Chapter 13. Infectious Diseases: I. Mechanisms of Tissue Changes in Infection

Infectious diseases have been the most feared diseases of humans because of their ability to affect large numbers of healthy people over a short period of time. Historically, plague (which killed 10% of the population of London in 1665; Table 13-1), smallpox, cholera, and yellow fever (which have killed large numbers of people in the Third World without historical record) have been the great scourges. Other diseases like measles (which killed entire tribes of Pacific Islanders when they were first colonized by Europeans because of their lack of prior exposure), tuberculosis, and malaria have also wreaked havoc. Until this century, childbirth was a great danger to the mother because of puerperal sepsis, and surgery was greatly restricted by the high incidence of postoperative sepsis. Basic discoveries in the past few centuries by Edward Jenner (immunization), Louis Pasteur (sterilization), and Alexander Fleming (antibiotics), as well as our increased understanding of the epidemiology of infectious diseases have led to our ability to control many of these diseases.

However, the battle against infectious agents is still being fought; the only disease successfully eradicated from the world is smallpox. Eradication of other diseases for which effective immunization is available, such as tetanus, measles, whooping cough, diphtheria, and poliomyelitis, is believed feasible by attaining a worldwide immunization rate of over 90%. Concerted efforts to achieve this target have produced dramatic results. The number of deaths worldwide from measles fell from 2.5 million in 1983 to 1.1 million in 1992; those from poliomyelitis fell from 360,000 to 140,000 in the same period. It was anticipated that poliomyelitis would be eradicated from most countries by 1995; however, falling immunization rates led to a significant increase in cases in Southeast Asia in 1993, delaying the target date for eradication. Although their importance as a cause of death (Table 13-1) has declined in the industrialized world, many of these infections are still prevalent in the Third World, where they extract a heavy toll both in human lives and economic hardship (Table 13-2). It has been estimated that over 80% of the children in some populations harbor an intestinal helminth; over 25% of the world's population has at least one helminthic infection. Malaria still kills an estimated 1–2 million people every year; and infectious diarrheas kill 4–6 million people, particularly malnourished children. Immigration from the Third World to industrialized nations has brought with it imported infectious diseases. In the United States, the incidence of tuberculosis is on the increase again. Also increasing in incidence in the United States are sexually transmitted diseases like syphilis, gonorrhea, and chlamydial infections. In the case of gonorrhea, the emergence of strains resistant to penicillin and tetracycline has complicated treatment and control.

While many of the causes of old epidemics have been controlled, new epidemics have emerged. The current epidemic of infection with human immunodeficiency virus (HIV) shows signs of devastating parts of Africa and Asia and is inexorably spreading in Europe and North America.

Transmission & Portals of Entry of Infectious Agents

(Table 13-3)

Successful parasitism requires an infectious agent to be transmitted from one host to another. In general, microorganisms must enter the new host's tissues and proliferate there to cause disease. Organisms such as Clostridium botulinum that produce exotoxin outside the body may cause disease and death without ever entering tissues; while these are considered under infectious diseases because they are caused by microorganisms, they do not satisfy the definition of infection.

The mode of transmission of a given agent depends largely on its portal of entry into the body (Table 13-3). Understanding the method of transmission represents a major method of preventing infectious diseases, eg, recognition that infectious diarrheas result from fecal contamination of food and water led to ensuring safe water supplies and sewage disposal, which has greatly decreased the prevalence of these diseases in industrialized countries. Recognition that malaria is spread by mosquitoes permitted malaria prevention by controlling mosquitoes long before antimalarial drugs became available. With sexually transmitted diseases such as HIV infection, controlling the method of transmission is more complex.

Infectious agents gain access to the body through tissues that are in contact with the external environment, such as the skin, upper respiratory tract, lung, intestine, and genitourinary tract (Table 13-3; Figure 13-1). These are primary portals of entry for infectious agents. Excepting direct inoculation by trauma, internal organs such as the brain, bones, muscle, heart, spleen, and adrenal glands can be infected only through the blood or lymphatics; agents infecting these organs gain access to the body at one of the primary portals of entry.

