Congresso ERS Copenhagen 2005




Mario C. Canciani



To know the epidemiology

To make a diagnosis

New agents

What therapy?

Is prevention possible?







Respiratory tract infections (RTIs) are common diseases  in childhood: the normal frequency is six to eight episodes during the autumn and winter months in infancy and two to four episodes in older children (1). General practitioners, paediatricians and ear-nose-throat specialist see many children with recurrent respiratory infections, even if most of these children are healthy and only a minority suffers of an underlying disease.

A part the infection per se, viral infections may be an important environmental stimulus for airway injury and remodelling, resulting in impaired lung function ad, ultimately, asthma, especially reinforced by the temporal coincidence of vulnerability to lower respiratory infections (LRIs) during a period of alveolarization and rapid lung growth  and the likelihood that virus-induced inflammatory responses could disrupt the finely tuned process of lung development (2).


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To know the epidemiology


S. pneumonaie and M. pneumoniae are the major bacterial causes of community-acquired pneumonia (CAP) in children, together accounting for up to 60% of cases. Streptococcus pneumoniae (SP) is the major cause of bacterial pneumonia after the newborn period (3,4). In developed countries the annual incidence of bacteremic pneumonia is between 4.7 and 29 per 1,00,000 under 2 years old and between 2.9 and 16.4 per 100,000 under 5 years old (5). Rates drop during later childhood, to rise again in older age. In developing countries, there is scant data: in Gambia, the incidence of bacteremic pneumococcal pneumonia is 129-240 per 100,000 under 5 years old (6), whereas in Chile is 37 per 100,000 under 5 years (7).

In developed countries, most Haemophilus influenzae type b (Hib) disease estimates have been based  on invasive disease, with little impact after the introduction of the Hib vaccine, despite dramatic reductions in other invasive Hib disease (8). In developing countries, each year an estimated 35,000 to 700,000 children die from approximately 1.7 billion Hib episodes (9).

Viruses are the causative agents of CAP in children in 15-35%, and viruses and bacteria together (mixed infection) in 5-35%. The proportion of viral aetiology alone is highest in young children, decreasing in relation to age. Respiratory syncytial virus (RSV), influenza A and B, parainfluenza 1,2 and 3, and adenoviruses, and also rhino- and enteroviruses, may be the causative agents. Among bacteria, Streptococcus pneumoniae  is common at all ages,  Mycoplasma pneumoniae from 5 years and Chlamydia pneumoniae from 10 years of age onwards (10).

The term croup refers to a clinical syndrome characterized by barking cough, inspiritory stridor and hoarseness of voice. It results from viral inflammation of the upper airway, including larynx, trachea and bronchi; hence the term laryngotracheobronchitis. The symptoms are typically worse at night and peak on about the second or third night. Differentiating spasmodic croup from viral croup is difficult and often not useful (11).

Bronchiolitis is the most frequent acute obstructive lower airways infection in the first year of life caused by respiratory syncytial virus (RSV) and – less frequently - parainfluenza, influenza and adenovirus. Rhinovirus, human metapneumovirus and, rarely, Mycoplasma pneumoniae, may also cause bronchiolitis. The disease occurs mainly within the first year of life with a maximum towards the end of the first half-year (12).


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To make a diagnosis


Serological methods are routinely used for in-hospital diagnosis of RTIs caused by viruses and bacteria and during the last 15 years they have also been applied  to study the etiology of pediatric CAP (13). After the pioneer study of Claesson from Sweden (14), in which pneumococcal serology was applied for the first time, many papares on the etiology of CAP in children, combining viral and bacterial data, have originated from Finland (15) or USA (16), thus reflecting only two western populations. Rapid diagnostic tests may be useful in detecting outbreaks or when deciding to whether to start antiviral drugs in high risk patients, e.g. during known periods  of community influenza activity, therapy should be given to high risk children suffering an influenza-like illness, within 48 hours of the onset of symptoms, even without laboratory confirmation, and should be considered in any child who is seriously ill with an influenza-like illness.

Croup diagnosis is based on constitutional state (toxicity, fever, pulse rate), Stridor, drooling, barky cough, speech quality, tachypnoea, tracheal tug on inspiration, intercostal and subcostal indrawing on inspiration, asynchrony of chest and abdominal wall movement, cyanosis in air. Signs of severe obstruction include pallor and lethargy, marked intercostal and sternal indrawing, restlessness, and tachycardia. Cyanosis is a late sign and always indicates very severe obstruction. The loudness of the stridor is not a good guide to the severity of illness. Auscultation of the chest usually reveals only transmitted upper airways noise. If breath sounds are reduced in volume this also indicates severe illness.

The diagnosis of bronchiolitis is clinical. Rapid laboratory tests (enzyme-linked immunosorbent assays / ELISA, immunofluorescent antibody / IFA staining)  for demonstration of RSV, parainfluenza, influenza, adenovirus infection are available for nasal secretions and should be used liberally to ascertain the epidemiological situation and to isolate patients in separate rooms. Transcutaneous pulse oxymetry is an easy non-invasive although not entirely reliable measure to monitor oxygenation.


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New agents


Human metapneumovirus (hMPV) is a newly isolated agent from children and adults with acute RTIs and has been found to be associated with bronchiolitis, croup, asthma and pneumonia.  hMPV is a RNA virus closely related to avian pneumovirus and has a spectrum of disease and seasonal distribution similar to that of respiratory syncytial virus (RSV), even if infection on household contacts seems to be significantlygreater than that due to RSV and similar to that of influenza viruses (17).

