Severe viral respiratory tract infections in children

Abstract: Respiratory tract infections (RTIs) are estimated to cause 703.000 deaths annually in children below five years. The majority of RTIs in children are caused by viruses, yet the number of antivirals approved for treatment of these infections is very limited. Moreover, it is sometimes complicated to distinguish between bacterial and viral RTIs, which results in overuse of antibiotics. The aim of this thesis is to improve the understanding of the causative role of respiratory viruses in children with severe RTI, with the long-term goal to improve diagnostics, facilitate the development of new antiviral drugs and reduce unnecessary antibiotic use. To achieve this, a number of specific objectives have been assessed. The spread of the Influenza A H1N1(pdm09) i.e. the swine flu pandemic was slower than expected when it reached Europe during Spring 2009. This was suggested to be due to negative viral interference by circulating rhinovirus (RV). In Paper I, children with influenza-like illness were assessed during the swine flu pandemic in 2009. Co-infections were specifically assessed in influenza-positive patients with regard to disease severity. No significant difference was found between patients with single versus viral co-infection. Co-infection with influenza and RV was not uncommon, which contradicted the proposed hypothesis of viral interference. Moreover, the study showed that several different viruses were present in the children with suspected influenza, underscoring the overlap of disease presentation of different respiratory viruses. PCR is a very sensitive method for detecting viruses, yet the significance of a finding in upper respiratory specimens has been questioned. In Paper II, we assessed the role of viruses in acute respiratory illness in a case-control study. Respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and parainfluenza virus were highly associated with acute respiratory illness. In contrast, detection of other viruses was common in asymptomatic controls, showing the complexity in interpreting PCR-positivity for these viruses. Community-acquired pneumonia (CAP) is a disease that traditionally has been considered a predominantly bacterial disease. Nevertheless, successful immunization against the two major bacterial causes, Streptococcus pneumoniae and Haemophilus influenza, has contributed to a declining incidence of the disease and has likely also led to a relative increase of other etiologic agents. In Paper III, the role of viruses in CAP was assessed in another case-control study. Viruses were detected in the majority of cases and RSV, hMPV and influenza were highly associated with CAP. The study suggests that viruses have a major role in childhood CAP and indicates that viral CAP is an underdiagnosed disease. Viral RTIs affect also immunosuppressed children. Neutropenia is a common adverse effect in children receiving chemotherapeutic treatment for malignancies. The condition highly increases the risk for septicemia, and fever is sometimes the only symptom. However, in the majority of episodes of febrile neutropenia, no causative agent can be identified. In Paper IV, respiratory viruses were assessed in immunosuppressed children during episodes of febrile neutropenia. Interestingly, respiratory viruses were detected in almost half of the episodes, whereas laboratory confirmed septicemia was infrequent (9%). Moreover, the majority of children had cleared their virus at follow-up suggesting a causal relationship between the detected viruses and the episodes of febrile neutropenia. This thesis has contributed to an improved understanding of the role of viruses in severe RTIs in children stressing the urgent need for new diagnostic tests that better distinguish between viral and bacterial disease. It also forwards the need for improved treatment options and new vaccines against viral RTIs in children.