In a child who has recalcitrant sinusitis, allergy should be excluded with skin prick tests or radioallergosorbent tests to aeroallergens; the exact panel should be determined by the child's environment. In very young children, genuine allergy may be present, but the skin prick test may not have become positive. As discussed later, it may be necessary to exclude CF, PCD, and immunodeficiency. Imaging of the sinuses with CT or MRI may enable rare anatomic diagnoses to be made.23 Endoscopy may need to be considered for unilateral disease. Endoscopy also can indicate the presence of reflux disease, which may be associated with one or more of the following observations;24

Cobblestoning of the mucosa of the larynx and pharynx

Inflammation of the upper respiratory tract

Sinus involvement

Rhinorrhea

Subglottic stenosis

Velopharyngeal insufficiency

Pharyngotracheitis

Tracheomalacia

Diagnosis may be confirmed by a pH study, or a therapeutic trial of medication may be given.

Recommendations
Most children who have sinusitis need no investigation. Unusually severe or chronic sinusitis may be the presenting feature of a local or systemic immunodeficiency or of gastroesophageal reflux. There is little evidence on which to make specific recommendations about the nature and timing of the most appropriate investigations for sinusitis. Level of evidence: low.

[Наталья П.]

Recurrent Acute and Chronic Otitis Media with Effusion
Acute otitis media is common: one study reported 1.72 episodes per child per year between 6 months and 3 years of age.6 Viral colds were complicated by acute otitis media (37%) and otitis media with effusion (24%).24 Chronic otitis media with effusion may be a sign of respiratory allergy (for investigation, see the previous discussion of sinusitis) and immunodeficiency. Eight or more new ear infections per year should be considered a sign of potential immunodeficiency.4 Curiously, middle ear disease is not increased greatly in CF but is an important feature of PCD. Particular features pointing to a diagnosis of PCD include early-onset and severe hearing loss and prolonged offensive otorrhea after tympanostomy tube insertion. Typically, there is chronic infection with Pseudomonas aeruginosa that can be eliminated only with quinolone eardrops. The child has an obvious smelly discharge running down the side of the face, and there is no improvement in hearing. Unfortunately, multiple procedures often are performed before the diagnosis is made.25

Recommendations
Most children who have otitis media with or without effusion need no investigation. The possibility of underlying immune deficiency, and in particular PCD, should be borne in mind. There is little evidence on which to make specific recommendations about the nature and timing of the most appropriate investigations for middle ear disease. Level of evidence: low.

[Наталья П.]

Croup and other Causes of Acute Upper Airway Obstruction
Viral croup typically presents with the sudden onset of barking cough, stridor, and respiratory distress in the setting of a coryzal illness. The acute management and differential diagnosis are well described in two recent reviews.[26] and 27 J.D. Cherry, Clinical practice. Croup, N Engl J Med 358 (2008), pp. 384–391. Full Text via CrossRef[27] Importantly, medical management with oral dexamethasone or another oral steroid and nebulized adrenaline should permit intubation to be avoided. Generally infants only have a single or very few episodes, but occasionally patients experience multiple episodes that extend into mid-childhood. In neither review is there any recommendation as to when and how to investigate further. The differential diagnosis includes spasmodic croup, an unsuspected congenital structural abnormality such as a web, subglottic hemangioma, and acquired laryngeal disorders such as a foreign body, subglottic stenosis secondary to previous intubation, or respiratory papillomatosis. Stridor caused by a subglottic hemangioma may present as croup and apparently respond to steroids, because they lead to shrinkage, only to recur subsequently as the hemangioma re-expands.28

Recommendations
A single episode of uncomplicated croup with rapid and complete recovery does not require further investigation. Croup should be investigated if

1. The episode is severe (prolonged intubation required).

2. There are atypical features in the history or on examination.

3. Symptoms or signs persist beyond an arbitrary time period (eg, 2 weeks). Croup can be complicated by subglottic stenosis if intubation has been required, and subglottic stenosis enters the differential diagnosis of persistent stridor in a previously well child.

4. There are recurrent episodes, particularly if severe.

There is, however, insufficient evidence to identify the point at which investigation is warranted. Level of evidence: low.

[Наталья П.]

Further investigations in upper airway obstruction
Before any investigation is undertaken, a detailed history and examination should be performed. If the child is old enough, a flow–volume curve should be performed; the typical truncated shape of extrathoracic obstruction may be seen (Fig. 1). In younger infants, a tidal flow–volume loop may be suggestive of large airway obstruction.29 A neck radiograph may reveal a radiopaque foreign body but generally is not helpful. The most useful investigations are a fiberoptic bronchoscopy, under general anesthesia using a pernasal approach via a facemask held by the anesthetist; and serum calcium levels (hypocalcemia may present as recurrent stridor) and C1-esterase inhibitor levels (deficiency presents as recurrent subglottic swelling leading to stridor).



