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Despite decades of dramatic progress in their treatment and prevention, infectious diseases remain a major cause of death and debility and are responsible for worsening the living conditions of many millions of people around the world. Infections frequently challenge the physician’s diagnostic skill and must be considered in the differential diagnoses of syndromes affecting every organ system. 

CHANGING EPIDEMIOLOGY OF INFECTIOUS DISEASES  
With the advent of antimicrobial agents, some medical leaders believed that infectious diseases would soon be eliminated and become of historic interest only. Indeed, the hundreds of chemotherapeutic agents developed since World War II, most of which are potent and safe, include drugs effective not only against bacteria, but also against viruses, fungi, and parasites. Nevertheless, we now realize that as we developed antimicrobial agents, microbes developed the ability to elude our best weapons and to counterattack with new survival strategies. Antibiotic resistance occurs at an alarming rate among all classes of mammalian pathogens. Pneumococci resistant to penicillin and enterococci resistant to vancomycin have become commonplace. Even Staphylococcus aureus strains resistant to vancomycin have appeared. Such pathogens present real clinical problems in managing infections that were easily treatable just a few years ago. Diseases once thought to have been nearly eradicated from the developed world-tuberculosis, cholera, and rheumatic fever, for example-have rebounded with renewed ferocity. Newly discovered and emerging infectious agents appear to have been brought into contact with humans by changes in the environment and by movements of human and animal populations. An example of the propensity for pathogens to escape from their usual niche is the alarming 1999 outbreak in New York of encephalitis due to West Nile virus, which had never previously been isolated in the Americas. In 2003, severe acute respiratory syndrome (SARS) was first recognized.This emerging clinical entity is caused by a novel coronavirus that may have jumped from an animal niche to become a significant human pathogen. By 2006,  H5N1 avian influenza, having spread rapidly through poultry  farms in Asia and having caused deaths in exposed humans,  had reached Europe and Africa, heightening fears of a new influenza pandemic. Many infectious agents have been discovered only in recent decades (Fig. 1-1). Ebola virus, human metapneumovirus, Anaplasma phagocytophila (the agent of human granulocytotropic ehrlichiosis), and retroviruses such as HIV humble us despite our deepening understanding of pathogenesis at the most basic molecular level. Even in developed countries, infectious diseases have made a resurgence. Between 1980 and 1996, mortality from infectious diseases in the United States increased by 64% to levels not seen since the 1940s. The role of infectious agents in the etiology of diseases once believed to be noninfectious is increasingly recognized. For example, it is now widely accepted that Helicobacter pylori is the causative agent of peptic ulcer disease and perhaps of gastric malignancy. Human papillomavirus is likely to be the most important cause of invasive cervical cancer. Human herpesvirus type 8 is believed to be the cause of most cases of Kaposi’s sarcoma. Epstein-Barr virus is a cause of certain lymphomas and may play a role in the genesis of Hodgkin’s disease. The possibility certainly exists that other diseases of unknown cause, such as rheumatoid arthritis, sarcoidosis, or inflammatory bowel disease, have infectious etiologies. There is even evidence that atherosclerosis may have an infectious component. In contrast, there are data to suggest that decreased exposures to pathogens in childhood may be contributing to an increase in the observed rates of allergic diseases. Medical advances against infectious diseases have been hindered by changes in patient populations. Immunocompromised hosts now constitute a significant proportion of the seriously infected population. Physicians immunosuppress their patients to prevent the rejection of transplants and to treat neoplastic and inflammatory diseases. Some infections, most notably that caused by HIV, immunocompromise the host in and of themselves. Lesser degrees of immunosuppression are associated with other infections, such as influenza and syphilis. Infectious agents that coexist peacefully with immunocompetent hosts wreak havoc in those who lack a complete immune system. AIDS has brought to prominence once-obscure organisms such as Pneumocystis, Cryptosporidium parvum, and Mycobacterium avium.

