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

[Наталья П.]

Box 4. Differential diagnosis of recurrent or chronic localized radiographic changes


Right middle lobe syndrome

Localized airway obstruction

Within the lumen
Congenital webs

Endobronchial foreign body

Mucus plug

Carcinoid or other pedunculated tumor

Inflammatory pseudotumor secondary to previous intubation

Within the airway wall

Localized malacia

Localized bronchiectasis (underlying cause must be sought)

Complete cartilage rings

Intramural tumor

Extrinsic compression

Congenital thoracic malformation

Enlarged cardiac chamber caused by right to left shunting, cardiomyopathy

Vascular ring, pulmonary artery sling

Lymph nodes: tuberculosis, lymphoma, other

Mediastinal or lung tumor

Fibrosing mediastinitis

Pulmonary parenchymal disease

Congenital: cystic congenital thoracic malformation

Acquired: infection in residual cystic change after a cavitating pneumonia or tuberculosis (tumor will be focal and progressive)

First manifestation of a cause of recurrent fluctuating multifocal consolidation (see Box 5)

[Наталья П.]

Right middle lobe syndrome probably is the most common clinically encountered focal consolidation for which there is some evidence to base recommendations. It is the most common recurrent focal investigation encountered in clinical practice and thus merits a separate section. Right middle lobe syndrome also may be related to the conditions listed in Box 4. The definition of right middle lobe syndrome is clinical: atelectasis of the right middle lobe or lingula persisting for more than 1 month or recurring twice or more despite treatment.73 The author's experience is that the lingula is affected only rarely in comparison with the right middle lobe, although others report right middle lung disease being as only twice as common as lingula disease.74 The likely explanation of the frequency of right middle lobe disease is the anatomy: every bronchoscopist is familiar with the acute take-off and often slitlike orifice of the right middle lobe bronchus, which intuitively makes it likely to be vulnerable to occlusion. A pathologic study of 21 resected specimens (adults and children) showed bronchiectasis (n = 10), chronic bronchitis and bronchiolitis with lymphoid hyperplasia (n = 7), patchy organizing pneumonia (n = 6), atelectasis (n = 5), granulomatous inflammation (n = 5), and abscess formation (n = 4).75 These findings obviously represent the most severe cases but suggest that infection is important, and thus early diagnosis and aggressive treatment of infection may be beneficial. Studies in which BAL was performed documented infection in one third to one half of cases; H. influenzae was the most common pathogen. Only 2 of 53 subjects had an endobronchial obstruction seen at bronchoscopy. More than 25% had bronchiectasis, and, unsurprisingly, their outcome after treatment was less good.73

The relationship between right middle lobe syndrome and atopy and asthma is controversial. One group made the diagnosis more commonly in atopic patients.74 Another group showed an increase in bronchial responsiveness, but not atopy, in children who had right middle lobe syndrome.76 By contrast, De Boeck and colleagues77 showed that one third of the children who had been diagnosed with right middle lobe syndrome had subsequent chronic asthmalike symptoms. It seems likely (but is unproven) that any hypersecretory respiratory syndrome such as asthma may be complicated by right middle lobe syndrome, but the series are too small to pick up such an effect (eg, in the largest recent series only 5 of 53 subjects had an eosinophilic lavage).[73] and [76] It would be wise to follow these children carefully.

Recommendations

1. Children who have right middle lobe syndrome may have underlying chronic infection and bronchiectasis. If radiologic changes have not cleared within 1 month, or if they recur after treatment, further investigation with bronchoscopy and perhaps HRCT scanning is indicated. The diagnostic yield of these tests probably is high, but there are no outcome data to show that aggressive investigation is beneficial. Level of evidence: moderate

2. The families of children who have right middle lobe syndrome should be advised that these children are at risk of chronic respiratory symptoms and asthma and should be followed carefully or should return for re-evaluation at the first signs of recurrent symptoms. Level of evidence: moderate.

[Наталья П.]

Other recurrent focal abnormalities in a single site
Important steps in the investigation of focal abnormalities are a fiberoptic bronchoscopy to rule out focal airway disease and HRCT scanning to exclude focal parenchymal disease. Other imaging modalities that may help include endobronchial ultrasound to demonstrate complete cartilage rings and CT reconstruction of the airway anatomy. It always is good practice to try to obtain previous imaging, to see if the abnormality is new or might be congenital. Ideally HRCT should be performed when the child is not acutely infected, because acute changes may complicate the interpretation of the scans. It is worth considering giving intravascular contrast with the HRCT to delineate vascular anatomy: if the abnormality has an arterial supply from the abdominal aorta or drains into the systemic circulation, a congenital thoracic malformation is likely. If mediastinal disease is thought to be an issue, an MRI scan may be indicated; the lack of radiation makes this modality attractive, but the current requirement for general anesthesia for small children in most centers militates against its use unless essential. An echocardiogram is a simple investigation which is often forgotten and which may show an enlarged cardiac chamber compressing the bronchus. The differential diagnosis is wide and is summarized in Box 4. If HRCT and bronchoscopy have not established the diagnosis, a more invasive approach, including surgical excision or lymph node biopsy, may be indicated. The possibility that a single-site change may be the first presentation of a generalized illness should not be forgotten.

