Necrotizing fasciitis (streptococcal gangrene)—There is extensive and very rapidly spreading necrosis of the skin, tissues, and fascia. Bacteria other than S. pyogenes can also cause necrotizing fasciitis. The group A streptococci that cause necrotizing fasciitis have sometimes been termed flesh-eating bacteria.

Beta-hemolytic streptococci are also referred to as pyogenic streptococci, which include the human-pathogenic species S. pyogenes, S. agalactiae, and S. dysgalactiae

A. Hemolysis ++ Many streptococci are able to hemolyze red blood cells in vitro in varying degrees. Complete disruption of erythrocytes with clearing of the blood around the bacterial growth is called β-hemolysis. Incomplete lysis of erythrocytes with reduction of hemoglobin and the formation of green pigment is called α-hemolysis. Other streptococci are nonhemolytic (sometimes called γ- hemolysis).

he classification of streptococci into major categories has been based on a series of observations over many years: (1) colony morphology and hemolytic reactions on blood agar, (2) serologic specificity of the cell wall group-specific substance (Lancefield antigens) and other cell wall or capsular antigens, (3) biochemical reactions and resistance to physical and chemical factors, and (4) ecologic features. More recently, molecular genetics have replaced phenotypic methods in the taxonomic assignment of these organisms.

he streptococci, enterococci, and related organisms are Gram-positive spherical bacteria that characteristically form pairs or chains during growth. They are widely distributed in nature. Some are members of the normal human microbiota; others are associated with important human diseases attributable to the direct effects of infection or in other cases to an immunologic response to them. Streptococci elaborate a variety of extracellular substances and enzymes.

The streptococci, enterococci, and related organisms are Gram-positive spherical bacteria that characteristically form pairs or chains during growth

Microbiology is the study of microorganisms, a large and diverse group of microscopic organisms that exist as single cells or cell clusters; it also includes viruses, which are microscopic but not cellular.

mmuno-responsive cells are found throughout the body in the circulation or at fixed locations in tissues. They are concentrated in the lymph nodes and spleen, and form a unified filtration network designed as a sentinel warning system. In the lymphoid series, cells destined to become T cells mature in the thymus (the source of their name). Thus, the thymus, spleen, and lymph nodes might be thought of as the organs of the immune system. These are collectively referred to as the lymphoid tissues.

Macrophages are found in the circulation and tissues, where they are sometimes given regional names such as alveolar macrophage. They possess surface receptors rich in mannose and fructose, which nonspecifically recognize components commonly found on pathogens and more specialized receptors able to recognize unique components of microbes such as the LPS of Gram-negative bacteria. They also have receptors that recognize antibody and complement.

Innate immunity acts through a series of specific and nonspecific mechanisms, all working to create a series of hurdles for the pathogen to navigate (Table 2–1). The first are mechanical barriers such as the tough multilayered skin or the softer but fused mucosal layers of internal surfaces. As discussed in Chapter 1, the microbiota on these surfaces present formidable competition for space and nutrients. Turbulent movement of the mucosal surfaces and enzymes or acid secreted on their surface make it difficult for an organism to efficiently colonize. Organisms that are able to pass the mucosa encounter a population of cells with the ability to engulf and destroy them. In addition, body fluids contain chemical agents such as complement, which can directly injure the microbe. The entire process has cross-links to the adaptive immune system. The endpoint of phagocytosis and digestion in a macrophage is the presentation of the antigen on its surface, the first step in specific immune recognition.

Infectious diseases remain as important and fascinating as ever. Where else do we find the emergence of new diseases, together with improved understanding of the old ones? At a time when the revolution in molecular biology and genetics has brought us to the threshold of new and novel means of infection control, the perpetrators of bioterrorism threaten us with diseases we have already conquered. Meeting this challenge requires a secure knowledge of the pathogenic organisms and how they produce disease, as well as an understanding of the clinical aspects of these diseases. In the collective judgment of the authors, this book presents the principles and facts required for students of medicine to understand the most important infectious diseases.

Fever, pain, and swelling are the universal signs of infection. Beyond this, the particular organs involved and the speed of the process dominate the signs and symptoms of disease. Cough, diarrhea, and mental confusion represent disruption of three different body systems. On the basis of clinical experience, physicians have become familiar with the range of behavior of the major pathogens. However, signs and symptoms overlap considerably. Skilled physicians use this knowledge to begin a deductive process leading to a list of suspected pathogens and a strategy to make a specific diagnosis and provide patient care.

he primary reason pathogens are so few in relation to the microbial world is that being successful at producing disease is a very complicated process. Multiple features, called virulence factors, are required to persist, cause disease, and escape to repeat the cycle. The variations are many, but the mechanisms used by many pathogens have now been dissected at the molecular level.

We are currently witnessing a new and extended Covid-19 pandemic, but the prospect of recurrence of old pandemic infections (influenza, cholera) remains. Modern times and technology have introduced new wrinkles to epidemiologic spread. Air travel has allowed diseases to leap continents even when they have very short incubation periods. The efficiency of the food industry has sometimes backfired when the distributed products are contaminated with infectious agents. The outbreaks of hamburger-associated E coli O157:H7 bloody diarrhea and hemolytic uremic syndrome are examples. The nature of massive meat-packing facilities allowed organisms from infected cattle on isolated farms to be mixed with other meat and distributed rapidly and widely

Among pathogens, there are degrees of potency called virulence, which sometimes makes drawing the dividing line between benign and virulent microorganisms difficult. Pathogens are associated with disease with varying frequency and severity. Yersinia pestis, the cause of plague, causes fulminant disease and death in 50% to 75% of persons who come in contact with it. Therefore, it is highly virulent. Understanding the basis of these differences in virulence is a fundamental goal of this book. The better students of medicine understand how a pathogen causes disease, the better they will be prepared to intervene and help their patients.

The field of probiotics is based on the notion that we can manipulate the microbiota by promoting colonization with “good” bacteria. Elie Metchnikoff originally suggested this in his observation that the longevity of Bulgarian peasants was attributable to their consumption of large amounts of yogurt; the live lactobacilli in the yogurt presumably replaced the colonic flora to the general benefit of their health. This notion persists today in capsules containing freeze-dried lactobacilli sold by the sizable probiotics industry and by promotion of the health benefit of natural (unpasteurized) yogurt, which contains live lactobacilli.

