The Microbe-Host Interface in Respiratory Tract Infections: Current Research and Hot Topics Chapter Abstracts

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Host genes, together with microbial and environmental factors, determine susceptibility, severity, and course of respiratory tract infections. Seldom occurring mutations in a single gene may cause a dramatically enhanced severity of infection. However, usually the course of infection is influenced by several, frequently occurring gene variants that each has a small positive or negative effect. The variation in disease susceptibility or severity accounted for by genetic factors may vary considerably for specific infections, but appears quite high for tuberculosis. Genetic studies emphasize that interferon-g-activated macrophage function is critical in controlling mycobacterial infection. Genes affecting respiratory syncytial virus (RSV) infections especially influence the innate immune system and the Th2 cytokine pathway. Genetic factors influencing pneumococcal infections relate to the complement pathway, opsonization, and phagocytosis. Knowledge of host genetic variants adds to our understanding of pathogenesis, and may identify critical steps to which prevention and therapy may be directed. New treatments and vaccines may be tailored to host genetic profile, for example to ethnic group or individual, or not. Genetic studies may further identify individuals that respond poorly to vaccination, or that develop adverse events upon vaccination or infection. Future work will expand our knowledge of gene variants that affect either a single or several respiratory tract infectious and allergic disorders.

Chapter 2
The Hygiene Hypothesis: The Role of Microbes in the Prevention of Atopy and Atopic Disease
L.E.M. Niers, T.J. Steenhuis and M.O. Hoekstra

During the last few decades, the prevalence of atopic disease has increased in countries with a Western lifestyle. The hygiene hypothesis states that this increase may be due to a decreased exposure to microbes or microbial products early in life. The evidence for this hypothesis is circumstantial and merely based on data derived from epidemiological studies. During the last few years, the hygiene hypothesis has been questioned repeatedly and a revision of the hygiene hypothesis has been proposed. This revision suggests that a normal development of the immune system requires interaction between the human host and microbes or microbial products. Due to this host-microbes interaction early in life, regulatory T-cells may develop, which prevent immune-mediated disease. The hygiene hypothesis offers new opportunities for prevention of atopic disease, like administration of BCG, M. vaccae, CpG's and probiotics which are recently being developed and tested in animal and human models.

Chapter 3
Respiratory Infection in the Immunocompromised Host: Recognition and Treatment
A.R. Gennery and A.J. Cant

Pulmonary infection is a frequent consequence of immunocompromise; specific immune defects often result in infection with particular organisms and characteristic clinical features. New methods of viral and fungal detection make early recognition of potentially serious infection easier in vulnerable immunocompromised paediatric patients. This allows close monitoring of disease progression and earlier intervention. The use of new modalities of imaging and microbial detection in conjunction with new antiviral and antifungal agents, mean that early pre-emptive treatment is more likely to be successful. This chapter will review the causes of immunocompromise, more common viral and fungal infections in particular outlining new methods of early detection and the use of new anti infective agents.

Chapter 4
New Diagnostic Modalities In Respiratory Tract Disease
Alex Van Belkum and Hubert G.M. Niesters

A diversity of viral and microbial pathogens can give rise to lower respiratory tract infections (LRTI). This diversity and the commonality among the clinical syndromes render differential diagnosis complicated and time consuming. In other words, the spectrum of causative organisms outweighs the technological possibilities of classical, culture-based microbiology and virology laboratories. Obviously, there is a lingering need for improvement in the complex field of infectious disease diagnosis. The development of molecular methodology was initially considered a panacea, but replacement of conventional tests by molecular procedures is a slow and cautious process. The nucleic acid-driven possibilities for improvement of diagnosis of LRTI, however, are large in number and several of these innovative tests are currently in their break-through state. This chapter surveys these novel possibilities and provides examples of the new nucleic acid detection and identification tests and their current and anticipated impact on the management of LRTI and other infectious diseases. Special focus will be with laboratory automation, quality control requirements and the rise and shine of quantitative real-time test formats. These technological improvements facilitate major new steps towards the integration of molecular technology in clinical diagnostics of all major infectious diseases.

Chapter 5
The Pathogenesis of Bacterial Respiratory Tract Infection and Bronchitis
Janine Zweigner and Elaine Tuomanen

Within the last decade our understanding about the pathogenesis of bacterial respiratory tract infection has been substantially increased. Advances in molecular biology promoted the identification and functional analysis of microbial genes and their proteins involved in the development of pulmonary infection. Recent studies have elucidated several pathways of the host's innate immune system which is specialized in rapidly detecting foreign microorganisms, in phagocytosing and killing them, and in possibly evoking further adaptive mechanisms against them. Here, we will discuss the host response in bacterial pneumonia emphasizing pattern-recognition receptors, such as the Toll-like receptors, and downstream effects such as production of cytokines and antimicrobial peptides as well as apoptosis. We will also describe general bacterial virulence factors in pneumonia as well as species specific virulence factors of Streptococcus pneumoniae, the most common microorganism of community-acquired respiratory tract infection.