Recommendations

1. The differential diagnosis of recurrent or chronic shadowing in a single site is wide, and investigation is indicated. There is no evidence base to inform the clinician of the optimal timing of investigation or the optimal sequence of tests. Level of evidence: low

2. If simple investigations have not yielded a diagnosis, aggressive investigation of recurrent or chronic shadowing in a single site, including surgical excision or mediastinoscopy as appropriate, is justified. Level of evidence: low.

[Наталья П.]

Recurrent multifocal radiologic shadowing
Again, the differential diagnosis for recurrent multifocal shadowing, as for recurrent radiologic shadowing in a single site, is wide (Box 5), and details of specific conditions are given elsewhere. Fixed or relentlessly progressing pulmonary shadowing (eg, caused by malignancy or interstitial lung disease) is not discussed here. This section suggests a few, perhaps less obvious, points that may be valuable in elucidating this problem, without attempting to all possibilities in detail.




Box 5. Differential diagnosis of recurrent fluctuating multifocal radiographic changes


Recurrent respiratory infection
Local immunodeficiency
Cystic fibrosis

Primary ciliary dyskinesia

Other subtle abnormalities of mucosal defense also likely

Systemic immunodeficiency (most require investigation by immunologic specialist)

Congenital (see Box 7)

Acquired (see Box 7)

Structural abnormality

Postinfective or idiopathic bronchiectasis

Neurologic disease causing weakness of particularly expiratory muscles

Unusual non-granulomatous infections

Hydatid disease (usually but not inevitably nonfluctuating)

Recurrent aspiration syndromes

Bulbar and pseudobulbar palsy
Central neurologic disease, peripheral nerve or muscle disease

Laryngeal cleft

Isolated, late-presenting H-type fistula

Esophageal dysmotility syndromes

After tracheoesophageal fistula repair

Achalasia

Others

Severe gastroesophageal reflux

Primary or secondary to respiratory disease

Anatomic defects: hiatus hernia

Delayed gastric emptying

Lipid inhalation

Oily medication and nose drops

Recurrent pulmonary edema

Left to right shunting (eg, ventricular septal defect, patent arterial duct)

Heart failure (eg, cardiomyopathy}

Major airway obstruction (trachea, carina, large bronchi)

Vascular rings and slings (look for a right-sided aortic arch on the chest radiograph)

Generalized bronchomalacia (Williams Campbell syndrome, others)

Multiple complete cartilage rings

Airway compression by an enlarged heart or great vessels (eg, absent pulmonary valve syndrome)

Latrogenic

Direct pulmonary drug toxicity

Indirect effects of medications (eg, on the heart)

Hypersecretory syndromes

Hypersecretory asthma

Plastic bronchitis syndromes

Pulmonary hemorrhagic syndromes

Secondary pulmonary hemorrhage
Pulmonary venous hypertensive syndromes

Coagulopathy

Bronchial circulatory hypertrophy of any cause

Isolated pulmonary syndromes

Idiopathic pulmonary hemosiderosis

Isolated pulmonary vasculitic syndromes

Pulmonary arteriovenous malformation

Part of a systemic disease

Goodpasture's syndrome

Other autoimmune diseases and vasculitis

Autoimmune disease unrelated to pulmonary hemorrhage

Systemic lupus erythematosus

Rheumatoid syndromes

Others

Allergic lung disease

Allergic bronchopulmonary aspergillosis (usually secondary to cystic fibrosis)

Extrinsic allergic alveolitis

Granulomatous disease

Sarcoidosis

Tuberculosis

Other chronic infections

[Наталья П.]

As always, a detailed history is essential. Because international travel is common, a detailed history of where the child has been is vital. A medication history is important and should not be limited to prescription drugs.78 Nervous system disease may affect the lung through many mechanisms. Neurologic incoordinate swallowing may be overlooked easily. Specific questions about choking and swallowing must be asked, and if there is any doubt, the child should be evaluated by an experienced speech therapist. Another cause of swallowing problems is a laryngeal cleft, which may be overlooked unless a rigid bronchoscope is used to examine the upper airway. Laryngeal cleft may coexist with esophageal atresia and enters the differential diagnosis of recurrent aspiration after surgical repair of the atresia.79 Cough is a fundamental defense mechanism, requiring both inspiratory and especially expiratory muscle strength. Disease such as spinal muscular atrophy may present first in the respiratory muscles and typically affects the expiratory muscles preferentially, leading to recurrent infection and mucus plugging.