Many species among the microbiota are opportunists in that they can cause infection when they reach protected areas of the body in sufficient numbers. For example, certain strains of E coli can reach the urinary bladder by ascending the urethra and cause acute urinary tract infection. Perforation of the colon from a ruptured diverticulum or a penetrating abdominal wound releases feces into the peritoneal cavity; this contamination may be followed by peritonitis or intraabdominal abscesses caused by members of the flora which have virulence factors allowing them to exploit this situation. There are now examples of the microbiota supplying a step in the pathogenesis of a classic pathogen. Attachment of Neisseria gonorrhoeae to the cervix has been shown to be enhanced when an enzyme produced by the cervicovaginal microbiota unmasks a crucial receptor. Caries and periodontal disease are caused by organisms that are members of the oral microbiota

Organisms of the microbiota may have a symbiotic relationship that benefits the host or may simply live as commensals with a neutral relationship to the host. A parasitic relationship that injures the host would not be considered “normal,” but, in most instances, not enough is known about the organism–host interactions to make such distinctions. Some have been characterized by genomic methods but not yet grown in culture. Like houseguests, the members of the microbiota may stay for highly variable periods. Residents are strains that have an established niche at one of the many body sites, which they occupy indefinitely. Transients are acquired from the environment and establish themselves briefly, but they tend to be excluded by competition from residents or by the host’s innate or immune defense mechanisms. The term carrier state is used when organisms known to be potentially pathogenic are involved, although its implication of risk is not always justified. For example, Streptococcus pneumoniae, a cause of pneumonia, and Neisseria meningitidis, a cause of meningitis, may be isolated from the throat of 5% to 40% of healthy people. Whether these bacteria represent transient flora, resident flora, or carrier state is largely semantic. The possibility that their presence could be the prelude to disease is presently impossible to determine in advance.

They range from unicellular amoebas of 10 to 12 μm to multicellular tapeworms 1 m long. The individual cell plan is eukaryotic, but organisms such as worms are highly differentiated and have their own organ systems. Most worms have a microscopic egg or larval stage, and part of their life cycle may involve multiple vertebrate and invertebrate hosts. Most parasites are free living, but some depend on combinations of animal, arthropod, or crustacean hosts for their survival.

The smallest of yeasts are similar in size to bacteria, but most are larger (2-12 μm) and multiply by budding. Molds form tubular extensions called hyphae, which, when linked together in a branched network, form the fuzzy structure seen on neglected bread slices. Fungi are eukaryotic, and both yeasts and molds have a rigid external cell wall composed of their own unique polymers, called glucan, mannan, and chitin. Their genome may exist in a diploid or haploid state and replicate by meiosis or simple mitosis.

Bacteria are the smallest (0.1-0 μm) independently living agents known. They have a cytoplasmic membrane surrounded by a cell wall; a unique interwoven polymer called peptidoglycan makes the wall rigid. The simple prokaryotic cell plan includes no mitochondria, lysosomes, endoplasmic reticulum, or other organelles (Table 1–2). In fact, most bacteria are approximately the size of mitochondria. Their cytoplasm contains only ribosomes and a single, double-stranded DNA chromosome. Bacteria have no nucleus, but all the chemical elements of nucleic acid and protein synthesis are present. Although their nutritional requirements vary greatly, most bacteria are free living if given an appropriate energy source. Tiny metabolic factories, they divide by binary fission and can be grown in artificial culture, producing progeny sometimes in a matter of hours. The Archaea are similar to bacteria but evolutionarily distinct. They are prokaryotic, but they differ in the chemical structure of their cell walls and other features. The Archaea (archebacteria) can live in environments humans c

Viruses are strict intracellular parasites of other living cells, not only of mammalian and plant cells but also of simple unicellular organisms, including bacteria (the bacteriophages). Viruses are simple forms of replicating, biologically active particles that carry genetic information in either DNA or RNA molecules. Most mature viruses have a protein coat over their nucleic acid and, sometimes, a lipid surface membrane derived from the cell they infect. Because viruses lack the protein-synthesizing enzymes and structural apparatus necessary for their own replication, they bear essentially no resemblance to a true eukaryotic or prokaryotic cell.

Like houseguests, the members of the microbiota may stay for highly variable periods. Residents are strains that have an established niche at one of the many body sites, which they occupy indefinitely. Transients are acquired from the environment and establish themselves briefly, but they tend to be excluded by competition from residents or by the host’s innate or immune defense mechanisms. The term carrier state is used when organisms known to be potentially pathogenic are involved, although its implication of risk is not always justified. For example, Streptococcus pneumoniae, a cause of pneumonia, and Neisseria meningitidis, a cause of meningitis, may be isolated from the throat of 5% to 40% of healthy people. W

either directly or by contact with a staff member. This additional risk is managed by the techniques of isolation, which place barriers between the infected patient and others on the ward. Because not every infected patient presents with suspect signs and/or symptoms, some precautions should be taken with all patients. In the system recommended by the Centers for Disease Control and Prevention, these are called standard precautions and include the use of gowns and gloves when in contact with patient blood or secretions. These are particularly directed at protecting healthcare workers from HIV and hepatitis infection. For those with suspected or proven infection, additional precautions are taken, the nature of which is determined by the known mode of transmission of the organism. These transmission-based precautions are divided into those directed at airborne, droplet, and contact routes. The airborne transmission precautions are for infections known to be transmitted by extremely small (<5 μm) particles suspended in the air. This requires that the room air circulation be maintained with negative pressure relative to the surrounding area and be exhausted to the outside. Those entering the room must wear surgical masks, and in the case of tuberculosis, specially designed respirators. Droplet precautions are for infections in which the organisms are suspended in larger droplets, which may be airborne, but generally do not travel more than 3 ft from the patient who generates them. These can be contained by the use of

Manipulations ranging from phlebotomy and hemodialysis to surgery carry the varying risks of blood containing an infectious agent reaching mucous membranes or skin of the healthcare worker. The major agents transmitted in this manner are hepatitis B, hepatitis C, and HIV. Control requires meticulous attention to procedures that prevent direct contact with blood, such as the use of gloves, eyewear, and gowns. Cuts and needle sticks among healthcare workers carry a risk approaching 2%. Identification of hepatitis virus and HIV carriers is a part of a protective process that must be balanced by patient privacy considerations. Healthcare facilities all have established policies concerning serologic surveillance of patients and the procedures to follow (eg, testing, prophylaxis) when blood-related accidents occur. Similarly, products for transfusion undergo extensive screening to protect the recipient.