HOST FACTORS IN INFECTION
For any infectious process to occur, the pathogen and the host must first encounter each other. Factors such as geography, environment, and behavior thus influence the likelihood of infection. Although the initial encounter between a susceptible host and a virulent organism frequently results in disease, some organisms can be harbored in the host for years before disease becomes clinically evident. For a complete view, individual patients must be considered in the context of the population to which they belong. Infectious diseases do not often occur in isolation; rather, they spread through a group exposed from a point source (e.g., a contaminated water supply) or from one individual to another (e.g., via respiratory droplets). Thus the clinician must be alert to infections prevalent in the community as a whole.A detailed history, including information on travel, behavioral factors, exposures to animals or potentially contaminated environments, and living and occupational conditions,must be elicited. For example, the likelihood of infection by Plasmodium falciparum can be significantly affected by altitude, climate, terrain, season, and even time of day. Antibiotic-resistant strains of P. falciparum are localized to specific geographic regions, and a seemingly minor alteration in a travel itinerary can dramatically influence the likelihood of acquiring chloroquine-resistant malaria. If such important details in the history are overlooked, inappropriate treatment may result in the death of the patient. Likewise, the chance of acquiring a sexually transmitted disease can be greatly affected by a relatively minor variation in sexual practices, such as the method used for contraception. Knowledge of the relationship between specific risk factors and disease allows the physician to influence a patient’s health even before the development of infection by modification of these risk factors and—when a vaccine is available—by immunization. Many specific host factors influence the likelihood of acquiring an infectious disease. Age, immunization history, prior illnesses, level of nutrition, pregnancy, coexisting illness, and perhaps emotional state all have some impact on the risk of infection after exposure to a potential pathogen. The importance of individual host defense mechanisms, either specific or nonspecific, becomes apparent in their absence, and our understanding of these immune mechanisms is enhanced by studies of clinical syndromes developing in immunodeficient patients (Table 1-1). For example, the higher attack rate of meningococcal disease among people with deficiencies in specific complement proteins of the so-called membrane attack complex (see “Adaptive Immunity” later in the chapter) than in the general population underscores the importance of an intact complement system in the prevention of meningococcal infection. Medical care itself increases the patient’s risk of acquiring an infection in several ways: (1) through contact with pathogens during hospitalization, (2) through breaching of the skin (with intravenous devices or surgical incisions) or mucosal surfaces (with endotracheal tubes or bladder catheters), (3) through introduction of foreign bodies, (4) through alteration of the natural flora with antibiotics, and (5) through treatment with immunosuppressive drugs. Infection involves complicated interactions of microbe and host and inevitably affects both. In most cases, a pathogenic process consisting of several steps is required for the development of infections. Since the competent host has a complex series of barricades in place to prevent infection, the successful pathogen must use specific strategies at each of these steps. The specific strategies used by bacteria, viruses, and parasites (Chap. 2) have some remarkable conceptual similarities, but the strategic details are unique not only for each class of microorganism, but also for individual species within a class.

THE IMMUNE RESPONSE INNATE IMMUNITY
As they have co-evolved with microbes, higher organisms have developed mechanisms for recognizing and responding to microorganisms. Many of these mechanisms, referred together as innate immunity, are evolutionarily ancient, having been conserved from insects to humans. In general, innate immune mechanisms exploit molecular patterns found specifically in pathogenic microorganisms.These “pathogen signatures” are recognized by host molecules that either directly interfere with the pathogen or initiate a response that does so. Innate immunity serves to protect the host without prior exposure to an infectious agent, i.e., before specific or adaptive immunity has had a chance to develop. Innate immunity also functions as a warning system that activates components of adaptive immunity early in the course of infection.  Toll-like receptors (TLRs) are instructive in illustrating how organisms are detected and send signals to the immune system.There are at least 11 TLRs, each specific to different biologic classes of molecules. For example, even minuscule amounts of lipopolysaccharide (LPS), a molecule found uniquely in gram-negative bacteria, are detected by LPS-binding protein, CD14, and TLR4 (see Fig. 2-3).The interaction of LPS with these components of the innate immune system prompts macrophages, via the transcriptional activator nuclear factor B (NF-B), to produce cytokines that lead to inflammation and enzymes that enhance the clearance of microbes. These initial responses serve not only to limit infection but also to initiate specific or adaptive immune responses. 

