Chapter 113. Introduction to Infectious Diseases: Host–Pathogen Interactions (Part 5) The complement system (Chap. 308) consists of a group of serum proteins functioning as a cooperative, self-regulating cascade of enzymes that adhere to— and in some cases disrupt—the surface of invading organisms. Some of these surface-adherent proteins (e.g., C3b) can then act as opsonins for destruction of microbes by phagocytes. The later, "terminal" components (C7, C8, and C9) can directly kill some bacterial invaders (notably, many of the neisseriae) by forming a membrane attack complex and disrupting the integrity of the bacterial membrane, thus causing bacteriolysis. Other complement components, such as C5a, act as chemoattractants for PMNs (see below). Complement activation and deposition occur by either or both of two pathways: the classic pathway is activated primarily by immune complexes (i.e., antibody bound to antigen), and the alternative pathway is activated by microbial components, frequently in the absence of antibody. PMNs have receptors for both antibody and C3b, and antibody and complement function together to aid in the clearance of infectious agents. PMNs, short-lived white blood cells that engulf and kill invading microbes, are first attracted to inflammatory sites by chemoattractants such as C5a, which is a product of complement activation at the site of infection. PMNs localize to the site of infection by adhering to cellular adhesion molecules expressed by endothelial cells. Endothelial cells express these receptors, called selectins (CD- 62, ELAM-1), in response to inflammatory cytokines such as tumor necrosis factor α and interleukin 1. The binding of these selectin molecules to specific receptors on PMNs results in the adherence of the PMNs to the endothelium. Cytokine-mediated upregulation and expression of intercellular adhesion molecule 1 (ICAM 1) on endothelial cells then take place, and this latter receptor binds to β 2 integrins on PMNs, thereby facilitating diapedesis into the extravascular compartment. Once the PMNs are in the extravascular compartment, various molecules (e.g., arachidonic acids) further enhance the inflammatory process. Approach to the Patient: Infectious Diseases The clinical manifestations of infectious diseases at presentation are myriad, varying from fulminant life-threatening processes to brief and self-limited conditions to indolent chronic maladies. A careful history is essential and must include details on underlying chronic diseases, medications, occupation, and travel. Risk factors for exposure to certain types of pathogens may give important clues to diagnosis. A sexual history may reveal risks for exposure to HIV and other sexually transmitted pathogens. A history of contact with animals may suggest numerous diagnoses, including rabies, Q fever, bartonellosis, Escherichia coli O157 infection, or cryptococcosis. Blood transfusions have been linked to diseases ranging from viral hepatitis to malaria to prion disease. A history of exposure to insect vectors (coupled with information about the season and geographic site of exposure) may lead to consideration of such diseases as Rocky Mountain spotted fever, other rickettsial diseases, tularemia, Lyme disease, babesiosis, malaria, trypanosomiasis, and numerous arboviral infections. Ingestion of contaminated liquids or foods may lead to enteric infection with Salmonella, Listeria, Campylobacter, amebas, cryptosporidia, or helminths. Since infectious diseases may involve many organ systems, a careful review of systems may elicit important clues as to the disease process. The physical examination must be thorough, and attention must be paid to seemingly minor details, such as a soft heart murmur that might indicate bacterial endocarditis or a retinal lesion that suggests disseminated candidiasis or cytomegalovirus (CMV) infection. Rashes are extremely important clues to infectious diagnoses and may be the only sign pointing to a specific etiology (Chap. 18; Chap. e5). Certain rashes are so specific as to be pathognomonic—e.g., the childhood exanthems (measles, rubella, varicella), the target lesion of erythema migrans (Lyme disease), ecthyma gangrenosum (Pseudomonas aeruginosa), and eschars (rickettsial diseases). Other rashes, although less specific, may be exceedingly important diagnostic indicators. The prompt recognition of the early scarlatiniform and later petechial rashes of meningococcal infection or of the subtle embolic lesions of disseminated fungal infections in immunosuppressed patients can hasten life-saving therapy. Fever (Chaps. 17, 18, and 19) is a common manifestation of infection and may be its sole apparent indication. Sometimes the pattern of fever or its temporally associated findings may help refine the differential diagnosis. For example, fever occurring every 48– 72 h is suggestive of malaria (Chap. 203). The elevation in body temperature in fever (through resetting of the hypothalamic setpoint mediated by cytokines) must be distinguished from elevations in body temperature from other causes such as drug toxicity (Chap. 19) or heat stroke (Chap. 17). Laboratory Investigations Laboratory studies must be carefully considered and directed toward establishing an etiologic diagnosis in the shortest possible time, at the lowest possible cost, and with the least possible discomfort to the patient. Since mucosal surfaces and the skin are colonized with many harmless or beneficial microorganisms, cultures must be performed in a manner that minimizes the likelihood of contamination with this normal flora while maximizing the yield of pathogens. A sputum sample is far more likely to be valuable when elicited with careful coaching by the clinician than when collected in a container simply left at the bedside with cursory instructions. Gram's stains of specimens should be interpreted carefully and the quality of the specimen assessed. The findings on Gram's staining should correspond to the results of culture; a discrepancy may suggest diagnostic possibilities such as infection due to fastidious or anaerobic bacteria. . Chapter 113. Introduction to Infectious Diseases: Host–Pathogen Interactions (Part 5) The complement system (Chap. 308) consists of a. response to inflammatory cytokines such as tumor necrosis factor α and interleukin 1. The binding of these selectin molecules to specific receptors on PMNs results in the adherence of the PMNs to. fever, bartonellosis, Escherichia coli O157 infection, or cryptococcosis. Blood transfusions have been linked to diseases ranging from viral hepatitis to malaria to prion disease. A history of