These sites should always be suspected as a source of organisms whenever blood cultures are positive with no apparent primary site for the bacteremia. Contamination at the insertion site is generally staphylococcal, with continued growth in the catheter tip. Organisms may gain access somewhere in the lines, valves, bags, or bottles of intravenous solutions proximal to the insertion site. The latter circumstance usually involves Gram-negative rods. Preventive measures include aseptic insertion technique and appropriate care of the lines, including changes at regular intervals.

. Detailed studies of catheters and similar devices show that the risk of infection begins to increase after 24 to 48 hours of use and is cumulative even if the device is changed or disinfected at intervals.

Environmental contamination is relatively unimportant M tuberculosis and Legionella are risks

Cross-infection is usually by direct contact ❋ Infected medical attendants are particularly dangerous ++ Infection from carriers can transmit to patients

Hospital Personnel ++ Physicians, nurses, students, therapists, and any others who come in contact with the patient may transmit infection. Transmission from one patient to another is called cross-infection. The vehicle of transmission is most often the inadequately washed hands of a medical attendant. Another source is the actively infected medical attendant. Many hospital outbreaks have been traced to hospital personnel, particularly physicians, who continue to care for patients despite an overt infection. Transmission is usually by direct contact, although airborne

Infections occurring during any hospitalization could be either community-acquired or nosocomial. Community-acquired infections are defined as those present or incubating at the time of hospital admission. All others are considered nosocomial. For example, a hospital case of chickenpox could be community-acquired if it erupted on the fifth hospital day (incubating) or nosocomial if hospitalization was beyond the limits of the known incubation period (20 days). Infections appearing shortly after discharge (2 weeks) are considered nosocomial, although some could have been acquired at home. Infectious hazards are inherent to the hospital environment; it is there that the most seriously infected and most susceptible patients are housed and often cared for by the same staff.

Disinfection is a less precise term. It implies the destruction of pathogenic microorganisms by processes that fail to meet the criteria for sterilization. Pasteurization is a form of disinfection, but the term is most commonly applied to the use of liquid chemical agents known as disinfectants, which usually have some degree of selectivity. Bacterial spores, organisms with waxy coats (eg, mycobacteria), and some viruses may show considerable resistance to the common disinfectants. Antiseptics are disinfecting agents that can be used on body surfaces, such as the skin or vaginal tract, to reduce the numbers of pathogenic agents in the local microbiota. They have lower toxicity than disinfectants used environmentally, but are usually less active in killing vegetative organisms. ...

Pasteurization is the use of heat at a temperature sufficient to inactivate important pathogenic organisms in liquids such as water or milk, but at a temperature lower than that needed to ensure sterilization. For example, heating milk at a temperature of 74°C for 3 to 5 seconds or 62°C for 30 minutes kills the vegetative forms of most pathogenic bacteria that may be present without altering its quality. Obviously, spores are not killed at these temperatures. ++ ❋ Pasteurization uses heat to kill vegetative forms of bacteria

Sterilization is an absolute term. It means complete killing, or removal, of all living organisms from a particular location or material. It can be accomplished by incineration, nondestructive heat treatment, certain gases, exposure to ionizing radiation, some liquid chemicals, and filtration.

Death/killing as it relates to microbial organisms is defined in terms of how we detect them in culture. Operationally, it is a loss of ability to multiply under any known conditions. This is complicated by the fact that organisms that appear to be irreversibly inactivated may, sometimes, recover when appropriately treated. For example, ultraviolet (UV) irradiation of bacteria can result in the formation of thymine dimers in the DNA with loss of ability to replicate. A period of exposure to visible light may then activate an enzyme that breaks the dimers and restores viability by a process known as photoreactivation. In addition, mechanisms exist for repair of the damage without light. Such considerations are of great significance in the preparation of safe vaccines from inactivated virulent organisms.

From the time of debates about the germ theory of disease, killing microbes before they reach patients has been a major strategy for preventing infection. In fact, Ignaz Semmelweis successfully applied disinfection principles decades before bacteria were first isolated. This chapter discusses the most important methods used for this purpose in modern medical practice. Understanding how these methods work has become of increasing importance in an environment that includes immunocompromised patients, transplantation, indwelling devices, and Covid-19.

Enzyme immunoassay (EIA) or enzyme-linked immunoassay (ELISA) ++ These methods are more suitable for liquid phase assays and are amenable to batch testing and automated methods. They are also used in direct and indirect methods and many other ingenious variations such as the “sandwich” methods, so called because the antigen of interest is “trapped” between two antibodies (Figure 4–7). These extremely sensitive techniques are discussed further with regard to antibody detection. Related and complementary techniques used in surgical pathology are immunohistochemistry and immunoperoxidase methods (Figure 40–1). They can be a powerful adjunct to molecular methods, especially for viral pathogens in severely immunocompromised patients (eg, those after solid organ or bone marrow transplantation).

Features Used to Classify Bacteria and Fungi +++ Cultural Characteristics ++ Cultural characteristics include the demonstration of properties such as unique nutritional requirements, pigment production, and the ability to grow in the presence of certain substances (sodium chloride, bile) or on certain media (MacConkey, nutrient agar). Demonstration of the ability to grow at a particular temperature or to cause hemolysis on blood agar plates is also used. For fungi, growth as a yeast colony or a mold is the primary separator. For molds, the morphology of the mold structures (hyphae, conidia, etc.) is the primary means of identification.

heat

The differential staining procedure described in 1884 by the Danish physician Hans Christian Gram has proved one of the most useful in microbiology and medicine. The procedure (Figure 4–2A) involves the application of a solution of iodine in potassium iodide to cells previously stained with an acridine dye, such as crystal violet. This treatment produces a mordanting action in which purple insoluble complexes are formed with ribonuclear protein in the cell. The difference between Gram-positive and Gram-negative bacteria is in the permeability of the cell wall to these complexes on treatment with mixtures of acetone and alcohol solvents. This extracts the purple iodine-dye complexes from Gram-negative cells, whereas Gram-positive bacteria retain them. An intact cell wall is necessary for a positive reaction, and Gram-positive bacteria may fail to retain the stain if the organisms are old, dead, or damaged by antimicrobial agents. The stain is completed by the addition of a red counter-stain such as safranin, which is taken up by bacteria that have been decolorized. Thus, cells stained purple are Gram positive, and those stained red are Gram negative.