Full-size image (18K)


Fig. 1. Pulmonary function testing. Rigid tracheal obstruction is suggested by abrupt attenuation of flows in inspiration and expiration.


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The relationship between croup, croup with wheeze, and recurrent croup with subsequent asthma is controversial. In one study30 physician-diagnosed croup was inversely associated with atopy at school age. The Oslo study showed that atopic children who had a diagnosis of croup were less likely to have a subsequent diagnosis of asthma, whereas non-atopic children were more likely to have a later diagnosis of asthma.31 Another study showed that the odds ratio for a diagnosis of asthma was increased by a diagnosis of croup and increased still further if croup was recurrent.32 Croup with wheeze may be more predictive of subsequent asthma.33 Overall, although croup may be a marker for future asthma in some children, for most children it is an isolated illness with no long-term sequelae. Because the early institution of inhaled corticosteroids has not been shown to prevent recurrent croup and certainly does not prevent the progression of intermittent wheeze to multi-trigger wheeze,[34], [35], [36], [37] and [38] the debate about the relationship between croup and asthma is not of practical clinical importance at the moment.

Recently, the most important infectious cause of stridor is bacterial tracheitis.39 Immunization has almost completely abolished acute epiglottitis and laryngeal diphtheria, although these diseases should be considered in the nonimmunized child. Retropharyngeal abscess, which may be associated with a penetrating foreign body, is another rare cause of presentation with a crouplike illness, although the child usually is more toxic.

Recommendations for further investigations
There is no evidence on which to base guidelines for further investigation of children who have upper airway infections causing stridor not caused by viral laryngotracheitis. Most pediatricians would not investigate a single episode in an otherwise well child. Possibly, a single documented episode of type B Haemophilus Influenzae epiglottitis in a fully immunized child might merit further investigation. Level of evidence: low.

[Наталья П.]

Clinical scenarios: lower airway
This section is divided into three parts: chronic productive cough, recurrent wheezing lower respiratory tract infection, and recurrent radiologic shadowing. This approach has been found to be useful in personal practice, although some investigations that cut across clinical scenarios may be described inadequately or, conversely, there may be repetition. Specific conditions that are referred to in the differential diagnosis in these sections (eg, CF, PCD, and immunodeficiency) are discussed in the final sections of the article.

Many children are too young for pulmonary function testing, although increasingly techniques such as airway resistance using the interrupter technique (Rint)40 and the lung clearance index[41], [42] and [43] are applicable in preschool-age children. The shape of the tidal flow–volume loop may suggest an obstructive picture.29 If there are facilities to carry out spirometry, lung volumes, and carbon monoxide transfer, and the child is able to perform these tests, much useful information can be obtained. Pulmonary function testing provides only part of the clinical information, however, and the only specific diagnoses that can be made in the pulmonary function laboratory are exercise-induced asthma and hyperventilation syndromes.

Airway disease is suggested by the combination of hyperinflation (raised residual volume, functional residual capacity, and total lung capacity) with reduced 1-second forced expiratory volume (FEV1) and FEV1 to forced vital capacity (FVC) ratio. Elevated carbon monoxide transfer (DLco) is suggestive of asthma or bronchiectasis, whereas reduced DLco suggests parenchymal destruction as well as airflow obstruction (eg, the sequelae of chronic lung disease of prematurity). Parenchymal disease is suggested by reduced FEV1 and FVC, with a normal or elevated FEV1:FVC ratio and reduced residual volume, functional residual capacity, and total lung capacity. A high DLco per liter of accessible lung volume suggests chest wall restriction, such as scoliosis. An isolated reduction in DLco suggests pulmonary vascular disease, such as recurrent pulmonary embolism or primary pulmonary hypertension. An isolated elevation in DLco suggests recent pulmonary hemorrhage.

