Chapter 191. General Considerations of Viral Diseases

Cutaneous manifestations are a prominent feature in many viral infections and may arise from a direct result of viral replication in the epidermis or secondarily from viral replication in other organs. In the latter case, the cutaneous manifestations may be the presenting sign of a systemic infection requiring further evaluation. Although most viral infections with cutaneous involvement are mild and self-limited, occasionally severe or life-threatening complications can develop, especially in immunocompromised hosts. Developments in laboratory testing have improved diagnosis of viral infections in the skin. In addition antiviral medications have improved clinical management and outcomes for many of these viral illnesses. While specific diagnosis of the etiologic viral agent is not always feasible, laboratory diagnosis may also be important epidemiologically. Preventive vaccines are available for certain viruses and are currently the most effective strategy for decreasing morbidity and mortality associated with these diseases. Prophylactic vaccines led to the eradication of smallpox, and now include newer vaccines against herpes zoster virus and human papillomaviruses.

Viruses are unique and fascinating small subcellular agents that require host cells to replicate their genetic material.1 They contain genomic nucleic acid, a protein coat, and some viruses also have a lipid envelope. Lacking functional ribosomes or other organelles, viruses require host cellular machinery for replication of their genetic material.1,2 This dependence on the host cell for transcription and replication is why viruses are often referred to as obligate intracellular parasites. The intracellular location of the virus provides survival benefit to the virus against some of the host's immune mechanisms.

Viruses are an important means of horizontal gene transfer and evolutionary genetic diversity.3,4 Historically, there have been many discussions regarding the etiology and categorization of viruses. Most experts currently view viruses as biological particles that can interact with cells, as opposed to biological organisms or life forms.3 Viruses have features of both of these groups, which accounts for some of their enigma, but lack some of the defining features of living organisms and are not classified taxonomically amongst the kingdoms of life.

The viral nucleic acid contains the genetic information necessary for directing the host cell to replicate the virus. The assembled virus is referred to as a virion, and contains a highly organized protein coat or capsid.5 The protein coat protects the viral nucleic acid from extracellular environmental insults such as nucleases and it facilitates virion attachment to the membrane of the host cell.6 After the virion has infected a cell, the now intracellular viral genetic information is usually found in a nonparticulate form. The various virion components are synthesized in separate pieces within the cell and assembled to form progeny particles. This assembly type of replication is characteristic of viruses.7

Viruses are grouped based upon their type of genomic nucleic acid, DNA or RNA, and by the number of strands of nucleic acid within each virion.2 Other traditional categorization has focused on viral size, morphology, and presence of an envelope, as shown in Table 191-1. A given family of viruses usually shares functional, genetic, biochemical, and immunologic features as well. Other features that may be evaluated in viral categorization are antigenic cross reactivity and host cell tropism. With the advent of more sophisticated techniques, recent viral classification has focused on relatedness of genome sequences.8

On a morphological basis viruses can be grouped as helical, icosahedral, or complex as determined by the type of capsomer and overall shape of the virus.9 In certain virus families (such as herpesviruses and retroviruses), the capsids are located inside an envelope (composed of lipid, protein, and carbohydrate), which is required for infectivity5 (see Table 191-1). The viral envelope is sensitive to drying, so that infectivity is lost with drying. The virions of some other viruses (e.g., papillomaviruses) do not possess an envelope, so their capsids are called naked. Because the capsid proteins are usually stable in dry environments, viruses whose virions lack an envelope typically remain infectious for long periods after drying.10

Figure 191-1 shows examples of virions from the three main families of viruses that multiply in the epidermis and appendageal structures (papillomaviruses, herpesviruses, and poxviruses). The viral genomes of these three families are composed of DNA. As noted earlier, papillomaviruses possess naked (nonenveloped) capsids, and herpesviruses have enveloped virions. Poxvirus virions are large, have a very complex structure, and are enveloped, but their envelope is not required for their virions to be infectious. Hence, poxviruses can remain infectious even after drying.11

Viral particles do not multiply through cell division because they are acellular. Instead, replication of viruses requires certain host cell genes, proteins, and organelles. The viral replication cycle involves several steps: adsorption, cellular uptake, uncoating, biosynthesis, virion assembly, and release.5