Specimens should be transported to the laboratory as soon after collection as possible because some microorganisms survive only briefly outside the body. In contrast, some bacteria survive well and may even multiply after the specimen is collected. The growth of enteric Gram-negative rods in specimens awaiting culture may, in fact, compromise specimen interpretation or interfere with the isolation of more fastidious organisms. Significant changes are associated with delays of more than 3 to 4 hours.

e sterile swab is often used for specimen collection; however, it provides the poorest conditions for survival of bacterial pathogens, can only absorb a small volume of inflammatory exudate, and is easily contaminated with adjacent microbiota. The worst possible specimen is a dried-out swab; the best is a collection of 5 to 10 mL or more of the infected fluid or tissue when possible. The volume is important because infecting organisms that are present in small numbers may not be detected in a small sample. Throat swabs suffice for detection of group A streptococci by culture or antigen testing. Multiplex panels targeting respiratory viruses are validated for use with special (flocked) nasopharyngeal (NP) swabs, because these swabs collect some host epithelial cells in which the pathogenic viruses grow and thereby increase sensitivity of detection.

Frequently, the primary site of infection is in an area known to be colonized with many organisms (pharynx and large intestine) (Figure 4–1C). This is primarily an issue with bacterial diagnosis because they dominate the makeup of the microbiota. In such instances, examinations are made selectively for organisms known to cause infection that are not normally found at the infected site. For example, the enteric pathogens Salmonella, Shigella, and Campylobacter may be sought selectively in a stool specimen or only β-hemolytic streptococci in a throat culture. In these instances, selective media that inhibit growth of the other bacteria are used or, if growing, they are simply ignored. Molecular methods that target the specific pathogens in these specimens are becoming more widely used in place of the selective cultures.

Indirect Samples ++ Indirect samples (Figure 4–1B) are specimens of inflammatory exudates (expectorated sputum, voided urine) that have passed through sites known to be colonized with the resident microbiota. The site of origin is usually sterile in healthy persons; however, some assessment of the probability of contamination with resident microbiota during collection is necessary in interpretation of the results. This assessment requires knowledge of the potential contaminating flora as well as the probable pathogens to be sought. Indirect samples are usually more convenient for both physician and patient, but carry a higher risk of misinterpretation. For some specimens, such as expectorated sputum, guidelines to assess specimen quality have been developed by correlation of clinical and microbiologic findings.

Direct Tissue or Fluid Samples ++ Direct specimens (Figure 4–1A) are collected from normally sterile tissues (lung, liver) and body fluids (cerebrospinal fluid, blood). The methods range from needle aspiration of an abscess to surgical biopsy. In general, such collections require the direct involvement of a physician and may carry some risk for the patient. The results are always useful because positive findings are diagnostic and negative findings can exclude infection at the suspected site.

The primary connection between the clinical encounter and the diagnostic laboratory is the specimen submitted for processing. If it is not appropriately chosen and/or collected, no degree of laboratory skill can rectify the error. Failure at the level of specimen collection is the most common reason for failing to establish an etiologic diagnosis, or worse, for suggesting a wrong diagnosis. In the case of bacterial infections, the primary problem lies in distinguishing resident or contaminating normal floral organisms from those causing the infection. The three specimen categories illustrated in Figure 4–1A-C are discussed in the text that follows.

Predictive value of a test is determined by its sensitivity and specificity and the prevalence of disease in a population or the likelihood thereof in a patient based on the history, clinical findings, and epidemiology of the infectious disease agent being considered. The more sensitive a test, the greater its negative predictive value (NPV), thus a patient with a negative test is very unlikely to have the disease. A positive result with a more specific test makes a diagnosis more likely or has a higher positive predictive value (PPV) and basically confirms an etiologic diagnosis. When the prevalence of a disease is exceedingly low or the likelihood is virtually nil based on the history, clinical findings, and epidemiology, even tests with high sensitivity and specificity may have a low PPV. This reality highlights the ...

❋ Clinical diagnosis guides approach to etiologic diagnosis ++ Behind every clinical specimen submitted to the diagnostic laboratory should be a question. Does my patient have, can I exclude, does the result confirm the disease? Answers to such questions depend on understanding, whether articulated specifically or not, the characteristics of the tests ordered and performed. These characteristics are sensitivity (the test’s ability to rule out [snout] a disease because there are few false-negative results and thus fewer cases missed) and specificity (the test’s ability to rule in [spin] or confirm an etiology because there are few false-positive results). Ideally, a test would have both excellent sensitivity and specificity, but traditional methods often involved a trade-off between the two, which only emphasizes the need to know the clinical question or reason for ordering a test. Molecular methods, however, tend to have improved sensitivity as well as specificity, which is dramatically so for viral etiologic diagnoses. ++ ❋ Sensitivity is capacity of test to rule OUT a diagnosis ❋ Specificity is ability of test to rule IN or confirm diagnosis

The diagnosis of a microbial infection begins with an assessment of the clinical and epidemiologic features and formulation of a diagnostic hypothesis. Anatomic localization of the infection depends on physical and radiologic findings (eg, right lower lobe pneumonia, subphrenic abscess). This clinical diagnosis suggests a number of possible etiologic agents based on knowledge of infectious syndromes and their courses. The specific cause or etiologic diagnosis is then established by the application of methods described in this chapter. A combination of science and art on the part of both the clinician and laboratory worker is required: The clinician must select the appropriate tests and specimens to be processed and, where appropriate, suggest the suspected etiologic agents to the laboratory. The laboratory scientist must use the methods that will demonstrate the probable agents and be prepared to explore other possibilities suggested by the clinical situation or by the findings of the laboratory examinations. The best results are obtained when communication between the clinician and laboratory is optimal.

