Childhood community acquired pneumonia : aetiologic and predisposing factors

Abstract

Conjugate pneumococcal vaccines have been licenced for use in Australia since Dec 2000, became available around June 2001 and marketed towards the end of 2001. Its widespread use has however been limited by lack of affordability, not being part of the routine childhood vaccination schedule. In order to assess the potential benefits of the widespread use of pneumococcal conjugate vaccines in Australia, reliable estimates of the incidence of pneumococcal disease are required. The main manifestations are bacteraemia, pneumonia and otitis media. Pneumococcal bacteraemia, diagnosed on the basis of positive blood cultures, is relatively easy to identify and thus it is easy to track changes in incidence over time with reporting systems similar to those established for other vaccine preventable diseases such as Haemophilus influenzae type b. On the other hand, definite diagnosis of otitis media and pneumonia caused by Streptococcus pneumoniae is problematic. Blood cultures are rarely positive (5 to 10% of pneumonia requiring hospitalisation in developed countries) and especially in the case of otitis media, often not performed. In Australian hospitals, culture of affected tissue, usually entailing lung puncture or tympanocentesis, is rarely performed. Indirect laboratory tests for pneumococcal infection such as urinary antigen detection and pneumococcal serum antibodies and immune complexes, are not routinely available. There is also still considerable debate about the reliability of these latter assays, especially in the context of pneumococcal carriage in children. Thus the incidence of pneumococcal pneumonia and otitis media is significantly underestimated. Using a range of serologic and molecular techniques, it has been estimated that up to a third of all cases of childhood pneumonia in developed countries may be attributed to Streptococcus pneumoniae. This figure is supported by an American vaccine efficacy study demonstrating a 32% reduction in radiograph positive pneumonia in the first year of life, a 23.4% reduction in the first 2 years but only a 9.1% reduction between 2 and 5 years of age (Black et al, 2002). The issue is further complicated by the lack of a gold standard for the diagnosis of pneumonia, resulting in variability of case definition. There are few published data regarding the incidence of childhood pneumonia in urban Australian children. Such data are essential if conjugate pneumococcal vaccine efficacy against pneumonia is to be predicted and / or tracked.

There has been recent considerable interest in the role of deficiencies in the innate immune system in the predisposition to infection and autoimmune disease, as well as in modification of disease severity. Mannose-binding lectin (MBL) is an important protein of the innate immune system. It binds to mannose- and N-acetylglucosamine- rich oligosaccharides present on a wide range of bacteria, viruses, fungi and parasites. In doing so it interacts with mannose associated serine proteases (MASP—l and -2), leading to complement activation and resultant opsonization, phagocytosis and cell lysis. Three structural mutations are primarily responsible for MBL deficiency, although 3 promoter region polymorphisms also contribute to variation in serum protein concentrations. Homozygotic individuals have negligible levels whilst heterozygotic individuals have approximately an eighth of normal levels. Whilst the majority of these individuals manifest no significant propensity to increased infection due to other compensating mechanisms within the immune system, those with impaired primary or acquired immunity fimction, including young infants whose immune systems are still immature may be at increased risk. MBL infusions have been successfully used in some deficient individuals with significant recurrent infections. There have been conflicting data regarding the role of MBL deficiency in predisposition to respiratory tract infections and pneumococcal sepsis. This study there provides an excellent opportunity to study the association of MBL structural mutations with risk of respiratory tract infections, particularly with respect to age, aetiologic agents and other epidemiologic risk factors.