Similar diseases may have widely different portals of entry and modes of transmission, eg, hepatitis B is transmitted parenterally with entry through the skin, while hepatitis A enters the body in the intestine by fecal contamination of food. The risk factors for acquiring these two types of viral hepatitis and the methods that are needed to prevent them are therefore very different.

Humans encounter many microorganisms every day, but few enter the tissues. Susceptibility to an infectious agent depends on many factors in both the infectious agent and the host (Figure 13-2). Many organisms, usually of low pathogenicity, colonize the skin, upper respiratory tract, lower genitourinary tract, and intestine as normal resident (commensal) flora. These organisms help prevent infection by competing with more virulent organisms for growth factors.

Results of Infection

The entry and multiplication of an infectious agent in a host represents an infection. In a subclinical infection, there is no clinically apparent disease but the body shows evidence of an immune response against the agent, usually by the development of antibodies. In such cases, the host response probably controls the infection rapidly (Figure 13-3). A clinical infectious disease results when tissue damage occurs. Many infectious diseases are acute, with a rapid outcome ending either in complete recovery or death; some progress to chronic disease. The aim of physicians is to influence the natural history of an infectious disease in favor of recovery; this requires accurate diagnosis of the agent that is causing the disease and appropriate treatment when such is available (see Chapter 14: Infectious Diseases: II. Diagnosis of Infectious Diseases).

When infection occurs, the expression of the disease in a given patient can also vary greatly, depending on host factors (Table 13-4). In the majority of infectious diseases, infection is localized to the portal of entry of the agent, eg, streptococcal pharyngitis. In a few cases, organisms enter the lymphatics or the bloodstream and disseminate in the body. The frequency and ease with which a given organism causes disseminated infection is a function of the virulence of the organism and the immune status of the host.

In most infectious diseases, the host develops an immune response (Figure 13-3). This involves both humoral and cellular immunity and is usually beneficial to the host in providing immunity against future infection with the same agent. Immunity against many viruses is lifelong, while that due to bacteria and fungi is more transient. In some cases, the immune response itself results in disease even after the infection has been controlled. The best example of this is streptococcal infection, where the immune response may cause injury to the heart (acute rheumatic fever) and glomeruli (acute poststreptococcal glomerulonephritis). These pathologic events occur without entry of streptococci into the bloodstream or infection of these tissues by streptococci. Poststreptococcal glomerulonephritis is caused by deposition in the glomeruli of soluble immune complexes formed in the blood between streptococcal antigens and antibodies.

Infection of the Bloodstream

Infectious agents may enter the lymphatics and the bloodstream from any infected tissue. In some cases, there may be no sign of clinical disease at the site where the organism gains access to lymphatics or bloodstream—eg, in meningococcal bacteremia, the pharynx, which serves as the portal of entry, is usually normal; in poliomyelitis (a disease of the nervous system), the intestinal site of entry rarely shows clinical evidence of infection.

The presence of microorganisms in the blood (bacteremia, viremia, parasitemia, fungemia) is always abnormal and always of clinical significance. The diagnosis of bacteremia, viremia, and fungemia is established by blood cultures. Parasitemia can frequently be diagnosed by identifying the parasite in blood smears (eg, malaria).

Most bacteremias in clinical practice fall between the extremes of a transient bacteremia and septicemia (severe bacteremia).

Transient Bacteremia

In transient bacteremia, microorganisms are present in small numbers in the bloodstream and do not multiply there because they are rapidly removed by the body's defense mechanisms. This condition is relatively common—as in persons with infected teeth and gums, who may often liberate small numbers of pathogenic agents into the blood during mastication and while brushing their teeth—and does not produce clinical symptoms.

Transient bacteremia may produce disease in the following clinical situations: (1) in immunocompromised hosts, whose immune systems are unable to neutralize the organisms, which may therefore multiply and produce severe disseminated infections; (2) in patients with chronic cardiac valve disease or cardiac prostheses, in whom the organisms are able to grow in damaged or prosthetic valves and whose bacteremia may be complicated by infective endocarditis; and (3) in otherwise normal individuals, when organisms become established in an internal organ and cause infection, eg, viral encephalitis. Why only some individuals develop such infections is unknown.

