PATHOLOGY OF INFECTIOUS DISEASES

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I. ACUTE CELL DEATH AND TISSUE DESTRUCTION
II. GRANULOMAS AND MACROPHAGE-ASSOCIATED INFECTIONS
III. SOME PATHOGENS (VIRUSES) ELICIT A LYMPHOHISTIOCYTIC INFLAMMATORY RESPONSE

OVERVIEW:

The world of infectious diseases is a vast expanse that includes the environment, the microbial and sub-microbial worlds, and all forms of life above them up to and including humans. Only twenty years ago pundits were predicting the end of infectious diseases, much as they predicted the end of poverty, discrimination, and other facts of life. We have made a lot of progress on all fronts. The conquest of infectious diseases has been as much a matter of improving living conditions and education as of specifically directed medical interventions. The intervening years have chastened society, however, because the failure to eliminate war and poverty have perpetuated conditions that favor infectious diseases in some societies and because the pundits underestimated the complexity of the problems and the resourcefulness of the microbial enemy. The development of microbial resistance to a series of new antibiotics and the appearance of "new" infections, such as human immunodeficiency virus are all that is necessary to make the point.

You will consider many of the challenges associated with infectious agents and their diseases in your microbiology course. The goals for this morning are limited. In the first hour we will consider the effects on the host (from our anthropocentric viewpoint, human beings) of encounters with infectious agents. The discussion will focus on cellular pathology and in particular morphologic pathology -- both the damage to host tissues produced by infectious agents and the response of the body to that damage. Pathology in the complete sense is far broader than that. It includes the microbial and physiologic portions of the process, the whole of which combine to form a process known as pathogenesis. The intent, however, is to complement your microbiology course, not to recapitulate or anticipate large bodies of material.

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Tissue Response to Infectious Injury

I. ACUTE CELL DEATH AND TISSUE DESTRUCTION

This large group of infectious processes is primarily associated with bacteria that replicate extracellularly. As a result of bacterial growth, compounds that destroy cells and tissue or that elicit an acute inflammatory response cause a histologic reaction that is destructive. Although bacteria are the primary etiologic agents here, it is important to recognize that other types of infectious agents, such as viruses, may also elicit an acute inflammatory response. The types of tissue necrosis are variable, depending on the pathogenetic pathway followed.

• Pyogenic Inflammation: The most common response to this group of pathogens is the generation of an intense acute inflammatory response, which results in the formation of pus. Pus is a thick yellow-green exudate composed of polymorphonuclear neutrophils, macrophages, proteinaceous fluid, and bacterial or fungal fragments. Pus is essentially the acute inflammatory response, as produced by a superficial cut or abrasion, taken to the extreme. The difference between an acute non-infectious injury and a bacterial infection is the presence of a self-replicating injury in the latter.

Many bacteria produce toxins or enzymes that damage cells and tissues. The enzymes include proteases, elastases, collagenases, and various cytotoxins. The bacteria themselves and the damaged cells release chemotactic substances that attract polymorphonuclear neutrophils into the inflamed tissue. Activation of the complement cascade by bacterial endotoxin is one potent generator of acute tissue inflammation. Once the polymorphonuclear neutrophils enter the tissue, they also contribute to tissue damage because they produce additional proteases in their attempts to destroy the bacterial invaders.

The combination of bacterial replication and tissue destruction may result in a necrotizing process and the formation of an abscess. Abscesses are important factors in the tissue response to infectious agents for several reasons:

• Antibiotics penetrate poorly into the center of an abscess, so that they are less effective in eliminating the inciting agent.
• Both antibiotics and also polymorphonuclear neutrophils function less well in the anaerobic and acidic environment of an abscess than they do in better oxygenated and more neutral viable tissue.
• Destruction of the normal supporting framework of the organ means that if healing does eventually occur, it is more likely to be accompanied by permanent loss of functioning tissue and therefore some incremental loss of physiologic function. Scar tissue is more likely to result if an abscess has been formed.

Some of the important bacterial pathogens that produce a pyogenic response include:

• Staphylococci
• Streptococci and enterococci
• Enterobacteriaceae (E. coli, Klebsiella, Enterobacter, etc.)
• Pseudomonas

• Coagulative Necrosis: Some bacteria and fungi exert their pathogenic effect in whole or in part through damage to blood vessels. In these instances, the effect on tissues is dominated by ischemia and the appearance of the damaged tissue is primarily that of an infarct. If bacteria multiply in the ischemic tissue, purulence may be superimposed on the coagulative necrosis, a process known as a septic infarct.

A classic example of this type of process is the invasion of blood vessels (angioinvasion) by certain types of filamentous fungi. These mould pathogens are of relatively low virulence and do not ordinarily infect normal persons, but may produce lethal infection in those who have compromised host defenses. The two most common types of fungi to produce this response are Aspergillus fumigatus and the zygomycetes.