Adsorption proceeds with the attachment of virions to cells, involving a specific interaction between the viral capsid, or envelope, and host cell surface receptors. The specificity of this interaction between the viral protein and host receptor defines and limits the species and cell type that a particular virus can infect.6 Cells that lack the appropriate cell surface receptors for a particular virus are not susceptible to cellular viral entry and infection. For example, human immunodeficiency virus (HIV) enters cells via an interaction between viral envelope protein and two classes of receptors: cellular CD4 receptors and chemokine receptors.12 While the majority of people are known to be susceptible to HIV infection, rare genetic modifications of specific chemokine receptors have been identified which render hosts relatively resistant to HIV infection or the development of acquired immunodeficiency syndrome.13,14

After adsorption, the coat of enveloped viruses may fuse with the host cell membrane and release the virus nucleocapsid into the host cytoplasm. Alternately some viruses may enter the cell through invagination of the cell membrane forming vesicles in the cell cytoplasm.6 Uncoating subsequently occurs with release of the viral genome from its protective capsid, which begins the nonparticulate phase of the virus life cycle. The nucleic acid can now be transported within the cell.

In the genomic activation or biosynthetic phase, messenger RNA (mRNA) is transcribed typically from viral DNA and translated by the host cell under regulation by the virus. DNA viruses, such as papillomaviruses and herpeviruses typically replicate in the nucleus. (Figs. 191-2 and 191-3) RNA viruses mainly replicate in the cytoplasm. However this is not absolute, as exemplified by poxviruses that contains DNA but replicate in the host cell's cytoplasm15 (Fig. 191-4).

Early viral proteins are usually nonstructural and may code for important enzymes, while later proteins tend to be structural components for the virion. Nonvirion proteins (proteins that are not structural components of the mature virion) of certain viruses may redirect the cell to synthesize proteins required by the virus at the expense of those required for normal function of the cell, essentially hijacking the host's replication and transcription processes.15

Assembly of the viral nucleocapsids is the next step. This may occur in the nucleus, as it does with herpes viruses, or in the cytoplasm with polioviruses, or even at the cell surface with viruses such as influenza.16

Release of new infectious virions may occur by several mechanisms. The virions of most viruses, including papillomaviruses, herpesviruses, and poxviruses, are released upon cell lysis.10 Some virions are released by budding from the cell surface and contain a host cell membrane coat. This can occur when virus proteins and nucleic acid condense adjacent to the cell membrane with subsequent budding off of the cell. Virions with resultant cell membranes have a survival advantage of decreased antigenic stimulation and decreased activation of the host's immune system.10 Alternatively some viruses utilize the host cell's cellular secretory pathway via Golgi-derived transport vesicles and fuse with the cell membrane to exit the cell.

Typically, hundreds or thousands of new virions are produced from each infected cell, which can then go on to infect other cells. One cycle of viral replication may last from 3 to 36 hours, depending on the virus and cell type involved. Interruption of any step in viral cellular entry, uncoating, synthesis, assembly, or release may prevent the development of new infectious virions. Viruses can also establish several alternate pathways in the host cell, discussed further in the next section.

Each virus has specificity for cell type(s) it can infect. Human papillomaviruses can productively infect a very narrow range of cells, namely, certain differentiating human epidermal cells.17 Other viruses can infect a much broader range of cells. Herpes simplex viruses (HSVs) can replicate in many different human and nonhuman cell types.18

Even within a given tissue, a virus may be infectious only for cells with a specific degree of differentiation. The important role of the differentiated state of the cell in determining whether or not a virus will undergo replication is seen in the skin lesions caused by the molluscum contagiosum virus (MCV). Because MCV particles are sometimes found in cells of the upper dermis, the virus must be capable of attachment to and penetration of these cells. MCV does not, however, replicate in dermal cells, which indicates that an intracellular block to MCV synthesis in the dermal cells. MCV particles are also found in the basal layer of epidermal cells, but synthesis of new viral components does not begin until the cells reach the suprabasal layers, implying that MCV replication can take place only in partially differentiated epidermal cells.11 Individual viruses are discussed further in their respective chapters.