ADAPTIVE IMMUNITY
Once in contact with the host immune system, the microorganism faces the host’s tightly integrated cellular and humoral immune responses. Cellular immunity, comprising T lymphocytes, macrophages, and natural killer cells, primarily recognizes and combats pathogens that proliferate intracellularly. Cellular immune mechanisms are important in immunity to all classes of infectious agents, including most viruses and many bacteria (e.g., Mycoplasma, Chlamydophila, Listeria, Salmonella, and Mycobacterium), parasites (e.g., Trypanosoma, Toxoplasma, and Leishmania), and fungi (e.g., Histoplasma, Cryptococcus, and Coccidioides). Usually, T lymphocytes are activated by macrophages and B lymphocytes, which present foreign antigens along with the host’s own major histocompatibility complex antigen to the T-cell receptor. Activated T cells may then act in several ways to fight infection. Cytotoxic T cells may directly attack and lyse host cells that express foreign antigens. Helper T cells stimulate the proliferation of B cells and the production of immunoglobulins. Antigen-presenting cells and T cells communicate with each other via a variety of signals, acting coordinately to instruct the immune system to respond in a specific fashion. T cells elaborate cytokines (e.g., interferon) that directly inhibit the growth of pathogens or stimulate killing by host macrophages and cytotoxic cells. Cytokines also augment the host’s immunity by stimulating the inflammatory response (fever, the production of acute-phase serum components, and the proliferation of leukocytes). Cytokine stimulation does not always result in a favorable response in the host; septic shock (Chap. 15) and toxic shock syndrome (Chaps. 35 and 36) are among the conditions that are mediated by these inflammatory substances. The immune system has also developed cells that specialize in controlling or downregulating immune responses. For example,Treg cells, a subgroup of CD4+ T cells, prevent autoimmune responses by other T cells and are thought to be important in downregulating immune responses to foreign antigens.There appear to be both naturally occurring and acquired Treg cells.  The reticuloendothelial system comprises monocytederived phagocytic cells that are located in the liver (Kupffer cells), lung (alveolar macrophages), spleen (macrophages and dendritic cells), kidney (mesangial cells), brain (microglia), and lymph nodes (macrophages and dendritic cells) and that clear circulating microorganisms. Although these tissue macrophages and polymorphonuclear leukocytes (PMNs) are capable of killing microorganisms without help, they function much more efficiently when pathogens are first opsonized (Greek,“to prepare for eating”) by components of the complement system such as C3b and/or by antibodies.  Extracellular pathogens, including most encapsulated bacteria (those surrounded by a complex polysaccharide coat), are attacked by the humoral immune system, which includes antibodies, the complement cascade, and phagocytic cells. Antibodies are complex glycoproteins (also called immunoglobulins) that are produced by mature B lymphocytes, circulate in body fluids, and are secreted on mucosal surfaces. Antibodies specifically recognize and bind to foreign antigens. One of the most impressive features of the immune system is the ability to generate an incredible diversity of antibodies capable of recognizing virtually every foreign antigen yet not reacting with self. In addition to being exquisitely specific for antigens, antibodies come in different structural and functional classes: IgG predominates in the circulation and persists for many years after exposure; IgM is the earliest specific antibody to appear in response to infection; secretory IgA is important in immunity at mucosal surfaces, while monomeric IgA appears in the serum; and IgE is important in allergic and parasitic diseases. Antibodies may directly impede the function of an invading organism, neutralize secreted toxins and enzymes, or facilitate the removal of the antigen (invading organism) by phagocytic cells.Immunoglobulins participate in cell-mediated immunity by promoting the antibody-dependent cellular cytotoxicity functions of certain T lymphocytes. Antibodies also promote the deposition of complement components on the surface of the invader. The complement system 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 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 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
The clinical manifestations of infectious diseases at presentation are myriad, varying from fulminant lifethreatening 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 (Chaps. 8 and 10). 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 7 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. 7, 8, and 9) 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. 116). The elevation of 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. 9) or heat stroke (Chap. 7).

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. The microbiology laboratory must be an ally in the diagnostic endeavor. Astute laboratory personnel will suggest optimal culture and transport conditions or alternative tests to facilitate diagnosis. If informed about specific potential pathogens, an alert laboratory staff will allow sufficient time for these organisms to become evident in culture, even when the organisms are present in small numbers or are slow-growing. The parasitology technician who is attuned to the specific diagnostic considerations relevant to a particular case may be able to detect the rare, otherwise-elusive egg or cyst in a stool specimen. In cases where a diagnosis appears difficult, serum should be stored during the early acute phase of the illness so that a diagnostic rise in titer of antibody to a specific pathogen can be detected later. Bacterial and fungal antigens can sometimes be detected in body fluids, even when cultures are negative or are rendered sterile by antibiotic therapy. Techniques such as the polymerase chain reaction allow the amplification of specific DNA sequences so that minute quantities of foreign nucleic acids can be recognized in host specimens.   