Gastroesophageal reflux and respiratory disease have a complex relationship. There is no doubt that respiratory disease can worsen aspiration by multiple mechanisms. Also, reflux can cause respiratory disease, both by direct aspiration and by an esophagobronchial reflex,80 or reflux can be an incidental finding of no consequence. The diagnosis of reflux also is controversial. The reference standard for a diagnosis of acid reflux is 24-hour pH-metry. This technique has been refined by the use of an upper and lower esophageal electrode, to try to determine the significance of any esophageal acid,81 but, as pointed out previously, acid reflux confined to the lower esophagus is not necessarily benign. The significance of non-acid reflux has been debated. Although non-acid reflux now can be detected, its measurement between 24-hour periods is more variable than that of pH-metry,82 and currently the evidence that this measurement adds anything of clinical importance to the standard test is, at best, controversial.83

If reflux is difficult to identify, is it possible to diagnose direct aspiration of gastric contents into the respiratory tract? This finding would be unequivocal evidence of harm. The use of lipid-laden macrophages measured on BAL has long been popular, but this test lacks specificity.84 Perhaps the best evidence is negative: if there are no lipid-laden macrophages in the BAL, significant aspiration is unlikely. Measurement of BAL pepsin may be more specific,85 but this test is not widely available. Finally, simultaneous measurement of intra-esophageal and intratracheal pH has been described,86 but this tool is unlikely to be practical in children.

Late-presenting congenital H-type fistula may be difficult to diagnose.87 A tube esophagram is the usual investigation, but in the author's experience a normal test does not exclude a fistula, and direct visualization at bronchoscopy may be needed. For suspected esophageal dysmotility defects, sophisticated manometry may be needed.

Pulmonary hemorrhagic syndromes may result in a diagnostic challenge if the child swallows rather than expectorates blood. Presentation then may be with iron deficiency anemia, and an extensive gastroenterologic work-up must be performed.88 Iron-laden macrophages on the BAL are pathognomonic of pulmonary hemorrhage but cannot distinguish between the various causes of primary and secondary bleeding. Generally, if there is no evidence of a systemic disease or secondary cause of pulmonary hemorrhage, the condition is considered to be idiopathic pulmonary hemosiderosis, and a confirmatory lung biopsy is not performed. If the child bleeds repeatedly, however, open lung biopsy to exclude a neutrophilic capillaritis should be considered,89 because this diagnosis may prompt treatment with cyclophosphamide. If a connective tissue disease is suspected, the help of a pediatric rheumatologist should be sought. If immunodeficiency is suspected (discussed later), the author performs simple screening investigations but refers the patient for more sophisticated testing. A reasonable series of screening tests for the pediatric pulmonologist who suspects a connective tissue disease consists of an erythrocyte sedimentation rate, anti-neutrophil cytoplasmic antibody studies, double-stranded DNA, rheumatoid factor, complement studies, anti-glomerular basement membrane antibody (for children who have pulmonary hemorrhage and renal disease), and circulating immune complexes.

Recommendations

1. Children who have recurrent multifocal chest radiographic changes should be investigated, but there is no evidence base to guide the clinician as to the most appropriate timing or sequence of investigations. Level of evidence: low

2. The differential diagnosis of recurrent multifocal chest radiographic changes is so wide, and the number of possible tests is so great, that a targeted approach, based on clinical suspicion driven by history and physical examination, is recommended. Level of evidence: low.

[Наталья П.]

Diagnosing specific conditions presenting as chronic or recurrent acute on chronic productive cough
Cystic Fibrosis
Increasingly, most cases of CF are diagnosed by newborn screening. Even in areas where screening is routine, however, mild atypical cases are missed. In areas where the prevalence is thought to be a low, the diagnosis may be forgotten. The respiratory phenotype suggestive of CF as against other causes of recurrent infection is chronic productive cough with positive cultures for typical CF-related organisms, especially when combined with suggestive extrapulmonary features. Typical CF organisms include Staphylococcus aureus, Pseudomonas aeruginosa (especially mucoid strains), other gram-negative rods such as Burkholderia cepacia and Stenotrophomonas maltophilia, and nontuberculous Mycobacteria. H. influenzae also is found in CF but is not particularly specific to that disease. Extrapulmonary manifestations that must be sought actively include pancreatic insufficiency, rectal prolapse, electrolyte disorders (heat exhaustion, hyponatremia), liver disease (which occurs only if the child has pancreatic insufficiency), very severe sinus disease, and particularly nasal polyps, which in childhood are almost pathognomonic of CF.

Once CF is suspected, diagnosis usually is straightforward. The sweat test is diagnostic in more than 98% of cases.90 For practical purposes, a properly performed sweat test with a chloride concentration of more than 60 mmol in duplicate can be considered diagnostic. The most common cause of a false-positive finding is operator inexperience, followed by eczema. Although a number of extremely rare conditions are reported to elevate sweat chloride,91 this writer has never encountered them in practice. Although most cases are diagnosed easily, a small minority presents a very vexatious problem. The diagnosis of CF has undergone a revolution in the last 20 years: whereas the sweat test previously was considered the reference standard for the diagnosis of CF, it has become clear that patients who have CF may have normal sweat electrolytes. These cases often, but not invariably, have a mild or atypical phenotype. A study in adults suggested that in equivocal cases, giving fludrocortisone, 3 mg/m2, on two successive days, and repeating the sweat test on the third day may be helpful; healthy persons who had an equivocal sweat sodium then present in the normal range.92 In the absence of pediatric data, however, this test should be used with caution.

Genetic testing may be helpful; however, at least 1300 variants of the CF transmembrane conductance regulator (CFTR) gene have been described, and routine laboratory testing detects the only most common 90% to 95%. There are marked ethnic differences in CFTR gene frequencies, and if the genetic laboratory is to be used most efficiently, race-specific panels should be used. Even with this approach, in many cases only a single gene or no gene is detected, leaving the diagnosis still in doubt. Complete gene sequencing may be helpful but is not widely available.