Severe Bacteremia (Septicemia)

Septicemia is often used synonymously with severe bacteremia to denote a serious infection in which large and increasing numbers of microorganisms have overwhelmed the body's defense systems and are actively multiplying in the bloodstream. Severe bacteremia is associated with toxemia (presence in the blood of bacterial toxins) and is manifested clinically by high fever, chills, tachycardia, and hypotension. Death may result.

This chapter discusses the various classes of infectious agents and the ways in which tissues infected by them are altered. Specific infectious diseases are considered in analytic form in Chapter 14: Infectious Diseases: II. Diagnosis of Infectious Diseases and in detail in the organ system chapters, which explain the functional changes arising from infectious diseases in these organs.

Classification According to Structure

Infectious agents can be arranged in order of increasing structural complexity, beginning with prions and proceeding through viruses, rickettsiae, chlamydiae, mycoplasmas, bacteria, fungi, and protozoa to metazoa (Table 13-5). Protozoa and metazoa are sometimes collectively termed parasites, although the designation parasite is sometimes also used more generally to describe all infectious agents.

Each group of infectious agents can be further subdivided on the basis of several additional classification criteria (Table 13-5). For example, viruses are classified as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) viruses on the basis of the type of nucleic acid in their genomes. Bacteria are classified as cocci, rods (bacilli), spirochetes, and vibrios on the basis of their shape; they are termed gram-positive or gram-negative on the basis of their reaction on Gram staining; and they are called aerobic or anaerobic on the basis of their oxygen requirement for growth. Rickettsiae and chlamydiae are small bacteria that are obligate intracellular parasites. Fungi may be yeasts or molds (mycelial fungi) or may be dimorphic (having both yeast and mold forms). Protozoa and metazoa are classified into genera and species according to structural criteria.

Classification According to Pathogenicity

The ability of an infectious agent to establish itself in tissues is called infectivity, and its ability to cause disease is called pathogenicity. Pathogenic agents can be classified as low-grade or high-grade; the latter are said to be virulent. The distinction is important, because although virulent organisms may readily cause disease in normal people, low-grade pathogens cause disease only in immunocompromised hosts (opportunistic infections). Such individuals lack resistance to various agents that typically do not cause illness in immunocompetent persons.

Classification According to Site of Multiplication

The ability of infectious agents to multiply inside or outside cells can be used as a basis for classification (Table 13-6). This scheme is useful in understanding the host response to infection because the types of inflammatory and immune responses elicited by infection are largely determined by the site of multiplication of the agent.

Obligate Intracellular Organisms

Obligate intracellular organisms can grow and multiply only in host cells and require the metabolic apparatus of the host cell for growth. They infect parenchymal cells in particular. Culture of such organisms requires living cell systems, eg, embryonated eggs, tissue cell culture, or laboratory animals.

Facultative Intracellular Organisms

Facultative intracellular organisms are capable of both extracellular and intracellular growth and multiplication. Intracellular growth usually occurs in macrophages. The multiplication pattern in these organisms ranges from that of Mycobacterium leprae, which almost never multiplies outside cells, to that of Actinomyces israelii, which rarely multiplies intracel-lularly. Most of the agents in this group can be cultured on artificial media; an exception is M leprae, which cannot be grown on artificial media or in cell culture.

Extracellular Organisms

As the name implies, extracellular organisms multiply outside cells. Except for protozoa and metazoa, which cannot be cultured at all, extracellular organisms can be cultured on artificial media. Treponema pallidum, the spirochete that causes syphilis, also cannot be cultured.

When a tissue is infected, pathologic changes (and disease) may result from the combined effects of cellular damage induced by the infectious agent, the host inflammatory response, and the host immune response (Figure 13-4). Infection does not necessarily cause disease, however. In latent infections, the causative agent, often a virus, remains dormant in infected cells without causing any cell damage. At a later date—often years after the primary infection—evidence of disease may appear as a result of reactivation of the infectious agent.