The shape of the flow–volume loop may give additional clues. Rigid tracheal obstruction is suggested by abrupt attenuation of flows in inspiration and expiration (see Fig. 1). Attenuation in only the expiratory limb suggests variable obstruction (eg, malacia) of the intrapulmonary trachea or large airways. Isolated attenuation of the inspiratory limb may be caused by variable obstruction of the extrathoracic trachea, inspiratory muscle (diaphragm) dysfunction, or stiff lungs. Marked variability, and in particular a very variably impaired inspiratory flow–volume curve, is highly suggestive of vocal cord dysfunction.44

Another important issue is the state of the child's immune system. In the following sections, it is assumed that the child does not have a known and diagnosed immune deficiency but is thought at presentation to have a normal immune system. The special problems of the immunodeficient child are discussed in a separate section or are referred to specifically where applicable. For example, recurrent infiltrates would be investigated very differently, and much more urgently, in a child who has pancytopenia after chemotherapy than in an otherwise well child who has similar radiologic appearances.

[Наталья П.]

Chronic, Usually Productive Cough
It is important to distinguish recurrent, acute, productive-sounding cough, which usually is secondary to a series of viral colds, from a continuous productive cough, which needs investigation if it persists beyond a certain time period. In a group of children who had cough severe enough to be referred to a specialist pediatrician and who then were submitted to a detailed diagnostic algorithm after 3 weeks of cough (nearly 90% of which was productive), more than 20% got better spontaneously, suggesting this duration of cough is too short to merit referral.1 The British Thoracic Society recommends 8 weeks as the definition of chronic cough,45 but this recommendation is not based on any firm evidence. Clearly context is crucial: if the child is clinically unwell, investigation may need to begin at once, and it would be wrong to specify a duration that warrants investigation. In a hospital context, it is clear that parental report of a productive cough correlates well with the finding of secretions in the lower airway.46 A.B. Chang, J.T. Gaffney and M.M. Eastburn et al., Cough quality in children: a comparison of subjective vs. bronchoscopic findings, Respir Res 6 (2005), p. 3. Full Text via CrossRef46 The largest study systematically investigating children who had chronic cough used a protocol of successively performing laboratory tests (sweat chloride, common CF mutations, serum Mycoplasma pneumoniae IgM, and Bordetella pertussis IgA serology, immunoglobulins G, A, M, and E and IgG subclasses), bronchoscopy (occasionally induced sputum), chest high-resolution CT (HRCT), and a pH probe. Finally, when necessary, blind trials of therapy were performed. A number of important lessons emerged. The first is that the adult causes of chronic cough (asthma, gastroesophageal reflux disease, and upper airway disease) are uncommon causes of chronic cough in children. Indeed, many lines of evidence support the view that isolated cough in children is rarely caused by asthma and should not be treated as such.[47] and [48] The most common cause identified was persistent bacterial bronchitis (PBB) in nearly 40% of children.1 In this report the diagnostic criteria for confirmed PBB were a history of chronic moist cough, a positive bronchoalveolar lavage fluid (BAL) culture, and response to antibiotic treatment (amoxicillin/clavulanic acid suspension) with resolution of the cough within 2 weeks. Probable PBB was defined as a history of chronic moist cough and either positive BAL culture or immediate response to antibiotic therapy with resolution of the cough within 2 weeks. In most cases of probable PBB, the BAL culture reached only 103 or 104 colony-forming units (cfu)/mL rather than an arbitrary 105 cfu/mL, or the patients required additional antibiotic therapy before the cough disappeared. A subsequent article suggested that multiple courses of antibiotics were needed to resolve the cough,49 and that the rapid response to a short course reported by Marchant and colleagues1 might reflect the relatively short duration of symptoms in their group. It also is not clear whether it would be more cost effective to prescribe an empiric course of antibiotics before embarking on investigations.

PBB is undoubtedly a real and important entity, but most clinicians believe that the diagnostic criteria should be tighter than those listed in the previous paragraph. PBB is a diagnosis of exclusion; it should be suspected in the child who has chronic productive cough lasting longer than 8 weeks, and investigations should show a neutrophilic BAL with positive cultures (with normal BAL cytology, a positive culture may represent a contaminant) but also must eliminate bronchiectasis, gastroesophageal reflux disease, and local and systemic immunodeficiency as a cause for the symptoms. BAL findings alone are insufficient for the diagnosis. The relationship between PBB and subsequent idiopathic bronchiectasis is unclear. An attractive hypothesis is that untreated PBB can progress to idiopathic bronchiectasis, but at the moment there is no evidence that PBB is pre-bronchiectatic.50 There also is no knowledge of the etiology; PBB may be the result of a congenital or acquired postinfective localized immune deficiency, which subsequently may improve. The presence of PBB in children older than age 10 years suggests that the abnormality is acquired.