There are a number of potential problems with genetic testing.93 First, it is essential to distinguish harmless polymorphisms from disease-producing mutations. At least in theory, a second CFTR mutation can cancel out the effects of the first. Even with normal exon amino acid sequences, CF may be produced by intron modifications. Finally, phenotypic CF has been described with completely normal CFTR gene sequences.94 The explanation of these findings is unknown, but a likely possibility comes from consideration of the biology of CFTR. CTFR is a multifunctional protein that interacts with many other proteins at the cell surface and also requires interaction with many other proteins to traverse to the cell surface.95 It may be that CF with a normal CFTR gene sequence is caused by a mutation in one of these interacting proteins. There is precedent for such an idea: the histologic pattern of pulmonary alveolar proteinosis may be produced by mutations in either the surfactant B or C genes but also occurs without abnormality in these genes but with mutations in a surfactant protein-processing gene, ABCA3.96

A further direct test of CFTR function is the measurement of electrical potential differences in the nose,97 the lower airway,98 or on rectal biopsy in an Ussing chamber.99 All these tests require sophisticated apparatus and operator skill and experience and are not widely available. The nasal test requires cooperation from the patient and is difficult in unsedated young children. Protocols usually involve making baseline measurements referenced to a peripheral electrode, then perfusing the nose with amiloride to block sodium transport, and then stimulating CFTR by perfusion with isoproterenol and low-chloride solution.97 Compared with unaffected persons, the CF patient has a more negative baseline PD, a bigger positive deflection with amiloside, and no negative deflection with low-chloride/isoproterenol, this last being the most discriminatory test. Lower airway potentials measured during bronchoscopy are a research technique that probably will find a place as an end point in clinical trials of novel therapies. Rectal biopsy and in vitro measurement of CFTR function is available in only a very few centers.

[Наталья П.]

Ancillary testing may be helpful in the diagnosis. Human fecal elastase 1 can be measured in a small sample of stool and is sensitive and specific for pancreatic insufficiency,100 which supports a diagnosis of CF. In males, absence of the vas deferens (which may be diagnosed on ultrasound) or azoospermia also is supportive. The complete absence of upper airway disease on HRCT scanning would be very unusual in CF.

Where does this discussion leave the diagnosis of CF in the twenty-first century? Most cases are obvious, but how should the clinician proceed in the gray areas? The question has been reviewed,93 and the conclusion was almost paradoxical: despite the advent of ever-more-sophisticated testing, the diagnosis of CF must be a clinical one. The two main difficult situations are (1) the child who has positive tests but no symptoms, and (2) the child who has clinical indications of CF (eg, bronchiectasis with chronic infection with S. aureus and mucoid P. aeruginosa) but negative tests. For the well child in whom tests are positive, the term “pre-CF” has been proposed but has not been uniformly accepted. The chances of progression to full-blown clinical CF depend on the nature of the tests, progression being inevitable for the asymptomatic child who is homozygous for ΔF508 but less certain for an asymptomatic elevation in sweat chloride with no or mild genetic mutations discovered on testing. These children, who are well, certainly cannot be said to have a disease, but they should be monitored carefully to ensure that the earliest signs of disease are detected. For the second group, the diagnostic tests should be reviewed in detail, and other possibilities should be considered. If a different diagnosis is not found, these children should be followed and treated exactly as if they had CF, with treatment of any complication such as P. aeruginosa infection along standard lines. The alternative, of reassuring the family that the tests are negative, the child does not have CF, and therefore no follow-up is needed, can have catastrophic consequences. In a proportion of children, the sweat test or other test may be positive when repeated, and the child then is found to have CF after all; even if the child only has a CF-like illness, the consequences may be as bad as for CF itself.101 The management of CF, once diagnosed, is described in standard texts and reviews and is beyond the scope of this article.

Recommendations

1. The diagnosis of CF should be suspected, particularly if the child has a chronic infection with typical CF-associated organisms and associated with extrapulmonary features of CF, but CF also enters the differential diagnosis in many less specific scenarios. Level of evidence: high

2. In most cases the diagnosis of CF can be made by a properly performed sweat test, but rare and atypical cases may need more sophisticated testing. Both false-positive and false-negative CF diagnoses have been described. Level of evidence: high

3. If the diagnosis of CF is in doubt, the patient still should be followed carefully, because in a proportion of cases either the diagnosis will become clear, or, while still undiagnosed, the child may develop significant complications. Level of evidence: moderate.

[Наталья П.]

