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Chapter 1: Microbes, the Host and SepsisThe speciality of infectious diseases encompasses a wide variety of clinical areas. Some micro-organisms may cause specific infections such as hepatitis, while having little effect on the rest of the body. Other micro-organisms, such as Staphylococcus aureus, can sometimes cause local disease, such as impetigo, or can disseminate and affect many organ systems. The differential diagnosis of patients with suspected sepsis is broad and its elaboration requires a systematic approach (Fig. 1.1). The clinical history is important in all realms of medical practice. In patients with infectious disease, aspects of the history that need to be emphasized include:
- a travel history;
- a history of exposure to environmental risks and to others with infection; and
- a history of previous serious infection (perhaps suggesting
Whatever the pathological process, the management of patients with infection requires close co-operation between the clinician and the laboratories, especially the microbiology laboratory. Knowledge of the epidemiology of micro-organisms and their pathogenic mechanisms enable a better understanding of disease processes and may allow more focused investigation of the sick patient. Successful treatment relies on a good working knowledge of antimicrobial agents along with the recognition of the role of surgery and interventional radiology in obtaining appropriate microbiological specimens and removing foci of infection.
Although a detailed account of the pathogenesis of infection is beyond the scope of this book, a brief outline of some of the mechanisms involved can be helpful.
Most bacteria have to grow on some sort of surface; when they interact with humans, these organisms usually initially colonize a mucosal surface. Some streptococci are specifically adapted to colonize the oropharynx and adhere to epithelial cells in the mouth. Sonic strains of Escherichia coli produce surface antigens that allow specific adhesion to urothelial cells rather than colonic epithelium, increasing the risk of urinary tract infection. Many antigens expressed by bacteria to promote adherence arc encoded by plasmids and may thus be transferable to other bacteria.
Numerous bacteria elaborate a variety of toxins that may either facilitate invasion by the bacteria or damage the host in some way. Endotoxin, or lipopolysaccharide, is a constituent of the bacterial cell wall of Gramnegative organisms. Exotoxins, on the other hand, are produced and secreted by bacteria and can have a variety of effects. For example, cholera toxin specifically affects enzymes in the small bowel mucosa that arc responsible for ion and water transport, leading to profuse diarrhoea. S. aureus produces a variety of toxins, one of which is toxic shock syndrorne toxin-1 (TSST 1). This toxin can act as a superantigen, leading to T-lymphocyte proliferation. The resulting cytokine release can lead to a myriad of clinical problems.
Once organisms have become adherent to an epithelial surface and established colonization, they need to invade the host in order to cause disease. This may be facilitated by defects in the host but it often depends on a variety of bacterial attributes. For example, some Gramnegative bacteria have a protective cell wall that makes them relatively resistant to lysis by the host. The outer membrane proteins of these organisms may form a layer that blocks the attachment of antibody or complement so that the bacteria can evade the immune system. Gram-positive organisms, such as Streptococcus pneumoniae, have a thick polysaccharide capsule that is antigenically variable and often quite resistant to phagocytosis by host cells. Other organisms, such as mycobacteria, may be phagocytosed but can evade intracellular killing by remaining inside the phagosome and inhibiting fusion between the phagosome and the lysosome.
The human host has several layers of defence against infection, ranging from physical barriers through phagocytic cells to specialized lymphocytes.
The skin acts as an important barrier to infection. Keratin provides a tough and waterresistant shield against the invasion of organisms that may colonize the skin surface. In addition, specialized cells within the dermis provide immunological defences. Mucous membranes, as well as acting as physical barriers, also produce mucus as an extra defence; some, like the respiratory epithelium, are ciliated so that organisms and debris can be wafted away to the outside. The low pH of the gastric contents is a safeguard against ingested organisms and the regular and complete emptying of the urinary bladder reduces the chances of infection being established in the urinary tract.
The complement system is an important component of host defences and consists of a group of highly regulated proteins and cell membrane receptors. The key elements in defence against infection are the third component (C3) and the terminal components (CS-C;9). Complement can be activated by the 'classical pathway' when antigen-antibody complexes bind to and activate the first complement component (CI). C3 can be activated directly, via the 'alternative pathway', which does not depend on the presence of antibody. The activation of complement leads to a variety of inflammatory responses, including increasing vascular permeability and ncutrophil chemotaxis. Activated C3 acts as a potent opsonin when bound to micro-organisms. There is a spectrum of inherited complement deficiencies that result in increased susceptibility to certain infections. For example, deficiency of the terminal complement components can render the person susceptible to recurrent meningococcal disease.
The polymorphonuclear leucocyte, or neutrophil, accounts for most of the circulating white cells in the blood. Neutrophils move in an amoeboid fashion along the surface of vessels and can change shape, moving between endothelial cells and into the tissues. These phagocytcs are attracted to sites of inflammation by chemotactic signals from other cells and become activated. Phagocytosis is stimulated by the binding of the Fc portion of IgG or C3 to the neutrophil membrane. The infecting organism is engulfed by a neutrophil pseudopod and a 'phagosome' is formed. Granules within the neutrophil fuse with the phagosomc, releasing various microbicidal proteins, such as lysozymc. Neutrophils call also produce large quantities of hydrogen peroxide and other oxidants that act to damage bacteria. In chronic granulomatous disease, an inherited defect occurs in the polymorphs so that they are not able to undergo the respiratory burst required to generate these microbicidal products. Reductions iii the number of circulating neutrophils (e.g. after cancer chemotherapy) or abnormalities in their function (e.g. in congenital adhesion defects) can lead to recurrent infection. Monocytes and macrophages arc also important phagocytes involved in host defence against infection, particularly in the tissues.
Tlymphocytes are the mainstay of cell-mediated immunity. Antigens need to be processed by antigen-presenting cells and presented to the T-lymphocyte receptor in association with major histocompatibility complex (MHC) molecules on the cell surface. Binding to the T-ly mphocytc receptor can then trigger a series of events, depending on the T lymphocyte type. The release of cytokines, such as interferon-y and interleukin (IL)-2, by type I T-helper lymphocytes can help to recruit macrophages and promote phagocytosis. Cytotoxic T lymphocytes recognize and kill cells expressing foreign antigen in association with MHC Class I molecules. This is an important means of defence against viral infections. In addition, a small percentage of lymphocytes, called natural killer cells, can be activated by IL-2 and can directly kill some bacteria and virally infected cells.
Antibodies, in the form of immunoglobulins, form the basis of the Immoral immune system. B lymphocytes differentiate into antibody-secreting plasma cells when they are stimulated by the presence of antigen. Antigen binds to B lymphocytes via cell surface immunoglobulin (acting as the B-lymphocyte receptor) and the B lymphocyte differentiates into an antibodyproducing cell when stimulated by cytokincs, such as IL-4 and IL-l0, released from type I T-helper lymphocytes. Deficiencies of immunoglobulin may lead to recurrent pyogenic infections, particularly with encapsulated bacteria such as the pneumococcus...