Epidemiology, the study of the distribution and determinants of disease, is critical for recognition and control of emerging infectious diseases. Emerging infectious diseases are those that are increasing in incidence, whether due to the appearance of a new agent, pattern of resistance, or geographic spread. Communicable diseases differ from noncommunicable diseases in their propensity to cause both endemic disease and pandemics. Infections may be clinically inapparent or may cause disease. Those with subclinical disease can be important propagators of the infectious agent. Transmission can be vertical (mother to fetus or infant) or horizontal (direct or indirect person to person). Routes of horizontal transmission include respiratory, salivary, eye, skin, genital, fecal-oral, bloodborne, and vector-borne or zoonotic. The propensity for epidemic spread of an infection depends on agent, host, and environmental factors. Surveillance is a key to recognition and thereby to control. ++ Epidemiologic study is essential to identify, characterize, and control infectious diseases. Combating emerging infections requires recognizing new agents and patterns of disease, understanding their nature and spread, and then instituting control measures. The latter may involve prompt treatment of cases, prevention through selective chemoprophylaxis or immunization, implementation of environmental controls, and public education, depending on the specific agent. However, application of epidemiologic principles is essential for the health of both individuals and communities.

rolonged and extensive exposure to a pathogen during previous generations selects for a higher degree of innate genetic immunity in a population. For example, extensive exposure of Western urbanized populations to tuberculosis during the 18th and 19th centuries conferred a degree of resistance greater than that among the progeny of rural or geographically isolated populations. The disease spread rapidly and in severe form, for example, when it was first encountered by Native Americans. An even more dramatic example concerns the resistance to the most serious form of malaria that is conferred on people of West African descent by the sickle cell trait. These instances are clear cases of natural selection—a process that accounts for many differences in immunity in different races and populations. ++ ❋ Immunity in population influences spread ++ Occasionally, an epidemic arises from an agent for which immunity is essentially absent in a population, is of enhanced virulence, or appears to be of enhanced virulence because of the lack of immunity. When such an organism is highly infectious, the disease caused may become pandemic and worldwide. An example is the appearance of a new major antigenic variant of influenza A virus against which there is little, if any, cross-immunity from recent epidemics with other strains. The 1918 to 1919 pandemic of influenza was responsible for more deaths than World War I (>20 million). Subsequent, but less serious, pandemics have occurred periodically owing to the development of strains of influenza virus with major antigenic shifts (see Chapter 9). Another example, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), illustrates the same principles but also reflects changes in human ecologic and social behavior. ++ ❋ Sudden appearance of “new” agents can result in pandemic spread ++ A major feature of serious epidemic diseases is their frequent association with poverty, malnutrition, disaster, and war. The association is multifactorial and includes overcrowding, contaminated food and water, an increase in arthropod vectors, and the reduced immunity that can accompany severe malnutrition and overwhelming stress. Overcrowding and understaffing in day-care centers or institutions for the mentally impaired, the aged, or the infirmed can similarly be associated with epidemics of infections, such as C difficile and, more recently, COVID-19. ++ Social, ecologic factors determine epidemic aspects ++ In recent years, increasing attention has been given to healthcare-associated infections, including central-line-associated bloodstream infections, catheter-associated urinary tract infections, and ventilator-associated pneumonia that are associated in turn with intravascular catheters and intraurethral or intratracheal tubes. Unusually susceptible institutionalized individuals (whether because of age, chronic disease, or immunosuppressive therapy) are also at increased mortality when exposed to infected individuals from the community. Societal injustices are amplified in the setting of a pandemic, wherein those more susceptible often are also more vulnerable. As an example, non-Hispanic persons of American Indian, Alaska Native, Asian, and African American heritage, as well as Hispanic or Latino persons, have higher rates of infection, hospitalization, and death from COVID-19 compared with White, non-Hispanic Americans. Race and ethnicity are risk markers for multiple underlying conditions that impact health, including socioeconomic status, access to care, and increased exposure due to occupation (eg, frontline, essential, and critical infrastructure workers) or living conditions (crowded with close physical contact). Furthermore, despite scientific evidence, persons in positions of authority across the globe have not uniformly reinforced public health measures. ++ Healthcare-associated infections include nosocomial/hospital-acquired +++ Control of Epidemics ++ The first principle of control is recognition of the existence of an epidemic. This recognition is sometimes immediate because of the high incidence of disease but, often, the evidence is obtained from ongoing surveillance activities, such as routine disease reports to health departments and records of school and work absenteeism. The causative agent must be identified, and studies to determine route of transmission (eg, food poisoning) must be initiated. ++ Surveillance key to recognition of an epidemic ++ Measures must then be adopted to control the spread and development of further infection. These methods include: (1) blocking the route of transmission, if possible (eg, improved food hygiene, arthropod control, or masks/handwashing/physical distancing); (2) identifying, treating, and, if necessary, isolating infected individuals and carriers (quarantine); (3) raising the level of immunity in the uninfected population by immunization when vaccines are available; (4) making selective use of chemoprophylaxis for subjects or populations at particular risk of infection, as in epidemics of meningococcal infection; and (5) correcting conditions such as overcrowding or contaminated water supplies that have led to the epidemic or facilitated transfer. ++ Control measures can vary widely + KEY CONCLUSIONS Download Section PDF Listen +++ ++ KEY CONCLUSIONS Epidemiology, the study of the distribution and determinants of disease, is critical for recognition and control of emerging infectious diseases. Emerging infectious diseases are those that are increasing in incidence, whether due to the appearance of a new agent, pattern of resistance, or geographic spread. Communicable diseases differ from noncommunicable diseases in their propensity to cause both endemic disease and pandemics. Infections may be clinically inapparent or may cause disease. Those with subclinical disease can be important propagators of the infectious agent. Transmission can be vertical (mother to fetus or infant) or horizontal (direct or indirect person to person). Routes of horizontal transmission include respiratory, salivary, eye, skin, genital, fecal-oral, bloodborne, and vector-borne or zoonotic. The propensity for epidemic spread of an infection depends on agent, host, and environmental factors. Surveillance is a key to recognition and thereby to control. ++ Epidemiologic study is essential to identify, characterize, and control infectious diseases. Combating emerging infections requires recognizing new agents and patterns of disease, understanding their nature and spread, and then instituting control measures. The latter may involve prompt treatment of cases, prevention through selective chemoprophylaxis or immunization, implementation of environmental controls, and public education, depending on the specific agent. However, application of epidemiologic principles is essential for the health of both individuals and communities. Pop-up div Successfully Displayed This div only appears when the trigger link is hovered over. Otherwise it is hidden from view. 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Prior exposure of a population to an organism may alter immune status and the frequency of acquisition, severity of clinical disease, and duration of an epidemic. For example, measles is highly infectious and attacks most susceptible members of an exposed population. However, infection gives solid lifelong immunity. Thus, in unimmunized populations in which the disease is maintained in endemic form, epidemics occur at approximately 3-year intervals when a sufficient number of nonimmune hosts has been born to permit rapid transmission between them. When a sufficient immune population is reestablished, epidemic spread is blocked and the