Primary Ciliary Dyskinesia
The management of PCD in the lower airway is similar to that of bronchiectasis from any other cause, but it is important to make the diagnosis because the disease in the upper airway is managed in a different way,25 and there are genetic implications. PCD usually is inherited as an autosomal recessive, occasionally X-linked, condition. Cilia are complex structures formed from more than 250 different proteins. The complexity of the various genes discovered has been reviewed recently.102 A. Bush, R. Chodhari and N. Collins et al., Primary ciliary dyskinesia, Arch Dis Child 92 (2007), pp. 1136–1140. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (9)102 The prevalence is not known but is estimated to be 1 in 15,000. Particular features that should alert the clinician to the possibility of the diagnosis are given in Table 1. Typically, the child has a combination of upper and lower airway symptoms; isolated dry cough is unlikely to be caused by PCD. It is important to be alert to the diagnosis; it is missed frequently, probably because many of the symptoms of PCD (rhinitis, cough, otitis media with effusion) are common in normal children,103 and diagnosis is delayed.104 Diagnostic testing is a sequential process.102 Unless the clinical features are highly suggestive (for example, mirror image arrangement with neonatal onset of respiratory distress and chronic rhinorrhea), in which case direct diagnostic testing is indicated, other, more common conditions such as CF are excluded first. In vivo mucociliary clearance may be tested in the older, cooperative child by using the saccharine test or a variant thereof.105 A small saccharine tablet is placed on the inferior turbinate. The child is asked to lean forward without coughing, sneezing, or sniffing and should be able to taste saccharine within 60 minutes. If the child does not taste the saccharine, further testing is required; PCD cannot be diagnosed using this test alone. There also is a danger that PCD may be excluded wrongly, if the child tastes the saccharine because he has sniffed the microtablet into the pharynx. Nasal nitric oxide (nNO) measurements may be a more useful screening test. A normal nNO virtually excludes PCD, and if the history is not typical and nNO is normal, further testing may not be needed.106 There is much less experience with nNO in infants than in older children,[107] and [108] and measurements in uncooperative younger children should be interpreted with caution. If nNO is low, further testing is mandated; low nNO is reported in CF109 and also in diffuse panbronchiolitis.110


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Table 1.

Features leading to the diagnosis of primary ciliary dyskensia

Presenting Feature Number of Cases (%) (n = 55)
Significant neonatal respiratory distress 37 (67)
Abnormal situs 38 (69)
Cough most days 46 (84)
Sputum production 24 (44)
Rhinorrhea from the newborn period 42 (76)
“Wheeze” 16 (29)
Sinusitis 6 (11)
Serous otitis media 28 (51)
Hearing loss 14 (25)
Diagnosis made in a sibling 6 (11)

Full-size table
Most children had multiple symptoms, typically a combination of upper and lower airway disease.

Data from Coren ME, Meeks M, Buchdahl RM, et al. Primary ciliary dyskinesia (PCD) in children—age at diagnosis and symptom history. Acta Paediatr 2002;91:667–9.


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The test that usually is most specific is obtaining nasal brushings to study the function and morphology of cilia in vitro.102 This test is an out-patient procedure. Strips of ciliated epithelial cells are examined by light microscopy, and beat frequency and pattern are reported. The findings also are recorded digitally, and the sample is examined under an electron microscope. The most common finding is the absence of either or both of the inner and outer dynein arms, but many others have been described. Whether primary ciliary disorientation exists is controversial; disoriented cilia more usually are secondary to chronic infection. Key to the diagnosis is to distinguish primary (congenital) abnormalities from secondary ciliary dysfunction caused by a viral or other infection. Secondary postviral abnormalities may take many weeks to reverse, and if there is any doubt, the brushing should be repeated. It may be difficult to obtain an adequately ciliated sample if the child has chronic infective rhinitis, even after energetic medical treatment. In such cases, culture of the ciliary biopsy is useful. Secondary ciliary abnormalities disappear in culture, whereas primary ones persist. Genetic testing may be useful in some cases, although this service is far from being routinely available. Sophisticated immunofluorescence staining also may be helpful111 but is not widely available.

Recommendations

1. A diagnosis of PCD should be suspected if there is a combination of upper and lower airway symptoms, particularly with onset in the neonatal period. Although mirror image arrangement and heterotaxy are seen in nearly 50% of patients who have PCD,112 their absence does not exclude the condition. Level of evidence: moderate

2. Although simple screening tests such as the saccharine test and nNO may be useful to exclude the need for further testing for PCD, the diagnosis always should be confirmed by detailed examination of ciliary function and structure in an experienced center. If clinical suspicion is high, screening tests may be omitted, and the child should proceed directly to definitive testing. Level of evidence: high

3. PCD may be confused with secondary ciliary dysfunction caused by a viral infection; if there is any doubt, the tests must be repeated after a few months. Alternatively, cilia can be examined from another site or cultured in vitro. Level of evidence: high

[Наталья П.]

Idiopathic Bronchiectasis
Bronchiectasis has been described as an “orphan disease.” It is much more common and more severe in the developing world,113 but one group has estimated its prevalence to be at least 1 in 15,000 in a developed-world setting.114 A.M. Li, S. Sonnappa and C. Lex et al., Non-CF bronchiectasis: does knowing the aetiology lead to changes in management?, Eur Respir J 26 (2005), pp. 8–14. View Record in Scopus | Cited By in Scopus (18)114 The key symptom that should prompt consideration of the diagnosis is chronic productive cough lasting without remission for at least 8 weeks. Other diagnostic clues are summarized in Box 6. Suspicion should be particularly high if there also is an unexplained suggestive family history or if there are extrapulmonary features of a specific condition such as CF, PCD, or immunodeficiency.