Tissue Damage Caused by Infectious Agents

Direct tissue damage produced by infectious agents is an important cause of pathologic changes. The extent of direct damage is a function of the agent's virulence; highly virulent organisms such as Yersinia pestis (the etiologic agent of plague) cause rapid, extensive tissue necrosis. The mechanisms producing tissue damage differ with the various infectious agents.

Obligate Intracellular Organisms

When viruses infect cells, they cause various changes, as shown in Figure 13-5. Rickettsiae and chlamydiae also replicate in cells, causing many of the changes seen in viral infections. The interactions that prions have with infected cells are unclear.

Cell Necrosis

Infection of a cell by an obligate intracellular agent results in acute necrosis when replication of the agent is accompanied by a lethal abnormality in cell function. Different pathogenic agents have affinity for different parenchymal cells (organotropism). Even when an agent infects many different cell types, significant damage may occur only in some cell types; eg, in poliovirus infection, the main site of infection and viral replication is the intestinal mucosa, whereas the clinical picture is dominated by damage to motor neurons in the spinal cord and brain stem. Clinical manifestations of different viral infections result from injury to different cell types. Similar diseases may be produced by different agents causing acute necrosis of one particular cell type; thus, acute hepatitis may be caused by any of several different types of viruses, but the clinical presentation is similar for all of the agents.

In obligate intracellular infections associated with acute cell necrosis, patients may die in the acute phase of illness (eg, due to encephalitis, myocarditis, or massive liver cell necrosis), or they may recover. Recovery is due mainly to an effective immune response that neutralizes the virus. Return to normal function occurs unless necrotic cells are unable to regenerate, as occurs in encephalitis, in which case the loss of neurons leads to a residual neurologic deficit.

Less frequently, viral infection (or the immune response against the virus) causes slow cell necrosis over a long period, sometimes years. These persistent viral infections occur in the liver (chronic active viral hepatitis, which may be caused by hepatitis B and hepatitis C viruses), brain (subacute sclerosing panencephalitis, which is caused by the measles virus), and in T lymphocytes (human immunodeficiency virus). Prion infections of the brain, such as Creutzfeldt-Jakob disease, are characterized by slowly progressive loss of neurons.

Cell Swelling

Sublethal injury caused by obligate intracellular agents leads to various types of cellular degeneration, most commonly swelling. For example, diffuse swelling of surviving hepatocytes accompanies cell necrosis in acute viral hepatitis. Rickettsiae tend to grow in endothelial cells and cause endothelial cell swelling that may lead to thrombosis.

Inclusion Body Formation

Inclusion bodies are sometimes formed during viral and chlamydial replication in cells. They are visible on light microscopy and represent somewhat crude evidence of the presence of infection by obligate intracellular agents. They are composed either of assembled viral particles or of remnants of viral nucleic acid synthesis. Inclusion bodies occur in the nucleus or the cytoplasm and aid in the diagnosis of specific viral infections in histologic examination of tissues (Table 13-7; Figures 13-6, 13-7, and 13-8). In hepatitis B virus infection, the cytoplasm of infected hepatocytes has a ground-glass appearance (Figure 13-9A) and shows positive staining with orcein (Shikata) stain (Figure 13-9B) and with anti-hepatitis B antibodies when immunologic techniques are used. Immunologic techniques (eg, immunoperoxidase staining; Figure 13-10) that detect viral antigens and molecular biology techniques such as the use of DNA or RNA probes that recognize specific viral nucleic acid sequences are more sensitive methods of detecting virus in infected cells. These methods are useful in the diagnosis of viral infections when light microscopy fails to show diagnostic features.