The likelihood and characterization of epidemics and their recognition in a community involve several quantitative measures and some specific epidemiologic definitions. Infectivity, in epidemiologic terms, equates to attack rate and is measured as the frequency with which an infection is transmitted when there is contact between the agent and a susceptible individual. The disease index of an infection can be expressed as the number of persons who develop the disease divided by the total number infected. The virulence of an agent can be estimated as the number of fatal or severe cases per total number of cases. Incidence, the number of new cases of a disease within a specified period, is described as a rate in which the number of cases is the numerator and the number of people in the population under surveillance is the denominator. This is usually normalized to reflect a percentage of the population that is affected. Prevalence, which can also be described as a rate, is primarily used to indicate the total number of cases existing in a population at risk at a point in time. Diseases are more prevalent if they are especially common or less common but persist for a long time.

Classically the term vector was restricted to arthropods like ticks and mosquitoes; however, it is often used to refer to any animal that can transmit a pathogen to a human host. The probability of vector-borne transmission depends on the biology of the vector (mosquito, tick, snail, etc) and the infectivity of organism. ++ ❋ Vectorborne = vectors (e.g., mosquitos, ticks, snails) to humans

Various transmissible infections may be acquired from others by direct contact, indirectly through contaminated inanimate objects or materials, or by aerosol transmission of infectious secretions. Some infections, such as malaria, dengue, and chikungunya, involve an animate insect vector. These routes of spread are often referred to as horizontal transmission, in contrast to vertical or perinatal transmission—from mother to fetus or infant. +++ Vertical or Perinatal Transmission ++ Some infections can spread from mother to fetus through the placenta, during childbirth, or during breastfeeding. For example, rubella virus may cause birth defects when transmitted from the mother’s bloodstream across the placenta during the first trimester of pregnancy. Neonatal infections with group B streptococci, Chlamydia trachomatis, and Neisseria gonorrhoeae can occur following passage through the birth canal. Cytomegalovirus (CMV) can be acquired prenatally (across the placenta) or perinatally (from passage through an infected cervix, contact with blood, or through breast milk).

Zoonotic infections are spread from animals, where they have their natural reservoir, to humans. Some zoonotic infections such as rabies are directly contracted from the bite of the infected animal, whereas others are transmitted by vectors, especially arthropods (eg, ticks, mosquitoes). Many infections contracted by humans from animals are dead-ended in humans, whereas others may be transferred between humans once the disease is established in a population. Plague, for example, has a natural reservoir in rodents. Human infections contracted from the bites of rodent fleas may produce pneumonia, which may then spread to other humans by the respiratory droplet route. Humans can contract Zika virus from the bite of a

The inherent infectivity and virulence of an agent are also important determinants of attack rates of disease in a community. In general, organisms of high infectivity spread more easily, and those of greater virulence are more likely to cause disease than subclinical infection. The infecting dose of an organism also varies with different organisms and, thus, influences the chance of infection and development of disease.

Communicability of a disease in which the organism is shed in secretions may occur primarily during the incubation period. In other infections, the disease course is short but the organisms can be excreted from the host for extended periods. In yet other cases, the symptoms are related to host immune response rather than the organism’s action and, thus, the disease process may extend far beyond the period in which the etiologic agent can be isolated or spread. Some viruses can integrate into the host genome or survive by replicating very slowly in the presence of an immune response. Such dormancy or latency is exemplified by the herpesviruses, and the organism may emerge long after the original infection and potentially infect others.

The incubation period is the time between the exposure to the organism/infection and the appearance of the first clinical manifestations of the disease. Organisms that multiply rapidly and produce local or systemic infections, such as gonorrhea and influenza, are associated with short incubation periods (eg, 2-4 days). Diseases such as typhoid fever, which depend on hematogenous spread and multiplication of the organism in distant target organs to produce symptoms, often have longer incubation periods (eg, 10 days to 3 weeks). Some diseases have even more prolonged incubation periods because of slow passage of the infecting organism to the target organ, as in rabies, or with slow growth of the organism, as in tuberculosis or leprosy. Incubation periods for one agent may also vary widely depending on route of acquisition and infecting dose; for example, the incubation period of hepatitis B virus infection may vary from a few weeks to several months.

An important consideration in the study of the epidemiology of communicable organisms is the distinction between infection and disease. Infection involves multiplication of the organism in or on the host and may be clinically inapparent, such as during the incubation period or latency (when little or no replication is occurring, eg, with herpesviruses). Disease occurs when the infection becomes clinically apparent, that is, there is evidence of injury to the host as a result of the infection. With many communicable organisms, infection is much more common than disease, and asymptomatic infected individuals are important for propagation of the infectious agent. A recent example is Zika infection, which during the most recent epidemic was found to be nearly always clinically inapparent or mild, except for a developing fetus. Inapparent infections are termed subclinical, and the individual is sometimes referred to as a carrier. The latter term is also applied to situations in which an infectious agent establishes itself as part of a patient’s microbiota or causes low-grade chronic disease after an acute infection. For example, the clinically inapparent presence of S aureus in the anterior nares is termed carriage, as is chronic gallbladder infection with Salmonella serotype Typhi that can follow an attack of typhoid fever and result in fecal excretion of the organism for years. C difficile can colonize the gastrointestinal tract but cause severe disease only when associated with the production of a toxin

Communicable infections require an organism to leave the body in a form that is either directly infectious or able to become so after development in a suitable environment. The respiratory spread of influenza virus is an example of direct communicability. In contrast, the malarial parasite requires a developmental cycle in a blood-feeding female anopheline mosquito before it can infect another human. Communicable infections can be endemic, present in the population at a low and constant level, or epidemic, present at a level of infection higher than that usually found in the community or population. With some infections, such as influenza, the infection can be endemic and persist at a low level from season to season; however, introduction of a new strain may result in epidemics, as illustrated in Figure 5–2. Communicable infections that are both widespread, for example, worldwide, and have high attack rates are termed pandemic. Pandemics have occurred throughout history, as illustrated in Figure 5–2, but have become increasingly frequent. Four new pandemics, three viruses with respiratory spread and one transmitted sexually were experienced in the 20th century. Just 20 years into the 21st century, we have now had five new pandemics, the latest and deadliest (SARS-CoV-2) of which has resulted in over 1 million deaths worldwide in its first 6 months and is still far from being controlled.