Box 6. Diagnostic pointers to the presence of bronchiectasis in the child in whom the diagnosis is suspected for the first time


Chronic unremitting productive cough lasting more than 8 weeks

Atypical “asthma” that does not respond to therapy

A single positive sputum culture for an unusual organism (eg, S. aureus, P. aeruginosa, B. cepacia)

Nonresolving pneumonia

Recurrent or persistent radiographic changes

Prior infection with known predisposing organisms (eg, B. pertussis, adenovirus serotype 7, 14, and 21)

Palpable secretions on coughing, persistent over time

Persistent crackles on auscultation

Severe esophageal disease

Localized bronchial obstruction including right middle lobe syndrome



There is no evidence base to guide the clinician in the sequence and timing of the investigation. When the diagnosis is suspected, the author first confirms that bronchiectasis is present with a HRCT scan. Although the distribution of any bronchiectasis offers some diagnostic clues (eg, CF initially is an upper lobe disease, and PCD predominantly affects the lower lobes), in general the distribution is not a reliable basis for diagnosis. Even if the HRCT does not demonstrate frank bronchiectasis, the clinician should not be lulled into a false sense of security but should continue to investigate the child (as discussed previously in the section, “Chronic, Usually Productive, Cough”) and should institute appropriate treatment to prevent airway damage. The next series of investigations is to determine the underlying cause. A detailed protocol applied in two tertiary referral centers in the United Kingdom determined the cause in about two thirds of patients, and the diagnosis led to a management change in more than half the patients.114 A specific cause may have consequences for the airway management (eg, recombinant human deoxyribonuclease is very effective in many children who have CF115 but not in children who have idiopathic bronchiectasis)116 and for extrapulmonary management (chronic secretory otitis media in PCD is managed very differently from the same condition in otherwise healthy children).25 There may be specific treatments, such as immunoglobulin replacement therapy; and there may be genetic implications for the extended family, as in CF, PCD, and immunodeficiency. The diagnostic protocol should be very different in a developed-world setting, where tuberculosis and other infections are a major cause. (The diagnosis of tuberculosis is discussed in detail in a later section.)

There are numerous causes of bronchiectasis, and hence there are many possible investigations. The author's practice is to exclude CF and PCD, to screen for immunodeficiency (as described later), and to exclude reflux and aspiration (as described previously) in all cases. The need for more sophisticated testing is determined by the history, examination, and the initial test results. Finally, the consequences of bronchiectasis should be assessed. If the disease is severe, nocturnal hypoxemia may lead to pulmonary hypertension; if in doubt, it is wise to perform an overnight oximetry study and a baseline echocardiogram.

Recommendations
Children suspected of having bronchiectasis should be investigated in detail to determine the cause. In more than 50% of cases, this investigation leads to a change in management. Level of evidence: moderate.

[Наталья П.]

продолжение следует..

[Наталья П.]

The Special Problems of Congenital and Acquired Immunodeficiency
The number of immunodeficiencies is large, and the diagnosis and management of many of these conditions requires the expertise of a specialist pediatric immunologist (Box 7). Many immunodeficiencies, however, are seen first by a pediatric pulmonologist. The clinical picture and simple tests may indicate the presence of an underlying immunodeficiency. The acronym “SPUR” was introduced in the opening section of this article. Additional pointers to immunodeficiency include hepatosplenomegaly, arthropathy, failure to thrive, and a family history of immunodeficiency.




Box 7. Important congenital and acquired immunodeficiencies that may have a respiratory presentation


Congenital immunodeficiencies
Antibody deficiency
X-linked

Common variable immunodeficiency

IgA deficiency (not invariably significant)

Hyper IgM (CD40 deficiency)

IgG subclass deficiency (may be insignificant)

Complement disorders

C3 deficiency

Mannose-binding lectin deficiency

Neutrophil disorders

Autoimmune neutropenia of infancy

Cyclical neutropenia

Shwachman-Diamond syndrome

Kostman syndrome

Chronic granulomatous disease

Other syndromes

Di George syndrome (T-cell deficiency)

Down syndrome

Heterotaxic syndromes with asplenia (right isomerism, Ivemark's syndrome)

Ataxia telangiectasia

Wiskott-Aldrich syndrome

Hyper-IgE (STAT-3 mutations)

Interferon gamma receptor mutations (suspect if disseminated mycobacterial disease)

Interleukin-12 pathway mutations (suspect if disseminated mycobacterial disease)

Acquired
Infective

HIV

Iatrogenic

Steroids or immunosuppressant medication

Postradiotherapy

Post bone marrow and solid organ transplantation

Malignancy (often also associated with iatrogenic)

Leukemia and lymphoma

Solid organ

Miscellaneous

Acquired hyposplenism (trauma, sickle cell anemia)

Malnutrition of any cause

Chronic renal or liver failure

Diabetes

Burns

[Наталья П.]