Most viral infections eventually result in the host cell death as a result of cell lysis or alterations to the cell's normal surface membrane leading to cellular apoptosis.9 Infections of this type are known as lytic or cytocidal. However certain enveloped viruses can replicate without causing irreversible damage to the host cell. In noncytocidal infections other possible interactions with the host cell are persistent infection, viral latency, and tumor transformation.19

Persistent cellular viral infections without mass cell destruction are possible and occur when there is survival of the infected cell, or only a few host cells are initially infected. This can occur with cytomegalovirus or papillomavirus infections.17

Latent infections, via viral integration into the host genome or into the host cell episomally, are another possibility. Viral DNA replication thus proceeds with the cell's genome but does not result in acute mass viral replication or cell lysis.20 Viral latency is a mechanism for evading the host immune response and may have consequences for the cell. Latently infected cells either produce very small numbers of new virions so that spread to uninfected cells is minimal or they synthesize no virions but retain an intact and potentially inducible viral genome.20 Ultimately, the state of latent infections can become disrupted with production of new virions. This is commonly seen with herpes viruses HSV-1, HSV-2, and VZV; reactivation of the virus can ensue under conditions that allow viral genome induction.18

Tumor viruses possess the ability to alter the normal control of cellular proliferation and transform cells. The phenomenon of latent viral integration with expression of viral proteins known to have an effect on cell cycle regulation has been demonstrated with several viruses, most recently the Merkel cell polyomavirus (MCPyV).21,22 In many of the genomically evaluated cases to date, the MCPyV DNA sequence has demonstrated a mutation resulting in loss of viral replication ability but retained ability to establish latency in the host cell and express viral proteins.22,23 Among the viral proteins that have been found to be expressed are those involved in regulation of the host cell, which is a common feature of tumor viruses. Papillomaviruses similarly can encode nonvirion proteins that increase cell growth and lead to inappropriate control of cell division.17

The link between certain viruses and cancer was a pivotal discovery in the past century. The viral infectious nature of specific tumors has important implications for prevention, diagnosis, and therapy. Viral induced neoplasia is discussed in greater detail in subsequent chapters.

In addition to complete cellular destruction or transformative consequences for the cell, characteristic effects of a particular virus infection can be microscopically visualized. Cytopathic effects can be pathognomonic for the specific viral infection. These cell effects are typically the result of viral protein synthesis or subcellular degeneration, and can be seen as membrane blebbing, multinucleated giant cell formation, and inclusion body formations, to name a few.

Since a virus must grow within a host cell, the virus must be viewed together with its host in any consideration of pathogenesis, epidemiology, host defenses, or therapy. Transmission of an infecting virus to a susceptible individual can occur through several routes. In warts, herpes simplex, primary varicella infections, herpes zoster, molluscum contagiosum, and smallpox, viral shedding from human skin lesions represents an important source in the transmission of virus to other people. For other viruses with cutaneous manifestations, respiratory secretions, blood, genital secretions, or animal vectors are involved in carrying virus to susceptible individuals. Skin involvement may occur by three different routes: direct inoculation, systemic infection, or local spread from an internal focus. The resulting skin lesions may be due to the direct effect of viral replication on infected cells, the host response to the virus, or the interaction of replication and host response.

The viruses of warts, MCV, vaccinia, orf, milker's nodules, and (primary) herpes simplex, all of which infect the skin by direct inoculation, replicate in the epidermis.10 Their viral cytopathic effects account for the appearance of early lesions. The immune system presumably contributes to the evolution of these lesions by inducing an inflammatory response. The incubation period is generally short, because the lesions develop at the site of inoculation. For warts, however, the incubation period is longer, presumably because the virus replicates slowly or cellular spread of virus is limited.

In systemic infections, the skin is infected during viremia, so that the dermis is generally infected earlier than the epidermis. It is unclear what determines the specific cutaneous distribution of viral exanthemas. In primary varicella infections and smallpox, the lesions seen are a secondary result of the cytocidal damage that the viral infection produces.18 In contrast, there is some evidence from patients with impaired cellular immunity that suggests that cutaneous manifestations of rubella and measles result at least partly from a cell-mediated immune response to the virus. The basis of most viral exanthemas, such as with enteroviral infections, remains to be established.