Infectious diseases of humans may be caused by exclusively human pathogens such as Shigella, by environmental organisms such as Legionella pneumophila, or by organisms that have their primary reservoir in animals such as Salmonella. ++ Noncommunicable infections are those that are not transmitted from human to human and include: (1) infections related to the patient’s microbiota gaining access to a previously sterile site, such as peritonitis after rupture of the appendix; (2) infections caused by the ingestion of preformed toxins, such as botulism; and (3) infections caused by organisms found in the environment, such as clostridial gas gangrene. Some diseases transmitted from animals to humans (zoonotic infections), such as rabies and brucellosis, are not transmitted between humans, but others such as plague may be. Noncommunicable infections may still occur as common-source outbreaks, such as food poisoning from an enterotoxin-producing Staphylococcus aureus–contaminated chicken salad or multiple cases of pneumonia from extensive dissemination of Legionella through an air-conditioning system. Because these diseases are not transmissible to others, they do not lead to secondary spread.

Emerging and resurging infections on the rise globally include bacteria, viruses, and fungi that have outpaced us (antimicrobial resistance); emerging and resurging zoonotic and vector-borne diseases (including those newly emerging with global warming and human encroachment into previously uninhabited areas); global scourges that have eluded vaccine development (malaria and HIV); and infections for which action has trailed science (control measures exist but have not been effectively deployed). Tragically, much of the world has yet to experience the reduction in infectious diseases–related mortality enjoyed by wealthier countries owing to improved sanitation and the development and provision of effective vaccines. Measles has persisted in poor countries and reemerged in wealthy ones when deployment of effective vaccines is inadequate, or acceptance resisted. Control of HIV globally has been stymied not only by lack of a vaccine but also by inability to deploy known preventive measures and provide access to proven therapies. The global distribution of newly emerging and reemerging (resurging) infectious diseases is illustrated in Figure 5–1.

Human and animal demographics and population movement with intrusion into new habitats (particularly tropical forests) Irrigation, especially primitive irrigation systems, which fail to control arthropods and enteric organisms Uncontrolled urbanization, with vector populations breeding in stagnant water Increased international commerce and travel with contact or transport of vectors and pathogens (globalization) Breakdown in public health measures, including sanitation, vector control, immunization programs related to social unrest, civil wars, and major natural disasters Ecological changes, including global climate change and deforestation, with farmers and their animals exposed to new arthropods, floods, and drought Microbial evolution whether related to indiscriminate use of anti-infective agents that leads to selection of multidrug-resistant strains (eg, methicillin-resistant staphylococci or carbapenem-resistant Enterobacteriaceae) or pathogens that mutate readily (eg, virulent strains of influenza A and HIV-1

An emerging disease is an infectious disease whose incidence has increased in the past two decades and/or that threatens to increase soon. Emerging infectious diseases reflect the arrival of a new pathogen (newly emerging) or an old pathogen that is increasing in incidence, clinical or laboratory characteristics, or geographic range (re-emerging or resurging). An unusual third group is “deliberately emerging” infections, such as anthrax bioterrorism. The appearance of novel coronaviruses (eg, the severe acute respiratory syndrome [SARS] coronavirus and now SARS-CoV-2 [the cause of COVID-19]) are examples of new pathogens, multidrug-resistant Mycobacterium tuberculosis represents an old pathogen with new characteristics, and cholera and Zika in the Americas are examples of old pathogens with a new geographic range (Asia to South America). New methods of detection (eg, molecular) and surveillance (eg, global) have greatly improved our ability to detect and characterize emerging and reemerging infectious diseases. The fundamental methodologies of molecular epidemiology are described in Chapter 4, and their specific applications are discussed in many other chapters throughout this book

+++ EMERGING INFECTIOUS DISEASES ++ An emerging disease is an infectious disease whose incidence has increased in the past two decades and/or that threatens to increase soon. Emerging infectious diseases reflect the arrival of a new pathogen (newly emerging) or an old pathogen that is increasing in incidence, clinical or laboratory characteristics, or geographic range (re-emerging or resurging). An unusual third group is “deliberately emerging” infections, such as anthrax bioterrorism. The appearance of novel coronaviruses (eg, the severe acute respiratory syndrome [SARS] coronavirus and now SARS-CoV-2 [the cause of COVID-19]) are examples of new pathogens, multidrug-resistant Mycobacterium tuberculosis represents an old pathogen with new characteristics, and cholera and Zika in the Americas are examples of old pathogens with a new geographic range (Asia to South America). New methods of detection (eg, molecular) and surveillance (eg, global) have greatly improved our ability to detect and characterize emerging and reemerging infectious diseases. The fundamental methodologies of molecular epidemiology are described in Chapter 4, and their specific applications are discussed in many other chapters throughout this book.

Overview Epidemiology is the study of the distribution and determinants of disease, both infectious and noninfectious, and other perturbations in health. Most epidemiologic studies of infectious diseases have focused on the factors that influence acquisition and spread with the goal of identifying methods for prevention and control. Epidemiologic studies have informed public health measures and thereby have been critical to the control of epidemics, such as those due to cholera, plague, smallpox, yellow fever, and typhus. Knowledge of the principles and practice of epidemiology is essential for clinicians (those treating individual patients) and public health practitioners (those focused on the health of the community) alike. Care of patients with suspected infections requires consideration of the likelihood of possible exposures in the community (acquisition) and to the community (spread to others). For example, what infections, especially viral, are currently circulating in the community? Has the patient traveled recently to an area where other infections are present? Is a nosocomial or other healthcare-associated infection possible because the patient has been hospitalized recently or resides in a long-term care facility? Does the patient’s infection pose a risk to his/her family, school- or workmates, or friends?

