Narrow-spectrum ß-lactam monotherapy in hospital treatment of community-acquired pneumonia: a register-based cohort study

摘要

Respiratory tract infections (RTIs) are estimated to cause 703.000 deaths annually in childrenbelow five years. The majority of RTIs in children are caused by viruses, yet the number ofantivirals approved for treatment of these infections is very limited. Moreover, it is sometimescomplicated to distinguish between bacterial and viral RTIs, which results in overuse ofantibiotics. The aim of this thesis is to improve the understanding of the causative role ofrespiratory 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. Toachieve 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 thanexpected when it reached Europe during Spring 2009. This was suggested to be due to negativeviral interference by circulating rhinovirus (RV). In Paper I, children with influenza-like illnesswere assessed during the swine flu pandemic in 2009. Co-infections were specifically assessed ininfluenza-positive patients with regard to disease severity. No significant difference was foundbetween patients with single versus viral co-infection. Co-infection with influenza and RV wasnot uncommon, which contradicted the proposed hypothesis of viral interference. Moreover,the study showed that several different viruses were present in the children with suspectedinfluenza, 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 inupper respiratory specimens has been questioned. In Paper II, we assessed the role of viruses inacute respiratory illness in a case-control study. Respiratory syncytial virus (RSV), humanmetapneumovirus (hMPV) and parainfluenza virus were highly associated with acuterespiratory illness. In contrast, detection of other viruses was common in asymptomaticcontrols, showing the complexity in interpreting PCR-positivity for these viruses.Community-acquired pneumonia (CAP) is a disease that traditionally has been considered apredominantly bacterial disease. Nevertheless, successful immunization against the two majorbacterial causes, Streptococcus pneumoniae and Haemophilus influenza, has contributed to adeclining incidence of the disease and has likely also led to a relative increase of other etiologicagents. 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 highlyassociated with CAP. The study suggests that viruses have a major role in childhood CAP andindicates that viral CAP is an underdiagnosed disease.Viral RTIs affect also immunosuppressed children. Neutropenia is a common adverse effectin children receiving chemotherapeutic treatment for malignancies. The condition highlyincreases the risk for septicemia, and fever is sometimes the only symptom. However, in themajority of episodes of febrile neutropenia, no causative agent can be identified. In Paper IV,respiratory viruses were assessed in immunosuppressed children during episodes of febrileneutropenia. Interestingly, respiratory viruses were detected in almost half of the episodes,whereas laboratory confirmed septicemia was infrequent (9%). Moreover, the majority ofchildren had cleared their virus at follow-up suggesting a causal relationship between thedetected viruses and the episodes of febrile neutropenia.This thesis has contributed to an improved understanding of the role of viruses in severeRTIs in children stressing the urgent need for new diagnostic tests that better distinguishbetween viral and bacterial disease. It also forwards the need for improved treatment optionsand new vaccines against viral RTIs in children.