Complexities and Exceptions:

Some viral infections that cause lytic destruction of the infected cell are also likely to generate an acute inflammatory response. A good example of such a lytic infection is the pneumonia produced by herpes simplex virus or adenovirus. The histologic response to these infections, as opposed to rabies, is acute inflammation. On more than one occasion the etiology of these pneumonias has been incorrectly ascribed to an unknown bacterium, because it was assumed that a purulent inflammatory response could not result from a bacterial infection. The intensity of inflammation and extent of tissue destruction is usually less in viral infections than in bacterial infections. Abscesses do not occur in viral infection.

Not all bacteria elicit a pyogenic response. Some produce their effects by elaboration of toxins that have profound pathophysiologic effects but do not cause a morphologic change in tissue. Examples are cholera and botulism. Still other bacteria elicit a granulomatous inflammatory response, as discussed below. Rarely, a bacterial infection may resemble a viral disease in the type of host response (Mycoplasma pneumoniae infection and Bordetella pertussis [whooping cough]).

 

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II. GRANULOMAS AND MACROPHAGE-ASSOCIATED INFECTIONS

A group of organisms that have a close association with macrophages are collectively referred to as facultative intracellular pathogens. This term indicates that the infectious agent grows within an infected human host within the cytoplasm of macrophages, but is also capable of growing on the surface of agar media or in broth. They are thus distinguished from obligate intracellular pathogens, such as viruses and rickettsia, which are incapable of replicating outside of a cell because they do not possess all the genetic and metabolic machinery for survival on their own.

These facultative intracellular pathogens are primarily fungi and mycobacteria, but other bacteria may also demonstrate this characteristic. The immunologic response to these pathogens is primarily mediated by the cellular immune system and the morphologic correlate of most of these infections is the granuloma. A granuloma is an organized collection of macrophages that have been activated by immunologically stimulated T lymphocytes. In some cases the cells in the central portion of the granuloma are destroyed.

Most bacteria and fungi are effectively destroyed after they have been phagocytized by macrophages or circulating blood monocytes. Facultative intracellular pathogens, however, have evolved methods to bypass the killing mechanisms of macrophages. As the immune response is activated, however, cytokines produced by specifically sensitized T lymphocytes are able to "activate" macrophages and monocytes. These activated cells are able to inhibit the growth of phagocytized bacteria and in some cases to kill them effectively. The activated macrophages also change shape and may fuse together to form multinucleated giant cells. These cells are the macrophages that are present in granulomas.

The Components of a Classic Granuloma Are:

• Macrophages (histiocytes)
  
• Multinucleated giant cells in which the nuclei are arranged around the edge of the cytoplasmic membrane (Langhans' giant cells). These giant cells result from the fusion of histiocytes in the process of activation.
  
• Epithelioid histiocytes are activated macrophages that have an elongated appearance and line up in a parallel fashion that resembles epithelial tissue.
  
• Lymphocytes
  
• Fibroblasts
  
• Necrosis

Several types of necrosis may occur, each of which is characteristic of (but not diagnostic of) certain infections. It is important to realize that most pathogens can elicit more than one type of granulomatous reaction. For instance, Mycobacterium tuberculosis may produce both non-caseating and caseating granulomas, even in the same patient. From a practical diagnostic point of view one has to look for mycobacteria and fungi in granulomas of all types.

• Non-caseous (or non-necrotizing) granuloma: an organized collection of macrophages and/or giant cells with little or no cellular destruction.
  
• Caseous granuloma (from its supposed resemblance to crumbly cheese). The underlying cells and tissue are totally destroyed in the process of caseous necrosis. This type of necrosis is classically associated with mycobacteria and some fungi, particularly dimorphic fungi.
  
• Necrotizing granuloma: The center of the granuloma consists of necrotic macrophages and polymorphonuclear neutrophils. The walls of the granuloma are usually composed of well defined macrophages and elongated macrophages (epithelioid). These epithelioid macrophages or histiocytes often line up in a linear fashion that is called palisading. This type of response is associated with certain bacterial infections:
  
  • Yersinia pestis (plague)
  • Yersinia pseudotuberculosis and Y. enterocolitica
  • Chlamydia trachomatis, serotypes L1-L3 (lymphogranuloma venereum)
  • Franciscella tularensis (tularemia)
  • Bartonella henselae (cat-scratch fever)
    
• Stellate granuloma: the outlines of the granuloma are serpiginous, rather than round or oval. A star-shape may result. The pattern is sometimes referred to as geographic. These granulomas usually have a necrotizing appearance, and the primary differential diagnosis is the same as that listed under necrotizing granuloma (#3 above).
  
• Fibrinoid granuloma: the necrotic center has an intensely eosinophilic, amorphous appearance. The edges of the granulomas are often palisading. This type of granuloma is often found in non-infectious diseases, such as rheumatoid arthritis.

Complexities and Exceptions:

• It should be noted that some facultative intracellular pathogens, notably Legionella and Listeria, elicit an acute inflammatory response or cause granulomas only under special circumstances.
  