Chapter 6
The Role of Atypical Agents in Respiratory Tract Disease
Monica Fonseca-Aten, Ana Maria Rios and R. Doug Hardy

M. pneumoniae, C. pneumoniae, and Legionella species are the most important causes of "atypical" pneumonia, excluding early childhood where respiratory viruses predominate. This chapter will therefore focus on the role of these agents in respiratory tract infections. After presenting the emerging epidemiology of these agents in children and adults, an up-to-date general description of each will be followed by a discussion of recent developments in the literature for these agents. For M. pneumoniae and C. pneumoniae, the growing association with wheezing and asthma will be focused upon. For Legionella species, as current developments are many, a wide array of recent information on this pathogen will be presented.

Chapter 7
Infections in Patients with Cystic Fibrosis: Effects of a Longer Survival
Heather E. Elphick and Rosalind L. Smyth

Cystic fibrosis (CF) is a common genetic disease in the Caucasian population. Long-term survival is improving due to a better understanding of the basic underlying defects. Respiratory infection remains the major cause of morbidity and mortality and although early aggressive treatment of infection and new management philosophies have led to a better prognosis, new treatment challenges have emerged as a result. Recent advances in the understanding of the pathogenesis of some of the common pathogens in CF have led to new treatment strategies, including antibiotic prophylaxis and prevention of colonisation of the lungs with Pseudomonas aeruginosa, as well as clinical trials of new drugs such as the macrolide antibiotics and methods of drug delivery such as nebulised antibiotic therapy. Difficult new issues include the increasing problem of antibiotic resistant organisms and cross-infection of these drug-resistant organisms as well as the emergence of a number of possible new multi-drug resistant organisms in the CF lung. This review outlines some of the recent advances in the management of respiratory infections and discusses specific issues related to respiratory infection and long-term survival.

Chapter 8
Antibiotic Treatment of Lower Respiratory Tract Infection
Faryal Ghaffar and Octavio Ramilo

Pneumonia is the sixth leading cause of mortality in United States. The majority of pediatric pneumonias are viral in origin, but a bacterial etiology should always be considered in the differential diagnosis because antibiotic administration may be crucial to the patient's management. Streptococcus pneumoniae is the most common bacteria responsible for community-acquired pneumonia in children of all ages. Mycoplasma pneumoniae and Chlamydophila pneumoniae are important from the age of 5 years onwards. Nosocomial pneumonia is a common hospital-acquired infection in children which can be fatal. Approximately 60% of cases of nosocomial pneumonia are caused by aerobic gram-negative bacilli. Staphylococcus aureus is the most common Gram-positive bacteria causing nosocomial pneumonia but infections with these organisms have a better outcome than those caused by Gram-negative bacteria. The selected antibiotics should be effective against the most common bacterial pathogens found in the child's age group and will account for antibiotic-resistant organisms in the child's community and local hospitals.

Chapter 9
Vaccines in the Prevention of Bacterial Respiratory Tract Infections in Children
Reinier H. Veenhoven and Elisabeth A.M. Sanders

Bacterial vaccines for prevention of upper respiratory tract infections have gained high priority in view of antibiotic resistance, the burden of disease and health care costs for the community. At present, pneumococcal vaccines are the only vaccines available for prevention of bacterial respiratory tract infections. The recently licensed 7-valent pneumococcal conjugate vaccine Prevnar® was shown to prevent 7% of overall AOM episodes and 9% of recurrent AOM episodes in infants and toddlers, provided vaccinations were started early in life at age 2 months. Similarly, a tertiary post-hoc analysis in a randomised trial in healthy infants showed the conjugate vaccine to prevent radiographically confirmed episodes of lower respiratory tract infections by 20-30%, at least in children younger than 2 years. Afterwards, the efficacy seems to fall off. Vaccination with pneumococcal conjugate vaccine after 1 year of age in children with a history of recurrent acute otitis failed to show any benefit in prevention of new AOM episodes. The 23-valent pneumococcal polysaccharide vaccines are not currently recommended at childhood age for prevention of respiratory tract infections. In the near future, 9- to 11-valent pneumococcal conjugate vaccines as well as pneumococcal protein vaccines administered separately or in combination might enhance the efficacy against pneumococcal respiratory tract infections. Other candidate bacterial vaccines targeting the respiratory pathogens non-typable Haemophilus influenzae and Moraxella catarrhalis are underway. Prevention of AOM by viral influenza vaccines has already been successful and proves that viral vaccines offer an alternative approach in the prevention of bacterial mucosal infections.