Giant-Cell Formation

The formation of multinucleated giant cells occurs in some viral infections. Measles virus produces massively enlarged cells (Warthin-Finkeldey giant cells) that contain 20–100 small uniform nuclei (Figure 13-11). These cells may be seen in any tissue infected by the measles virus, commonly the lung and lymphoid tissues of the appendix and tonsil. Herpes simplex and varicella-zoster infections produce giant cells in infected stratified squamous epithelial cells (skin, mouth, external genitalia, and esophagus). These cells have three to eight nuclei that either have a glassy appearance or contain Cowdry A inclusions (Figure 13-7).

Latent Viral Infection

Many viruses can remain latent in the infected cell, often for the lifetime of the host. Reactivation of latent infection may occur at any time, however.

Reactivation

Herpes simplex and varicella-zoster viruses tend to remain latent in sensory ganglia that have been infected during primary infection. Repeated reactivation may occur for various reasons (stress, trauma, coexistent disease, immunodeficiency); virus then migrates via the nerves to the skin or mucosa, where cell necrosis occurs and blisters form. Viral reactivation in herpes simplex type 1 infection causes ulcerating blisters (cold sores or fever blisters) that typically occur around the lips. Following an attack of chickenpox in childhood, varicella-zoster virus may remain dormant in dorsal ganglia, to become manifest as zoster (shingles) as late as 40 years after the childhood disease.

Oncogenesis (Production of Neoplasms, Including Cancer)

(See Chapter 19: Neoplasia: III. Biologic & Clinical Effects of Neoplasms.) Some viruses are thought to cause neoplasms in animals (eg, Rous sarcoma virus, mouse mammary tumor virus) and humans. Epstein-Barr virus has been implicated as a cause of Burkitt's lymphoma and nasopharyngeal carcinoma; the retrovirus human T cell lymphotropic virus type I (HTLV-I) is thought to cause Japanese T cell lymphoma.

Facultative Intracellular Organisms

Facultative intracellular organisms such as mycobacteria and fungi frequently cause tissue damage and undoubtedly possess mechanisms that give them the capability of causing cell damage. These mechanisms are not well understood. In M tuberculosis, the presence of cord factor (trehalose dimycolate) is correlated with virulence. Much of the tissue effects of facultative intracellular organisms are attributed to the inflammatory (commonly granuloma formation), immune (delayed hypersensitivity responsible for caseous necrosis), and healing (fibrosis) responses to these infections.

Facultative intracellular agents, notably M tuberculosis and dimorphic fungi such as Histoplasma and Coccidioides, have the capability of remaining dormant in the tissues for long periods. Dormancy probably means that viable organisms in macrophages are held in check by the immune system. Reactivation of these dormant organisms, due commonly to a decrease in immune function, leads to their multiplication and the occurrence of disease (see Pulmonary Tuberculosis in Chapter 34: The Lung: I. Structure & Function; Infections).

Extracellular Organisms

Extracellular organisms such as bacteria, fungi, and protozoa cause cell injury in one of several ways (Figure 13-12).

Release of Locally Acting Enzymes

As they multiply, virulent organisms produce many enzymes that are liberated into the tissues, where they break down various substrate molecules. The specific enzymes that cause pathologic changes are not defined in many bacterial infections. In others, information derived from in vitro studies of bacteria may be used to explain tissue changes resulting from infection.

Staphylococcus aureus produces coagulase, which converts fibrinogen to fibrin. Coagulase production is closely linked to virulence, and coagulase-negative staphylococci (eg, Staphylococcus epidermidis) have low virulence. In vivo, coagulase is believed to cause the bacterium to become coated with a layer of fibrin that may increase its resistance to phagocytosis. This resistance to phagocytosis may be linked not only to the virulence of staphylococci but also to their tendency to cause suppurative inflammation with tissue necrosis.

Streptococcus pyogenes produces hyaluronidase, which degrades hyaluronic acid in ground substance and facilitates the spread of infection; streptokinase, which activates plasminogen and promotes breakdown of fibrin; and several hemolysins that hemolyze erythrocytes. These enzymes are responsible for the spreading nature characteristic of streptococcal infections and the thin, blood-stained exudate that may occur.