The initial investigations may contain clues that often are overlooked. Neutropenia is always sought on a full blood cell count, but lymphopenia (<2.8) often is overlooked and may be a clue to the diagnosis of severe combined immunodeficiency. In one series, 28 (88%) of 32 infants would have been diagnosed before 6 months of age if the possibility of immunodeficiency had investigated after the first low lymphocyte count.117 In this report, the first symptoms occurred at a median of 5 weeks (range, 1 day to 8 months) and included respiratory infection (91%), vomiting and diarrhea (81%), failure to thrive (88%), candidiasis (50%), and skin lesions (28%). The median delay between the first abnormal lymphocyte count and diagnosis was 7 weeks (range 1 day to 13 months). This report and others highlight unusually severe mucocutaneous candidiasis as a sign of possible immunodeficiency. The chest radiograph may yield clues. Bronchial situs should be determined, because right isomerism (bilateral right lung morphology, Ivemark's syndrome) and hence susceptibility to overwhelming pneumococcal sepsis is associated with asplenia in around 80% of cases.118

The type of infection may give a clue to the nature of the immunodeficiency. In one series,2 pneumonia was diagnosed in 92%, 81%, and 77% of patients who had antibody, combined, and cellular deficiencies, respectively. Other major illnesses such as bronchiolitis, acute gastroenteritis, otitis media, and bacteremia did not differ in prevalence. Skin abscess, pneumonia, and lymphadenitis (in 55%, 45%, and 27% of cases, respectively) were the most common infections in patients who had phagocyte defects. Age at onset of infection was around 3 years in common variable immunodeficiency but was as early as 4 months in the hypogammaglobulinemias. Combined deficiencies presented at around 6 months of age. Sixty percent of all patients were hospitalized initially for infection. A specific microbiologic diagnosis could be made in a little more than half the episodes. Patients who have antibody deficiencies have a propensity for infection with capsulated organisms, Pneumocystis jiroveci and enterovirus; intracellular pathogens are a feature of cellular deficiency. Chronic granulomatous disease may present with B. cepacia or catalase-positive infection, whereas disseminated nontuberculous Mycobacterial infection suggests a defect of the interferon gamma/interleukin-12 axis.119 A large study of common variable immunodeficiency3 reported that respiratory presentations, especially bronchitis, sinusitis, pneumonia and bronchiectasis, are very common. Associated diarrhea was a feature in more than one third of cases. Although there is evidence that diagnostic delays are lessening over time, they still are unacceptably long in many children, underscoring the need for the respiratory pediatrician to be alert to the possibility of immunodeficiency.

The investigation of the immunocompromised child who has single or multiple infiltrates is likely to be much more urgent than in the otherwise well child. The differential diagnosis includes the full spectrum of infectious disease (bacterial, viral, fungal, parasitic, and mycobacterial, depending on the nature of the immunodeficiency, and, in a transplanted child, on the time from transplantation), iatrogenic complications such as pulmonary drug toxicity, pulmonary edema caused by iatrogenic cardiomyopathy or as part of the spectrum of acute lung injury, and recurrence of leukemia or lymphoma, if that was the primary cause of the immunodeficiency. HRCT scanning may be suggestive of specific diagnoses (for example, the halo sign suggests invasive aspergillosis) or may guide the site of BAL. In most children, early bronchoscopy and BAL are performed. The author's practice is not to perform a transbronchial biopsy in this setting because of the risk of bleeding and pneumothorax. The diagnostic yield varies with the underlying condition and with the duration and nature of any anti-infection prophylaxis and blind therapy. There are no satisfactory evidence-based guidelines to determine the optimal timing of bronchoscopy. If no diagnosis is made on the initial BAL, and the child is continuing to deteriorate, it is preferable to proceed straight to an open-lung biopsy rather than perform further BAL.120

[Наталья П.]

Tuberculosis
This section summarizes a huge topic very briefly, and the reader is referred to a recent evidence-based guideline.121 Readers in the developing world may need to modify the recommendations substantially in the light of resources available to them. In developing countries, tuberculosis should be considered in almost all clinical settings. In the developed world, particularly in these days of easy international travel, the possibility of tuberculosis should not be overlooked. Most work on the symptoms that should lead to a suspicion of pulmonary tuberculosis has come from the developing world. These symptoms may be very nonspecific, but highly suggestive in a high-prevalence area is the combination of persistent, unremitting cough lasting longer than 2 weeks, documented failure to thrive for 3 months, and fatigue.122 This combination was less reliable in children under 3 years of age and in HIV-positive children (a minority of tuberculosis-infected children, even in regions where HIV is common). In other studies, weight loss, fatigue, and chest pain were fairly specific for tuberculosis but were poorly sensitive.123 In general, a high index of suspicion is needed, especially in young children (in whom treatment legitimately may be started on clinical suspicion alone, because of the horrific potential consequences of miliary and, in particular, central nervous system and meningeal tuberculosis) and in those who are HIV infected.

The particular diagnostic algorithms used depend on the setting and available resources (Box 8).