Chapter 10
Pathogenesis of Respiratory Syncytial Virus Bronchiolitis: Immunological Aspects
J. Heidema, J.L.L. Kimpen and G.M. van Bleek

Bronchiolitis induced by infection with respiratory syncytial virus is a common cause for hospitalization in infants under 6 months of age. Moreover, epidemiological studies show a relationship between early lower respiratory disease as a result of RSV infection and development of asthma-like symptoms during childhood. An effective and safe licensed vaccine for RSV is not available. A formalin-inactivated whole RSV vaccine (FI-RSV) used in a trial performed in the 1960s primed vaccinees for substantial immune pathology following infection with the natural virus. This event has set back the development of novel vaccines. The mechanism behind FI-RSV induced enhanced disease as well as the mechanism of severe disease during primary infections is still poorly understood. The present review summarizes our current understanding of possible elements of the adaptive and innate immune responses that may determine the balance of efficacious immunity versus virus induced or immune mediated pathology.

Chapter 11
Viral Infections and Childhood Asthma
M.J.J. Ermers and L. Bont

Viral respiratory tract infections (VRTI) have a strong epidemiological relationship with wheezing disorders. At least three different types of relationships between VRTI and wheezing disorders have been described. First, VRTI during early childhood can induce recurrent wheezing. For example, respiratory syncytial virus (RSV) infection is followed by post-bronchiolitis wheezing in about 50% of cases. Pre-existent diminished lung function is probably an important mechanism of virus-induced wheezing. It is debated whether viral infections can change immunological status or induce allergy. Second, viral infections are the most important triggers of asthma exacerbations in atopic patients. In 85% of asthma exacerbations in children VRTI are found in airways. In the majority of cases rhinovirus is the infectious agent. Third, exposure to respiratory viruses during infancy might prevent allergy development. The mechanism of virus-induced prevention of asthma is by skewing the immune system towards a Th1-phenotype. Different types of relationships between VRTI and wheezing can co-exist in one individual. For example, common colds during infancy may induce both increased risk of recurrent wheezing during childhood and decreased risk of allergic asthma later in life. The temporal relationship between viral infection and allergy development, as well as the interplay between genetic factors and viral infection, appear the keys to understand the intriguing relationship between viruses and asthma.

Chapter 12
Adenovirus
L.M. Haveman, M. Bierings and T.F.W. Wolfs

Adenovirus infections are endemic in the general population and frequently cause acute respiratory infections, which are usually self-limiting. However, in the immunocompromised host, especially in children, adenoviruses have been increasingly recognised as important pathogens. Adenoviral infections may cause severe disease with a high morbidity and mortality rate. No specific antiviral therapy of proven value currently exists for severe adenovirus infection. It is important to detect adenovirus at an early stage to start with antiviral agents before adenoviral disease develops. Therefore, new rapid and sensitive methods for detection of adenoviruses as real time quantitative polymerase chain reaction have been developed. Due to the increasing knowledge of the immune response to adenovirus, adoptive immunotherapy could play an important role in the treatment of adenoviral infections in the near future. Until today, vaccination strategies to prevent adenoviral infections in high risk populations have not been successful.

Chapter 13
Rhinovirus: Is It Really a Relevant Pathogen?
Olli Ruuskanen and Timo Hyypiä

Rhinovirus is probably the most common causative agent of infections worldwide. Although the atomic structure of rhinovirus has been solved, our knowledge on the human rhinovirus is still limited. The symptoms of rhinovirus infection are induced by complex inflammatory reactions in the respiratory epithelium and not so much by direct viral effects. The clinical relevance of rhinovirus infections has been now better documented due to development of reverse transcription-polymerase chain reaction (RT-PCR) methods which are much more sensitive than conventional virus culture in detecting rhinoviruses. Rhinovirus is a causative agent of half of the cases with common cold. It is the most common virus predisposing children to acute otitis media. It is well established that rhinovirus can also induce lower respiratory infections. One third of exacerbations of asthma and wheezing in children and in adults is associated with rhinovirus infection. Rhinovirus may be a more common causative agent of pneumonia than has been recognized. It can also induce severe illness in immunocompromised host. Rhinovirus has been detected by PCR in 10-30% of asymptomatic subjects. This may be due to previous infection, ongoing asymtomatic infection or an emerging illness. There are currently no specific antiviral drugs or prophylactic measures against rhinovirus infections in clinical use. However, transmission of rhinovirus can be reduced by careful hand desinfection and environmental manipulation.

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