Treatment
Optimal therapy for infectious diseases requires a broad knowledge of medicine and careful clinical judgment. Life-threatening infections such as bacterial meningitis or sepsis, viral encephalitis, or falciparum malaria must be treated immediately, often before a specific causative organism is identified.Antimicrobial agents must be chosen empirically and must be active against the range of potential infectious agents consistent with the clinical scenario. In contrast, good clinical judgment sometimes dictates withholding of antimicrobial drugs in a self-limited process or until a specific diagnosis is made.The dictum primum non nocere should be adhered to, and it should be remembered that all antimicrobial agents carry a risk (and a cost) to the patient. Direct toxicity may be encountered—e.g., ototoxicity due to aminoglycosides, lipodystrophy due to antiretroviral agents, and hepatotoxicity due to antituberculous agents such as isoniazid and rifampin. Allergic reactions are common and can be serious. Since superinfection sometimes follows the eradication of the normal flora and colonization by a resistant organism, one invariant principle is that infectious disease therapy should be directed toward as narrow a spectrum of infectious agents as possible.Treatment specific for the pathogen should result in as little perturbation as possible of the host’s microflora. Indeed, future therapeutic agents may act not by killing a microbe, but by interfering with one or more of its virulence factors. With few exceptions, abscesses require surgical or percutaneous drainage for cure. Foreign bodies, including medical devices, must generally be removed in order to eliminate an infection of the device or of the adjacent tissue. Other infections, such as necrotizing fasciitis, peritonitis due to a perforated organ, gas gangrene, and chronic osteomyelitis, require surgery as the primary means of cure; in these conditions, antibiotics play only an adjunctive role. The role of immunomodulators in the management of infectious diseases has received increasing attention. Glucocorticoids have been shown to be of benefit in the adjunctive treatment of bacterial meningitis and in therapy for Pneumocystis pneumonia in patients with AIDS. The use of these agents in other infectious processes remains less clear and in some cases (in cerebral malaria, for example) is detrimental. Activated protein C (drotrecogin alfa, activated) is the first immunomodulatory agent widely available for the treatment of severe sepsis. Its usefulness demonstrates the interrelatedness of the clotting cascade and systemic immunity. Other agents that modulate the immune response include prostaglandin inhibitors, specific lymphokines, and tumor necrosis factor inhibitors. Specific antibody therapy plays a role in the treatment and prevention of many diseases. Specific immunoglobulins have long been known to prevent the development of symptomatic rabies and tetanus. More recently, CMV immune globulin has been recognized as important not only in preventing the transmission of the virus during organ transplantation, but also in treating CMV pneumonia in bone marrow transplant recipients. There is a strong need for well-designed clinical trials to evaluate each new interventional modality. 

PERSPECTIVE
The genetic simplicity of many infectious agents allows them to undergo rapid evolution and to develop selective advantages that result in constant variation in the clinical manifestations of infection. Moreover, changes in the environment and the host can predispose new populations to a particular infection.The dramatic march of West Nile virus from a single focus in New York City in 1999 to locations throughout the North American continent by the summer of 2002 caused widespread alarm, illustrating the fear that new plagues induce in the human psyche.The intentional release of deadly spores of Bacillus anthracis via the U.S. Postal Service awakened many from a sense of complacency regarding biologic weapons. “The terror of the unknown is seldom better displayed than by the response of a population to the appearance of an epidemic, particularly when the epidemic strikes without apparent cause.” Edward H. Kass made this statement in 1977 in reference to the newly discovered Legionnaire’s disease, but it could apply equally to SARS, H5N1 (avian) influenza, or any other new and mysterious disease. The potential for infectious agents to emerge in novel and unexpected ways requires that physicians and public health officials be knowledgeable, vigilant, and open-minded in their approach to unexplained illness. The emergence of antimicrobialresistant pathogens (e.g., enterococci that are resistant to all known antimicrobial agents and cause infections that are essentially untreatable) has led some to conclude that we are entering the “postantibiotic era.” Others have held to the perception that infectious diseases no longer represent as serious a concern to world health as they once did. The progress that science, medicine, and society as a whole have made in combating these maladies is impressive, and it is ironic that, as we stand on the threshold of an understanding of the most basic biology of the microbe, infectious diseases are posing renewed problems.We are threatened by the appearance of new diseases such as SARS, hepatitis C, and Ebola virus infection and by the reemergence of old foes such as tuberculosis, cholera, plague, and Streptococcus pyogenes infection. True students of infectious diseases were perhaps less surprised than anyone else by these developments. Those who know pathogens are aware of their incredible adaptability and diversity. As ingenious and successful as therapeutic approaches may be, our ability to develop methods to counter infectious agents so far has not matched the myriad strategies employed by the sea of microbes that surrounds us.Their sheer numbers and the rate at which they can evolve are daunting. Moreover, environmental changes, rapid global travel, population movements, and medicine itself—through its use of antibiotics and immunosuppressive agents—all increase the impact of infectious diseases. Although new vaccines, new antibiotics, improved global communication, and new modalities for treating and preventing infection will be developed, pathogenic microbes will continue to develop new strategies of their own, presenting us with an unending and dynamic challenge.