Although asthma is not an infectious disease, the problem of cough-variant asthma is considered here because it is misdiagnosed so frequently. There is no doubt that cough-variant asthma does exist, but it is rare and is virtually unknown in non-atopic children. The author is reluctant to diagnose any form of asthma in the absence of significant breathlessness. Indeed, it is rare to find airway eosinophilia suggestive of asthma even in atopic children who have cough as their sole symptom.48 In children old enough to perform pulmonary function tests, cough-variant asthma should not be diagnosed unless clear-cut evidence of variable airflow obstruction can be demonstrated. In the younger child, in whom pulmonary function testing is not be practical in most circumstances, a three-stage therapeutic trial is recommended:

1. Commence inhaled corticosteroids. There is some evidence that some children who seem not to respond to inhaled salbutamol respond to inhaled corticosteroids.[51] and [52] Oral steroids are not recommended because of potential systemic effects and also because of possible upper airway effects (eg, shrinking adenoidal tissue), which may confuse the issue. There is no evidence on which to base the dose and duration of inhaled corticosteroids; anecdotally, a moderately high-dose (800 μg/d) beclomethasone equivalent for 8 weeks is suggested.

2. Stop therapy after a period of time. The duration of the trial should be sufficient to ensure that any possible response is detected. If there is no response, the child does not have cough-variant asthma. An apparent response, however, may in fact be a spontaneous regression of cough, in which case treatment is not indicated.

3. Restart therapy only if the symptoms recur on stopping treatment. This precaution eliminates the possibility of labeling transient symptoms as cough-variant asthma. Treatment then is titrated down to the lowest dose needed to control symptoms.

It is convenient to consider what role, if any, exhaled nitric oxide measurements (FeNO) have in the diagnostic process. Nasal NO is discussed in the section devoted to PCD. In general, there is too much overlap between the FeNO measurements for CF, bronchiectasis, PCD, and asthma for this test to be of much use in diagnosing individuals.53 A very high FeNO (twice the upper limit of normal) was reported only in children who had asthma. Some individuals, however, seem to have a constitutively high FeNO in the absence of symptoms,54 and a high FeNO should not be equated uncritically with a diagnosis of asthma. At the present time, FeNO cannot be recommended as a diagnostic test in recurrent respiratory infections.

Recommendations

1. A child who has a true chronic cough (as opposed to recurrent acute cough) of several weeks' duration should be investigated systematically. The duration of symptoms before investigation is not clear but should not exceed 8 weeks and should be shorter in a child who is unwell. Systematic, protocol-driven evaluation leads to a high diagnostic yield. Level of evidence: moderate

2. Chronic isolated cough is rarely caused by asthma and should not be treated as such. Cough-variant asthma usually is a diagnosis of exclusion. Level of evidence: moderate

3. FeNO is not a useful test in the diagnosis of recurrent respiratory infections. Level of evidence: moderate to high

[Наталья П.]

Recurrent Wheezing Lower Respiratory Tract Infection
In young children, recurrent wheezing in the lower respiratory tract almost always is caused by recurrent viral infection. It is important to note that patients' families often use the term “wheeze” imprecisely. Some European languages do not have such a term; in England, many different airway sounds may be described as “wheeze,” including upper airway rattling and even stridor.[7], [8], [9] and [10] The use of a video questionnaire may help define the noise. In one study, physician assessment of wheeze correlated with objective measurements, but parents and nurses were not so accurate.55 Furthermore, the nomenclature of this condition is confused: wheeze can be defined either by symptom pattern or by epidemiologic course. Symptom pattern is more useful prospectively, and the history should categorize the pattern as either episodic (viral) or multi-trigger wheeze. Epidemiologically, wheeze is either transient (disappearing after the first 3 years of life) or persistent (present throughout the first 6 years of life). It sometimes is assumed that the terms “viral” (episodic) and “transient,” and “multi-trigger” and “persistent” can be used interchangeably, but there is no evidence that this is the case. Thus, further investigation should be considered in three scenarios:

1. Recurrent acute or chronic nonspecific airway sounds (not true wheeze)

2. Episodic (viral) wheeze

3. Multi-trigger wheeze (usually a combination of episodic, viral-associated symptoms and interval, multi-trigger wheeze)

There also has been interest in the role of bacterial coinfection in viral wheeze. The Copenhagen Prospective Study on Asthma in Childhood (COPSAC) study showed that positive upper airway cultures for bacterial pathogens in babies are associated with subsequent wheeze.56 A smaller study showed that serologic investigation frequently revealed evidence of bacterial coinfection with respiratory virus–induced wheeze,57 although features suggestive of a major infection, such as systemic toxicity and elevation in C-reactive protein, were rare. The most likely hypothesis is that the propensity for viral wheeze and low-grade mucosal bacterial infection are both manifestations of a subtle and probably maturational mucosal immune deficiency,58 which may be related to antenatal events such as maternal smoking[59], [60] and [61] and possibly to epigenetic mechanisms.62 Further discussion of this possibility is beyond the scope of this article.