Recurrent HSV and herpes zoster represent the local spread of virus to the skin after reactivation of the latent virus present in sensory nerve ganglia. Cytocidal activity is involved in the pathogenesis of these viral associated cutaneous lesions, although the immune response appears to also be an etiologic factor in the blister formation.18

The severity of illness induced by a particular virus has considerable intraspecies variation. The size of the viral inoculum and the portal of entry play some role in the clinical manifestation of disease, but it is believed that host factors usually account for the majority of clinical variation. Both innate and adaptive immunity play key roles in the coordinated immune response to viral infection.24 Conversely, viral infection may interrupt the normal functioning of the immune system, especially infection with those viruses that target lymphoid cells, such as Epstein–Barr virus and HIV.

Viral proteins have reactive epitopes, which are important for host cellular interaction during infection and replication.6 The host's defense mechanisms are directed against the viral antigenic epitopes. Antibody responses to viral infection represent the major host defense against reinfection by the same virus. The prophylactic administration of type-specific antibodies can prevent or modify some primary viral infections, even in patients with impaired cellular immunity. There are several mechanisms by which antibodies may inhibit the spread of virus. These include opsonization of virus and prevention of attachment to target cell receptors (which may be increased by complement), enhancement of phagocytic cell activity, and complement-mediated immune destruction of virally infected cells. However, humoral immunity is not believed to contribute substantially to the recovery from most primary viral infections. Viral infections in patients with isolated humoral immune deficiencies usually follow a normal course.

Cell-mediated immunity (CMI) is also elicited during viral infections, controlling viral spread and promoting viral clearance. CMI is a specific response to infection involving T cell recognition of viral fragments displayed on infected cell membranes. This leads to targeting for destruction by natural killer T cells. Some viruses such as HIV can effectively evade CMI by inducing variation in the amino acid sequence of virion surface proteins.25

Patients with impaired CMI often have difficulty handling primary or recurrent viral infections. Such patients are at risk of developing severe primary virus infections, problematic reactivations of dormant viruses such as VZV and CMV, and persistent warts, herpes simplex eruptions, and other viral cutaneous lesions. Virus-specific cytotoxic lymphocytes, natural killer cells, and antibody-dependent cell-mediated cytotoxicity all can inhibit infection under experimental conditions and are thought to be the primary players in clearing viral infections. Such genetic alterations in CMI have provided insights into how the immune system responds to viral infections.

Inflammatory cells may produce some of their antiviral effects via the production of interferons, a unique family of closely related cytokines that are active against viruses. Interferon, which can be induced by foreign RNA or DNA (including viral nucleic acids), is secreted into the extracellular fluid. Resistance to viral infection is increased in those cells that come in contact with interferon. Virtually all viruses are capable of inciting an interferon response and are susceptible to its action. However, there is great variability amongst viruses in the degree of interferon induction and the sensitivity to its effects.

Host genetic factors also play a role in the outcomes of viral infection. In animal models, cellular genes greatly influence the susceptibility to viral infection at several levels, including virion attachment to cells, viral replication, and viral-induced immune responses.

Viral infections can produce a wide spectrum of mucocutaneous lesions, from single papules to generalized pustulation to large, fungating tumors. Table 191-2 lists the viruses that most commonly cause a number of distinguishable skin lesions. Also, for many viruses with cutaneous manifestations, the combination of the exanthem with other clinical and systemic findings, when present, can be characteristic for a specific virus. Human herpesvirus 6 induced roseola subitum in a well appearing child after days of a very high fever or measles exanthem with its characteristic oral lesions, are examples.