Simkania nevegensis is an intracellular bacterium, sharing many characteristics with Chlamydia species. According to the new taxonomy, S. nevegensis belongs to a new family, Simkaniaceae, in the order of Chlamydiales. The organism can be detected in clinical samples by culture and polymerase chain reaction (PCR), and thus far, antibody responses have been studied by enzyme immune assay (EIA) modified from the EIA test for Chlamydia trachomatis and Chlamydophila (earlier Chlamydia) pneumoniae (18). In sero-epidemiologic studies, 39% to 80% of the adults have been seropositive for S. nevegensis. The highest rates have been observed among Bedouin adults in Israel (18, 19). In Israel, the age-specific seropositivity rates have been 13-29% in 1-2 years, 33-36% in 3-6 years, 42-57% in 7-10 years and 55-75% in 11-15 years old non-symptomatic children (18). S. nevegensis infection has been associated with pneumonia and exacerbation of chronic obstructive  pulmonary disease in adults, and with bronchiolitis in infants (20, 21).

 Korppi et al. (personal communication) recently published the results of C. pneumoniae and C. trachomatis  serology in 104 children aged 1-6 years with new, doctor-diagnosed asthma, and in 120 age-, gender-, and municipality-matched controls. No association between seropositivity and asthma was found for either bacteria.


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What therapy?


Amoxicyllin (oral), 40 mg/kg/day if low risk for pen-sensible  SP and 90 mg/kg/day if high risk of  pen-resistant SP is the drug of choice for outpatiens, whereas Penicillin G or Cefuroxime are indicated for inpatients less than 5 years, whereas macrolide are indicated in older patients, unless differently indicated by diagnostic tool. Dual coverage (b-lactam and macrolide) have been demonstrated to improve response to treatment (22); in this case, the added anti-inflammatory effect of macrolides is to be considered.

Research is directed on targeting diverse bacterial components, moving along the infection process, inhibiting and neutralizing bacterial lipopolysaccharide, using antisense agents to disrupt bacterial processes (23). Telythromycin, a new antibiotic showed promising efficacy and tolerability in old patients; it acts dually to inhibit bacterial ribosomal assembly  and rRNA translation (24). Linezolide, the first oxazolidinone, inhibits bacterial protein synthesis via disruption of the initiation complex. It shows activity against gram-positive organisms and is a therapeutic alternative to vancomycin (25).

Adrenaline by inhalation has a temporarily beneficial effect on airway obstruction in children with croup. It is not a definitive treatment, but may allow time for the basic pathology to resolve.

Contraindications to the administration of adrenaline include obstructive right, left or cyanotic cardiac lesions. Further caution should be used with hypertensive patients. Children receiving one adrenaline neb must be observed for a minimum of 2 hrs in the ED prior to discharge and should only be discharged after the clinician has assured himself/herself that the parent/guardian thoroughly understands the disease process and is able to return to the ED expeditiously should stridor recur. Children requiring two or more adrenaline nebs should be admitted to the hospital (26).

Minimal handling, rest and adequate oxygenation and hydration are the keystone of bronchiolitis management . Drug therapy is rarely indicated as the majority of the literature is controversial and contradictory. Bronchodilators and corticosteroids are commonly used treatments, but little consensus exists about optimal management strategies.


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Is prevention possible?


The influenza inactivated vaccine is safe and effective. Universal infant influenza vaccination has been recommended in the USA but not yet elsewhere. More needs to be known about the likely parental acceptance of annual vaccination in children and stronger evidence needs to be generated for the clinical and cost effectiveness of vaccination, for children in terms of direct benefit, and indirectly regarding effects on the wider community.

Vaccination provides a method of reducing the incidence of childhood pneumonia. Hib vaccine has shown a dramatic decline  in disease, where it has been introduced. The major barrier to the introduction of the vaccine has been establishing the disease burden and the cost of the vaccine. Efficacy against SP pneumonia for the 7-valent PCV has beeen established for low incidence population, whereas efficacy in high incident population and for infants with HIV is disappointing. The development of other, more affordable vaccine candidates with wider serotype coverage needs to be encouraged. Multivalent prenatal or antenatal Group B Streptococcus  vaccine shows promise in clinical development.

There is no benefit in the use of palivizumab (prophylactic only in selected cases when given at monthly intervals) (27).


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17. Bosis S, Esposito S, Niesters HGM, Crovari P, Osterhaus ADME, Principi N. Impact of human metapneumovirus in childhood: comparison with respiratory syncytial virus and influenza viruses. J Med Virol 2005; 75:101-104.


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20. Greenberg D, Banerji A, Friedman M, Chiu C-H, Kahane S. High rate of Simkania nevegensis among  Canadian Inuit infants hospitalized with lower respiratory tract infections. Scand J infect Dis 2003; 35: 506-8.


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25. Wilcox MH. Efficacy of linezolid versus comparator therapies in gram-positive infections. J Antimicrob Chemother. 2003 May;51 Suppl 2:ii27-35.


26. Chin R, Browne GJ, Lam LT et al. Effectiveness of a croup clinical patway in the management of children with croup presenting to an emergency department. J Paediatr Child Health. 2002 Aug;38(4):382-7.


27. Welliver RC. Therapy for bronchiolitis: help wanted. J Pediatr. 1997 Feb;130(2):170-2



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