Clostridium perfringens, which causes gas gangrene, produces many enzymes, including lecithinase (alpha toxin), which breaks down cell membrane lipid and causes cell necrosis; hyaluronidase; collagenase, which degrades collagen; and hemolysins. These enzymes are largely responsible for the severe spreading necrotizing inflammation that characterizes gas gangrene. Gas production in tissues is the result of fermentation of sugars during growth of the bacterium.

Production of Local Vasculitis

Highly virulent organisms—eg, anthrax bacillus (Bacillus anthracis), Aspergillus, and Mucor—may infect and cause thrombosis of local small vessels and cause ischemic necrosis in and around the area of infection. Vasculitis may be due to direct invasion of vessels by the organism or to production of toxins (eg, edema factor in anthrax).

Production of Remotely Acting Toxins

Some bacteria produce toxins that are carried in the circulation to cause cell injury far removed from the point of infection.

Endotoxins

Endotoxins are lipopolysaccharide components of the cell walls of gram-negative bacteria that are released into the bloodstream after the death and lysis of bacteria. In the blood, endotoxins act on small blood vessels to cause generalized peripheral vasodilation (leading to circulatory failure and shock), endothelial cell damage, and activation of the coagulation cascade (resulting in disseminated intravascular coagulation). The effect on small vessels is mediated by tumor necrosis factor (cachectin), production of which by macrophages is induced by endotoxin. Endotoxins also cause fever by inducing macrophages to release interleukin-1 and activate the complement system. Endotoxic (gram-negative) shock most commonly follows severe urinary tract infections or intestinal surgery, but it may occur in association with any gram-negative infection. Many of the effects of meningococcal bacteremia are due to endotoxin.

Exotoxins

Exotoxins are substances (often proteins) actively secreted by living bacteria that are released into the environment surrounding the organism and often exert their toxic effects at a site distant from their origin after distribution by the bloodstream. Their actions cause many diseases (Table 13-8) that are relatively specific for the exotoxin and organisms involved. Exotoxins are highly antigenic, inducing the formation of specific antibodies (antitoxins). Exotoxins usually are heat-labile and are destroyed by cooking or heating to temperatures above 60 °C. (By contrast, endotoxins are relatively heat-stable.)

Enterotoxins

Enterotoxins are exotoxins that act on intestinal mucosal cells. They are elaborated during bacterial multiplication either within the intestinal lumen (eg, Vibrio cholerae) or outside the body in foods that are subsequently eaten (eg, S aureus). The toxins attach to surface receptors on intestinal mucosal cells and cause either structural damage (eg, C difficile enterotoxin) or functional alteration (eg, V cholerae enterotoxin; see Figure 40-1).

Tissue Changes Caused by the Host Response to Infection

(Figure 13-13)

As noted previously (Figure 13-4), the multiplication of an infectious agent in tissues evokes both inflammatory and immune responses (Chapters 3, 4, and 5) whose functions are to inactivate or neutralize the agent, thereby protecting the host.

The host response frequently causes many of the clinical symptoms associated with the infection and may sometimes cause tissue damage and even death; eg, the accumulation of an inflammatory exudate in acute pericarditis may interfere with cardiac function and cause death.

The exact nature of the host response depends on various factors, the most important of which is the site of multiplication of the agent in tissues (Table 13-9). Identification of the type of cellular response to infection provides clues to the causative organism—eg, neutrophils in the cerebrospinal fluid of a patient with meningitis suggest meningitis caused by an extracellular agent (usually bacterial); increased numbers of lymphocytes point to viral or tuberculous meningitis. Relative changes in the proportions of various leukocyte types in peripheral blood (see Chapter 26: Blood: III. the White Blood Cells) are also helpful in this respect.

When information derived from a study of the host response is combined with knowledge of the frequency with which different agents infect specific tissues, the identity of the infecting agent may be narrowed further (See Chapter 14: Infectious Diseases: II. Diagnosis of Infectious Diseases).