There are several cutaneous eruptive diseases for which a virus is highly suspected as the etiologic agent, but this viral causation has not been proven. Asymmetrical periflexural exanthem of childhood and pityriasis rosea are two such diseases (although evidence does link pityriasis rosea to human herpesvirus 7 infection).26,27

In certain viral infections the lesions are very specific (e.g., the verrucous papules seen with papillomavirus infection), and a diagnosis can be made without any further testing. However, even during an acute viral infectious episode there is often considerable clinical evolution and variation in the lesions. For example, in many infections due to HSV, VZV, or coxsackievirus, the lesions begin as papules with erythema, progress to frank vesicles, and are followed by pustules, crusts, or shallow ulcers.

In other viral infections the lesions are either rather nonspecific (e.g., urticaria or erythema multiforme) and cannot be accurately distinguished from lesions of nonviral etiology, or semispecific for a limited number of viral diagnoses (e.g., the vesicles seen in HSV, VZV, coxsackievirus, and echovirus infections). In both of these circumstances additional diagnostic procedures may help clarify the cause. Evaluation of systemic signs and symptoms is crucial in formulating a differential diagnosis of skin eruptions and is particularly valuable in infections by viruses that do not replicate in the epidermis, such as Epstein–Barr virus and CMV.

Several laboratory methods are used for diagnosis of viral infections. These are methods based upon viral detection including viral culture and detection of viral antigens, and indirect techniques such as microscopic evaluation and serology. Molecular diagnostic techniques, which are based upon detection of viral nucleic acids, are a newer method increasingly used for laboratory diagnosis of viral infections. The results of any diagnostic method must be interpreted in the context of the clinical setting. Coincidental infection with a virus unrelated to the illness should always be considered. For many viruses, rapid molecular-based assays that are sensitive and specific are now commercially available.

Viral culture is the traditional diagnostic gold standard. If necessary, more precise identification of the cultured virus can be carried out with specific tests for viral nucleic acid or viral antigen. Culture techniques for HSV are quite sensitive, with diagnostic changes in cells often appearing within 1–2 days of inoculation.18 The closely related VZV is much more difficult to grow in culture, which frequently leads to false-negative results.18

When viral culture is of interest, specimens from an acute episode early in the disease process often yield more accurate results than samples taken from the later stages. In vesicular conditions, fluid from an early vesicle is typically a good source of virus. Lesional specimens are less likely to give positive results with nonvesicular exanthemas. Specimens are collected in a sterile tube with 2–5 mL of a buffered isotonic balanced salt solution containing penicillin and streptomycin. Preferably, they should be transported on ice immediately to the laboratory. Alternatively, specimens should be frozen if possible [−70°C (−94°F)]. The suspected pathogen(s) should be indicated, because it may determine the type of cell culture or test animal to be inoculated.28

Other diagnostic tests are available that can yield faster results than culturing the virus. This approach may be especially useful for detecting those viruses difficult to propagate in culture and those such as papillomaviruses for which no reproducible culture system is available. Direct microscopic analysis may identify characteristic cells, as with Tzanck smears for herpesviruses (this test will not distinguish between HSV and VZV) or characteristic inclusion bodies with CMV-infected cells. For those lesions that contain large numbers of viral particles, electron microscopy of a lesion or its extract may provide morphologic identification of the virus, although this method is labor intensive, costly, and not readily available.

Rapid diagnostic tests for viral antigens are useful and widely available. Fluorescent antibody detection is commonly used to identify and distinguish between HSV-1, HSV-2, and VZV infections. Radioimmunoassay, enzyme-linked immunosorbent assay, immunoelectron microscopy, and immunoperoxidase techniques are other methods of identifying viral antigen by the use of virus-specific antibody.

Serologic studies to detect viral antibodies may be important for epidemiologic purposes, for identification of infection with viruses such as HIV and hepatitis B virus, and for those situations in which acute sera contain diagnostic antibodies, as with heterophile antibodies in infectious mononucleosis. In general, the most accurate serologic method of diagnosing this acute viral illness is comparison of immunoglobulin G antibody titers from acute and convalescent sera. This comparison is limited to retrospective diagnosis. A single positive titer for immunoglobulin M antibody can also suggest acute illness. Acute specimens should be taken as early in the illness as possible and convalescent specimens 2–4 weeks later. Serum should be separated immediately from the coagulated blood and refrigerated or preferably frozen at −20°C (−4°F) until antibody tests can be run simultaneously on both specimens.28 A fourfold or greater rise in antibody titer between acute and convalescent sera generally indicates recent infection. A variety of assays are used to measure antibody levels, each detecting a certain type of antigen–antibody reaction, with the type of virus partly determining the utility of any particular assay.