Human blood cells. Stem cells in the bone marrow divide to form two blood cell lineages: (1) the lymphoid stem cell gives rise to B cells that become antibody-secreting plasma cells, T cells that become activated T cells, and natural killer cells. (2) The common myeloid progenitor cell gives rise to granulocytes and monocytes that give rise to macrophages and dendritic cells. (Reproduced with permission from Willey JM: Prescott, Harley, & Klein’s Microbiology, 7th ed. New York, NY: McGraw Hill; 2008.)

The immune response to infection is presented as two major components—innate immunity and adaptive immunity. The primary effectors of both are cells that are members of the white blood cell series derived from hematopoietic stem cells in the bone marrow (Figure 2–1). Innate immunity includes the role of physical, cellular, and chemical systems that are in place and that respond to all aspects of “foreignness.” These include mucosal barriers, phagocytic cells, and the action of circulating glycoproteins such as complement. The adaptive side is sometimes called specific immunity because it has the ability to develop new responses that are highly specific to molecular components of infectious agents, called antigens. These encounters trigger the development of new cellular responses and production of circulating antibodies, which have a component of memory if the invader returns. Artificially creating this memory is, of course, the goal of vaccines. ++ FIG

his chapter is not intended to fulfill that function, or, indeed, to be a shortened but comprehensive version of those sources. It is included as an overview of aspects related to infection for other students and as an internal reference for topics that reappear in later pages of this book. These include some of the greatest successes of medical science. The early and continuing development of vaccines that prevent and potentially eliminate diseases is but one example. In addition, knowledge of the immune response to infection is integral to understanding the pathogenesis of infectious diseases. It turns out that one of the main attributes of a successful pathogen is evading or confounding the immune system.

Within a very short period immunity has been placed in possession not only of a host of medical ideas of the highest importance, but also of effective means of combating a whole series of maladies of the most formidable nature in man and domestic animals. —Elie Metchnikoff, 1905 ++ The “maladies” Metchnikoff and the other pioneers of immunology were fighting were infections and, for decades, their field was defined in terms of the immune response to infection. We now understand that the immune system is as much a part of everyday human biologic function as the cardiovascular or renal systems. In its adaptive and disordered states, in

The major classes of microorganisms in terms of ascending size and complexity are viruses, bacteria, fungi, and parasites. Parasites exist as single or multicellular structures with the same compartmentalized eukaryotic cell plan of our own cells including a nucleus and cytoplasmic organelles like mitochondria. Fungi are also eukaryotic, but they have a rigid external wall that makes them seem more like plants than animals. Bacteria also have a cell wall, but with a cell plan called “prokaryotic” that lacks the organelles of eukaryotic cells. Viruses are not cells at all. They have a genome and some structural elements, but must take over the machinery of another living cell (eukaryotic or prokaryotic) to replicate. The four classes of infectious agents are summarized in Table 1–1, and generic examples of each are shown in Figure 1–3.

Some microbial species have adapted to a symbiotic relationship with higher forms of life. For example, bacteria that can fix atmospheric nitrogen colonize root systems of legumes and of a few trees, such as alders, and provide the plants with their nitrogen requirements. When these plants die or are plowed under, the fertility of the soil is enhanced by nitrogenous compounds originally derived from the metabolism of the bacteria. Ruminants can use grasses as their prime source of nutrition because the abundant flora of anaerobic bacteria in the rumen break down cellulose and other plant compounds into usable carbohydrates and amino acids. They can synthesize essential nutrients including some amino acids and vitamins. These few examples illustrate the protean nature of microbial life and their essential place in our ecosystem.

Microorganisms are responsible for much of the breakdown and natural recycling of organic material in the environment. Some synthesize nitrogen-containing compounds that contribute to the nutrition of living things that lack this ability; others (oceanic algae) contribute to the atmosphere by producing oxygen through photosynthesis. Because microorganisms have an astounding range of metabolic and energy-yielding abilities, some can exist under conditions that are lethal to other life forms. For example, some bacteria can oxidize inorganic compounds such as sulfur and ammonium ions to generate energy. Others can survive and multiply in hot springs at temperatures higher than 75°C.

Microbiology is a science defined by smallness. Its creation was made possible by the invention of the microscope (Gr. micro, small + skop, to look, see), which allowed visualization of structures too small to see with the naked eye. This definition of microbiology as the study of microscopic living forms still holds if one can accept that some organisms can reproduce only within other cells (eg, all viruses and some bacteria) and that others include macroscopic forms in their life cycle (eg, fungal molds, parasitic worms). The relative sizes of some microorganisms are shown in Figure 1–2. ++ FIGURE 1–2. Relative size of microorganisms. Graphic Jump Location

The science of medical microbiology dates back to the pioneering studies of Pasteur and Koch, who isolated specific agents and proved that they could cause disease by introducing the experimental method. The methods they developed lead to the first golden age of microbiology (1875-1910), when many bacterial diseases and the organisms responsible for them were defined. These efforts, combined with epidemiologic work begun by Semmelweis and Lister, which showed how these diseases spread, led to the great advances in public health that initiated the decline in disease and death. In the first half of the 20th century, scientists studied the structure, physiology, and genetics of microbes in detail and began to answer questions relating to the links between specific microbial properties and disease

Tuberculosis and other forms of pulmonary infection were the leading causes of premature death among the well-to-do and the less fortunate. The terror was due to the fact that, although some of the causes of infection were being discovered, little could be done to prevent or alter the course of disease. In the 20th century, advances in public sanitation and the development of vaccines and antimicrobial agents changed this (Figure 1–1), but only for the nations that can afford these interventions. As we move through the second decade of the 21st century, the world is divided into countries in which heart attacks, cancer, and stroke have surpassed infection as causes of premature death and those in which infection is still the leader. That is, unless there is a pandemic causing infection to again become the leading killer everywhere.

Humanity has but three great enemies: fever, famine, and war