Acute Inflammation

Pain, redness, warmth, and swelling associated with many infections are the result of acute inflammation. Fever is a complex response mediated by exogenous pyrogens (factors released by the organisms) or endogenous pyrogens such as interleukin-1. Acute inflammation caused by one infectious agent cannot be clinically distinguished from that caused by another.

Extracellular organisms (most bacteria) typically induce a host response characterized by the appearance of large numbers of neutrophils (Figure 13-14). The neutrophils are attracted by chemotactic factors released at the site of infection (Chapter 3: The Acute Inflammatory Response). There is an associated neutrophil leukocytosis in the peripheral blood.

Facultative intracellular organisms rarely evoke an acute inflammatory response, and when they do (eg, in typhoid fever caused by Salmonella typhi) they are characterized by a cellular infiltrate dominated by macrophages with few neutrophils. Peripheral blood neutropenia is also a feature of typhoid fever.

Obligate intracellular organisms (mainly viruses and rickettsiae) induce an acute cellular response characterized by the appearance of lymphocytes, plasma cells, and macrophages but few neutrophils (reflecting absence of factors chemotactic for neutrophils and a more prominent immune response) (Figure 13-15). The peripheral blood may show an increase in lymphocytes but not neutrophils, which may be decreased.

Suppurative Inflammation

Suppuration (pus formation) complicating acute inflammation is characterized by liquefactive necrosis; an abscess is a walled-off area of suppuration (Chapter 3: The Acute Inflammatory Response). Suppuration occurs when organisms (usually bacteria or fungi) multiply in the extracellular space. It is more likely to develop when anatomic abnormalities in a tissue interfere with resolution of acute inflammation. Obstruction of the lumen of the bronchi, urinary tract, or appendix is frequently complicated by suppurative inflammation. The causative bacteria in these situations vary; infection with multiple anaerobes (polymicrobial infection) is common.

Acute Suppuration

Acute suppuration occurs in infections due to certain kinds of bacteria that are relatively resistant to phagocytosis, eg, S aureus, encapsulated gram-negative bacilli such as Klebsiella, Pseudomonas, and Escherichia species, and type 3 pneumococci. The thickness of the pneumococcal capsule is directly related to the organism's ability to resist phagocytic killing. Pneumococci types 1 and 2, which have thin capsules, cause acute pneumonia without suppuration—in contrast to type 3 pneumococcus, which has a thick mucoid capsule and causes suppurative pneumonia.

Chronic Suppuration

Chronic suppuration represents either persistent acute suppurative inflammation (eg, chronic osteomyelitis) or a primary phenomenon due to infection with filamentous bacteria (Actinomyces and Nocardia species) or certain mycelial fungi (eg, Madurella and Streptomyces species). These infections are characterized by progressive tissue destruction, fibrosis, and multiple abscesses (Figure 13-16). The abscesses frequently form draining sinuses in the skin that discharge pus containing small yellow colonies of organisms (sulfur granules). Actinomycosis, caused by Actinomyces species, occurs in the jaw, lungs, and cecal region. Mycetoma is a more general term for this type of chronic suppurative inflammation.

Chronic Inflammation

This is best regarded as the visible evidence of an immune response occurring in infected tissue. The inciting antigens are mostly derived from the infectious agent but may include antigens released by damaged host tissues. Chronic inflammation may follow an acute response (as in chronic suppuration, described above), or it may occur de novo if the initial phase of infection causes little cellular damage and fails to excite an acute inflammatory response (as occurs in infections due to certain viruses and intracellular bacteria).

The term chronic inflammation encompasses several different kinds of cellular immune responses.

Chronic Granulomatous Inflammation

(Chapter 5: Chronic Inflammation.) Epithelioid cell granulomas represent a specific host response to infections that are caused by the multiplication of facultative intracellular agents in macrophages. The response is T cell-mediated and associated with type IV hypersensitivity. Activated T lymphocytes produce lymphokines that cause accumulation and activation of macrophages. The delayed hypersensitivity associated with this response leads to caseous necrosis. Granulomatous inflammation is always chronic, and it may be associated with extensive tissue necrosis. Repair is by fibrosis and usually occurs concurrently with ongoing necrosis.