• Some organisms that may produce granulomas, such as Aspergillus sp., do not have a special relationship to macrophages. The importance of the antigenic construction of the infectious agent is demonstrated by the fact that strains of Cryptococcus neoformans that possess a well-developed polysaccharide capsule usually produce a minimal inflammatory response in an infected host, whereas strains that lack a substantial capsule generate a granulomatous response.
  
• The normal response to bacterial pathogens, such as Staphylococcus aureus or Pseudomonas cepacia, is a polymorphonuclear influx, but patients with chronic granulomatous disease, a disorder of neutrophil function, typically produce a granulomatous response to these bacterial pathogens.
  

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III. SOME PATHOGENS (VIRUSES) ELICIT A LYMPHOHISTIOCYTIC INFLAMMATORY RESPONSE

In general, these are pathogens that infect cells and produce changes on the surfaces of those cells. Activated lymphocytes, primarily T cells, are the primary immunologic response as they attempt to eliminate the pathogens by attacking the cells that express the altered antigens on their surface.

An example of the host response to viral infection is primary influenza virus pneumonia, an uncommon but dreaded complication of influenza infection. The virus attacks respiratory epithelium and produces a histologic response that is referred to as "diffuse alveolar damage". The cellular inflammatory response consists of lymphocytes in the interstitium. In addition, alveolar lining cells proliferate as the damaged respiratory epithelium of the airspaces is repopulated.

A second example of lymphocytic response to viral infection is exemplified by viral encephalitis, where the histologic appearance of the brain, even in fatal cases, may be unremarkable. The only indication that a pathologic process is ongoing is the accumulation of reactive lymphocytes in the perivasular spaces.

Viruses may also produce primary injury to the vascular system, resulting in edema and/or hemorrhage in the affected organ(s). In contrast to the fungi, which invade arteries and veins, viruses (and other obligately intracellular organisms such as rickettsia) affect arterioles, venules, and capillaries. A recent example of the serious systemic effects of viral infection of endothelium is the hantavirus pulmonary syndrome that has been recognized in the past five years, primarily in the southwestern states of the US. Fulminant pulmonary edema and respiratory failure are the predominant manifestations of this infection. In Rocky Mountain Spotted fever, rickettsial damage to the vascular endothelium results in widespread hemorrhage, producing petechiae (pinpoint bleeding) and ecchymoses (larger areas of hemorrhage).

Complexities and Exceptions:

As mentioned earlier, some viral infections with extensive cytolysis may elicit an acute inflammtory response that suggests a bacterial infection, classically herpes simplex infections. On the other side, a few bacterial infections produce a lymphohistiocytic inflammatory response that suggests a viral infection. The classic example is whooping cough, in which both the clinical and pathologic differential diagnoses are between a bacterial infections (Bordetella pertussis) and viral infections.

Viral Inclusions:

Viruses, taking their cue perhaps from Dean Witter, produce their damage "one cell at a time." Viral particles are too small to be visualized with the light microscope, but some viruses produce masses of replicating nucleic acid and virions that form cellular inclusions. In general, viruses that contain DNA are assembled primarily in the nucleus and produce their inclusions there, whereas viruses that contain RNA are assembled in the cytoplasm and produce their inclusions in the cytosol. Not surprisingly, there are some exceptions and some viruses produce inclusions in both locations. As the viral nucleic acid fills the nucleus the host chromatin is pushed against the edge of the nuclear membrane. In some cells formalin fixation produces an artefactual separation between the host chromatin and the viral chromatin, known as a halo. Some cytoplasmic inclusions develop an inhomogeneous appearance when normal cytoplasmic contents are included in the viral nucleoprotein.

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A Summary of Viral Inclusions

Virus	Nucleic Acid	Location	Morphology	Comments
herpes simplex	DNA	nucleus	eosinophilic, halo; multinucleated cells	cannot be differentiated from VZV
varicella-zoster virus	DNA	nucleus	eosinophilic, halo; multinucleated cells	cannot be differentiated from herpes simplex
cytomegalovirus	DNA	nucleus and cytoplasm	amphophilic or basophilic, halo; enlarged cell; cytoplasmic inclusions inhomogeneous
adenovirus	DNA	nucleus	early: eosinophilic, halo; late: basophilic, smudge cells	early: resemble herpes
poxvirus	DNA	cytoplasm	eosinophilic	Guameri body
polyomavirus	DNA	cytoplasm	basophilic	in oligodendroglia
rabies virus	RNA	cytoplasm	eosinophilic, may be inhomogeneous	Negri body
measles virus	RNA	nucleus; may also be cytoplasmic	eosinophilic, halo; multinucleated cells	may resemble herpes simplex
respiratory syncytial virus	RNA	cytoplasm	eosinophilic; may have multinucleated giant cells
parainfluenza viruses	RNA	cytoplasm	eosinophilic; may have multinucleated giant cells	rarely seen

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[ CATS Home | About CATS | CATS Teaching Modules | UVM Department of Pathology | Other Pathology Sites | UVM College of Medicine | UVM ]

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Questions? Comments? Send a message to the CATS guru: jkessler@salus.uvm.edu