Culture systems possess some virus-specific constraints, but any virus should theoretically be detectable by recognition of viral nucleic acid if sufficient probes or primers can be obtained for the specific virus(es) of interest. Molecular-based diagnostic assays have had an important impact in direct laboratory identification as well as in improving our understanding of the role of microbes in certain diseases. Most commonly these molecular tests are based upon polymerase chain reaction (PCR) techniques, but many other molecular techniques can be used to diagnosis viral infections including Southern hybridization and in situ hybridization techniques.

Assays based on PCR and related techniques are extremely sensitive, often being able to detect as few as 1 infected cell in 10,000, and highly specific. The main pitfall of PCR is that its great sensitivity makes it very susceptible to yielding false-positive results via cross contamination with minute quantities of viral nucleic acid. Meticulous attention to detail and appropriate controls as well as closed system techniques that are increasingly available can usually overcome this potential liability. In situ PCR, which combines the sensitivity of PCR with histologic localization, is an even more sophisticated technique for viral detection.29

Cutaneous manifestations of viral infections are often sufficient for clinical diagnosis. The exact laboratory diagnostic method chosen, if any, will depend on a combination of factors such as resources, clinical disease suspicion, differential diagnosis, immediacy of results, and test accuracy.

Viruses are difficult to target therapeutically because of their replication only within host cells, relying on the host cell's biosynthetic processes. Specificity of antiviral therapy to target the virus without consequence to the host can be challenging. Strategies aimed at unique viral functions or proteins are critical for correct diagnosis, treatment, and prevention of disease. Effective treatment requires knowledge of the viral cycle and viral proteins.

More than 40 drugs are approved for the treatment of viral infections, and several of these have a key role in the treatment of cutaneous viral infections. The majority of these drugs are virostatic, not virocidal. Viral enzyme inhibitors, viral receptor inhibitors, chemotherapeutic agents, and immunomodulatory drugs are among the systemic and topical medications used to treat such infections.10 Our improved understanding of specific viral cycles, the viral interaction with the host cells, and the host immune response, has improved treatment for several viral infections. Specific antiviral treatments are covered in the respective disease chapters.

Although significant progress has occurred in antiviral therapy in recent decades, especially in the treatment of HIV, herpesviruses, and influenza virus infections, strategies aimed at prevention of viral infection have thus far proved more successful than the specific treatment of established infection for most viruses. Vaccines have been extremely useful in the prevention of a variety of viral illnesses and represent one of the premier medical achievements of the twentieth century. In 2006, the US Food and Drug Administration approved two new antiviral vaccines: a prophylactic VZV vaccine for the prevention of herpes zoster in persons 60 years of age and older, and a prophylactic vaccine against genital human HPV infection in women for prevention of cervical cancer caused by HPV-16 and HPV-18 and genital warts caused by HPV-6 and HPV-11. A second vaccine for the prevention of cervical cancer secondary to HPV-16 and HPV-18 (but not HPV-6 or HPV-11) was approved in 2009.30,31 A number of other vaccines are currently being researched for HSV, cytomegalovirus, dengue virus, West Nile virus, and HIV, among others.32

Recombinant DNA techniques are making it possible to develop effective, noninfectious subunit vaccines composed only of viral protein (as with the vaccines against HPV and hepatitis B virus), rather than traditional vaccines, which contain either an attenuated strain of the pathogen or an inactivated preparation of the entire virus. In addition to vaccines that induce active immunity, the passive administration of type-specific antibody soon after exposure is useful in select clinical situations, for example, in immunocompromised children exposed to varicella, and in acute rabies infections. Sensitive procedures for the detection of hepatitis B virus, hepatitis C virus, and HIV in potential blood donors has drastically reduced the incidence of transmission of these agents by transfusion. Public health measures such as safer sex, single use of needles, control of mosquitoes, and proper hand washing continue to be paramount in the prevention of viral disease.