Agents that cause epithelioid cell granulomas include (1) mycobacteria M tuberculosis, M leprae, atypical mycobacteria), (2) fungi that grow as nonmycelial forms in tissues (Coccidioides immitis [Figure 13-17], Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Sporothrix schenckii, and Paracoccidioides brasiliensis), (3) Brucella species, and (4) T pallidum, which causes necrotizing granulomas (gummas) late in the course of syphilis. T pallidum is an extracellular organism and is an exception. It is rarely identified in granulomas, which are probably the result of an abnormal immunologic response to treponemal antigens.

Identification of the specific agent causing granulomatous inflammation is most effectively achieved by culture. Histologic examination is also useful (Figure 13-17) because the agent can sometimes be identified with special stains for mycobacteria (acid-fast stain) or fungi (methenamine silver stain). In a significant number of cases, no organism can be demonstrated in histologic sections, and culture is essential.

Chronic Inflammation with Diffuse Proliferation of Macrophages

(Figure 13-18.) In this form of chronic inflammation, there is a deficient cell-mediated immune response, and T cell lymphokines are absent. Macrophages do not aggregate to form granulomas but infiltrate infected tissues diffusely. Macrophages have foamy cytoplasm containing numerous organisms; they do not become epithelioid cells. No caseous necrosis occurs because there is no delayed hypersensitivity.

Chronic inflammation with diffuse proliferation of macrophages occurs in response to infection caused by facultative intracellular organisms. Such organisms include the following: (1) Mycobacteria, including M leprae, M tuberculosis, and atypical mycobacteria, when disease (eg, lepromatous leprosy, tuberculosis in the elderly, and atypical mycobacteriosis in acquired immune deficiency syndrome (AIDS)) occurs in immunodeficient patients. Note that when these same infections occur in individuals with active T lymphocyte function, they elicit granulomatous inflammation. (2) Klebsiella rhino-scleromatis, occurring in the nasal cavity (rhinoscleroma [Figure 13-18]). (3) Leishmania species, protozoal parasites that cause infection in skin, mucous membranes, and viscera.

In these infections, the main defense against the invading microorganism appears to be nonimmune phagocytosis by macrophages. Nonimmune phagocytosis by macrophages is relatively ineffective in killing the organisms, which continue to proliferate within the cell. A common feature of all these infections is the presence of numerous organisms in the macrophages. Proliferation of macrophages frequently causes a marked degree of clinically detectable enlargement of affected tissues.

Chronic Inflammation with Lymphocytes and Plasma Cells

This type of inflammation typically occurs in response to persistent infection caused by obligate intracellular organisms (eg, viruses causing chronic viral hepatitis and chronic viral infections of the brain). It represents a combined humoral and cell-mediated immune response. The associated cell necrosis is followed by fibrosis.

Combined Suppurative & Granulomatous Inflammation

A combination of suppuration and granulomatous inflammation is commonly seen in deep fungal infections; it is probably due to multiplication of the causative organisms both within macrophages and outside the cell.

A less common but distinctive lesion in which there is a combined suppurative and granulomatous inflammation is the stellate abscess or granuloma, in which neutrophils are present in the center of an irregular epithelioid cell granuloma. Stellate granulomas may be seen in the following infections: (1) lymphogranuloma venereum (LGV), caused by Chlamydia trachomatis (types L1–L3) and characterized by genital ulceration and lymph node involvement (lymphadenitis); (2) cat-scratch disease, characterized by fever and lymph node enlargement and caused by Afipia felis, a small gram-negative bacterium that stains positively with silver stains; (3) tularemia (caused by Francisella tularensis); (4) glanders (caused by Pseudomonas mallei); and (5) melioidosis (caused by Pseudomonas pseudomallei).

All of these agents are facultative intracellular organisms except Chlamydia trachomatis, which is an obligate intracellular agent. The specific diagnosis of these infectious diseases depends on identifying the organisms in histologic sections or culture, or by serologic tests.