[Наталья П.]

Airway sounds that are not true wheeze
Commonly the child has viral colds with relatively prolonged symptoms or nonspecific upper airway noises that require no treatment other than reassurance of the family. Symptoms may persist beyond the third birthday. Occasionally, stridor may be misdiagnosed as wheeze and should be investigated along standard lines; most would advocate an early bronchoscopy.

Episodic (viral) wheeze
Wheeze with viral colds is common, often is not severe (ie, is not life threatening), but frequently is a cause of considerable morbidity and loss of time from work for the child's care givers. In some children, however, the attacks really may be severe. In an otherwise well child who has mild to moderate episodic wheeze, investigation is not necessary. If the wheezing illness really is severe, investigation may be indicated, as discussed later.

Multi-trigger wheeze
In older children, multi-trigger wheeze usually is associated with demonstrable variable airflow obstruction and responds to standard asthma therapy. When no other feature of the history or examination suggests an alternative diagnosis, no further investigation is required. One group used a detailed protocol to investigate severely affected wheezy (episodic and multi-trigger) preschool children.63 S. Saglani, A. Nicholson and M. Scallan et al., Investigation of young children with severe recurrent wheeze. Any clinical benefit?, Eur Respir J 27 (2006), pp. 29–35. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (20)63 Measurements included immunoglobulins and subclasses, a sweat test, nasal ciliary brushings, a pH probe, HRCT, and bronchoscopy. There was a high yield of abnormal findings, including gastroesophageal reflux, PBB, and airway eosinophilia, often despite oral or inhaled steroid therapy. What this group could not demonstrate was whether this aggressive approach leads to an improved outcome; a prospective clinical trial is required for this issue to be resolved.

Recommendations

1. Most children who have true wheezing caused by lower respiratory tract infections do not require further investigation. Level of evidence: moderate

2. Aggressive, protocol-driven investigation of severe wheeze will lead to new diagnoses, but the clinical relevance of these diagnoses often is not clear. Level of evidence: moderate.

[Наталья П.]

Recurrent Radiologic Shadowing
The vague term “radiologic shadowing” is used because many of these conditions can cause either consolidation or atelectasis. Although radiologic patterns may give a clue to the diagnosis, the patterns often are nonspecific, and detailed further investigation usually is indicated.

“Recurrent chest infection” in lay parlance usually means recurrent episodes of a productive cough, generally in association with viral colds, and is not the same as recurrent shadowing on chest radiographs. Recurrent bouts of coughing may require investigation, as discussed previously, but cough is normal,64 and the frequency of cough is notoriously poorly evaluated by parents and children.[65], [66], [67] and [68] At least two episodes of documented radiologic shadowing are required to merit investigation for possible recurrent lower respiratory tract infection. A single episode of uncomplicated lobar pneumonia in an otherwise well and thriving child does not require investigation. Indeed, if the child is seen by an experienced clinician and is thought to have made a complete recovery, even a follow-up chest radiograph is not necessary.[69] and 70 P. Surén, K. Try and J. Eriksson et al., Radiographic follow-up of community-acquired pneumonia in children, Acta Paediatr 97 (2008), pp. 46–50. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2)[70] Further investigation is mandated, however, if the child has had a previous history of unusual infections, there is a family history of an immune problem or an unexplained death from infection, there are any features to suggest a systemic illness, or the pneumonia is at all atypical in its course.

The child with recurrent shadowing on the chest radiograph should not be assumed to be having repeated infections, particularly if there is not complete radiologic clearing between episodes. The differential diagnoses and investigation of recurrent shadowing in the same area and of multifocal recurrent shadowing are described here in turn. The reader will need to consult standard texts for the further detailed investigation of many of these conditions.

Recurrent radiologic shadowing in the same place
A child with two or more radiologically documented episodes of shadowing in the same lobe or segment, particularly if there is incomplete clearing between episodes or with a single episode that does not clear should be investigated further. The differential diagnosis is summarized in Box 4. The radiologic changes of acute pneumonia may take 6 to 12 weeks or even longer to resolve, depending on the causative organism.[71] and [72] Determining when to investigate thus becomes a matter of clinical judgment, depending on the history, whether the child is improving clinically, and whether there are any other features suggestive of another condition. There are no evidence-based recommendations to guide the clinician.