Box 8. Potential diagnostic tests for tuberculosis


Obtaining an organism
Gastric aspirate

Spontaneously expectorated sputum (older child)

Induced sputum

String test

Bronchoscopy

Early-morning urine (disseminated tuberculosis)

Bone marrow biopsy (disseminated tuberculosis)

Lymph node aspiration or biopsy (lymph node tuberculosis)

Imaging (nondiagnostic)

Chest radiograph

CT scan (more sensitive for nodal involvement, but false positives likely)

Molecular test on infected material

PCR for Mycobacterium tuberculosis

PCR for genes encoding drug resistance

Skin tests

Heaf test

Mantoux test

Serologic tests

Specific T-cell interferon-γ synthesizing cells

Other tests

Organ biopsy

[Наталья П.]

Combinations of tests may be better than the individual tests alone; for example, the diagnostic yield with both gastric aspirates and induced sputum tests is better than that of either test alone. In the past, gastric aspirates were reported to be more sensitive than bronchoscopy, but with the use of PCR technology the differences are not great,124 although with bronchoscopy direct visualization of endobronchial tuberculosis may allow immediate confirmation of the diagnosis. The chest radiograph is used widely in children and has a sensitivity of 39% and a specificity of 74%,125 R.V. De Villiers, S. Andronikou and S. Van de Westhuizen, Specificity and sensitivity of chest radiographs in the diagnosis of paediatric pulmonary tuberculosis and the value of additional high-kilovolt radiographs, Australas Radiol 48 (2004), pp. 148–153. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (6)125 but interobserver agreement is not good, at least for the detection of lymphadenopathy.126 HRCT scan reveals more lymphadenopathy than a chest radiograph,127 although whether these nodes are always tuberculous is conjectural, and in most parts of the world, HRCT may not be readily available.

The use of serologic tests to diagnose tuberculosis is a current hot topic, and the place of these tests has yet to be determined, particularly in young children and those who are HIV infected. Two serologic tests currently are available.121 One measures the release of interferon-γ from whole blood after stimulation with early secreted antigenic target (ESAT)-6 and culture filtrate protein (CFP)-10, which are relatively specific for Mycobacterium tuberculosis. In the other test, individual ESAT-6 and CFP-10 T cells are delineated with enzyme-linked immunosorbent spot methodology. In the past, robust guidelines have been produced on the basis of skin tests and chest radiography; whether and how these newer tests can improve the diagnosis of tuberculosis has yet to be worked out fully.

In summary, it can be seen that the diagnosis of tuberculosis can be challenging even with newer investigations. The timeless principles remain: a high index of suspicion is essential, and when in doubt, particularly in high-risk situations such as very young children, blind treatment is safer than a prolonged period of diagnostic havering.

[Наталья П.]

Summary
The child who has recurrent infections poses one of the most difficult diagnostic challenges in pediatrics. The outcome may be anything from reassurance that the child is normal to the diagnosis of a life-threatening condition. A huge range of tests is available (Box 9).




Box 9. Summary of potential investigations in the child who has recurrent infections


Suspected CF
Sweat test

CF genotype

Electrical potentials (nasal, bronchial, rectal biopsy)

Supportive tests (eg, human fecal elastase-1)

Suspected PCD

Screening: saccharine test, nasal nitric oxide

Ciliary structure and function: high-speed videomicroscopy, electron microscopy

Culture of ciliary biopsy

Genetic studies

Immunostaining of specific dynein proteins

Screening for suspected immune deficiency (referral to a pediatric immunologist mandatory for most specific immunodeficiencies)

Full blood cell count (neutropenia, lymphopenia)

T-cell subsets

Immunoglobulins

Immunoglobulin subclasses

Vaccine antibody responses

Complement studies

HIV test

Suspected gastroesophageal reflux

pH-metry

Impedance probe

Isotope milk scan

Barium swallow (exclude anatomic causes such as hiatus hernia)

Esophageal manometry

Suspected incoordinated swallowing

Videofluoroscopy

Rigid endoscopy to exclude laryngeal cleft

Suspected aspiration

HRCT scan: dependant bronchocentric consolidation (not specific)

Lipid-laden macrophages (absence probably excludes significant aspiration)

BAL pepsin (gastric contents)

Suspected structural esophageal disease

Tube esophagram

Bronchoscopy (H-type fistula)

Barium swallow

Suspected structural airway disease

Bronchoscopy

Endobronchial ultrasound

CT reconstruction

Suspected bronchiectasis

HRCT scanning

Exclude CF, PCD, immunodeficiency, tuberculosis (see other sections)

Consider excluding esophageal disease, incoordinated swallowing, reflux, and aspiration

Echocardiogram, overnight saturation studies

Suspected tuberculosis

See Box 8

Suspected cardiovascular disease

Echocardiogram (enlarged cardiac chambers caused by left-to-right shunt, vascular ring)

Barium swallow (vascular ring)

CT or MRI with vascular reconstruction (vascular ring)

Suggested vasculitis or connective tissue disease (referral to pediatric rheumatologist probably is advisable)

Erythrocyte sedimentation rate, C-reactive protein

Double-stranded DNA

Rheumatoid factor

Antineutrophil cytoplasmic antibody studies

Circulating immune complexes

Anti-glomerular basement membrane antibodies



The clinician faces a twofold challenge in determining:

1. Is this child normal? (This question may be the most difficult in all clinical practice.)

2. If this child seems to have a serious disease, how can the diagnosis be confirmed or excluded 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.