Viral Illnesses

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Chapter 130

Viral Illnesses

Most viral infections are manifested as benign, self-limited upper respiratory tract or gastrointestinal infections, and therapy most often is directed at control of symptoms. Diagnosis of the specific illness is often neither necessary nor possible. On the other hand, emergency health care workers should be able to recognize viral diseases for which specific therapy or postexposure prophylaxis is available. In some cases, recognition of the manifestations of a specific viral illness and prompt institution of therapy or prevention can reduce morbidity and mortality and halt transmission of the disease to vulnerable populations. Examples include the early institution of acyclovir treatment of herpes simplex virus (HSV) encephalitis and the use of rabies vaccine and immune globulin for patients exposed to rabies. An example of how early recognition of disease can prevent widespread transmission was seen in the remarkable worldwide efforts that resulted in the halting of the SARS epidemic.

Classification

Viruses were first distinguished from other microorganisms by their ability to pass through filters of small pore size. Initial classifications of viruses were based on their pathologic properties (e.g., enteroviruses) or epidemiologic features (e.g., arthropod borne). More recently, classification has been based on the genetic relationships of the viruses. The components of the current classification are the type and structure of the viral nucleic acid, the type of symmetry of the virus capsid, and the presence or absence of an envelope (Table 130-1).

The genetic information of viruses is encoded in either DNA or RNA, which can be either single or double stranded and circular (closed ended) or linear (open ended). The genomes of the smallest viruses may code for only three or four proteins, whereas those of the largest viruses encode several hundred. A protein coat, called the capsid, is composed of a repeating series of protein subunits, called capsomeres. The viral nucleic acid and the surrounding protein coat are jointly referred to as the nucleocapsid. The use of repeating protein structures limits the shape of the capsid. All but the most complex viruses are either helically symmetrical or icosahedral. Finally, some virus nucleocapsids are surrounded by a lipid envelope acquired by the virus as it buds from the cell cytoplasm, nuclear membranes, or endoplasmic reticulum. Whereas this classification is important for the study and genetic identification of these organisms, for the purposes of clinical practice it is most useful to group viral illnesses by syndromic complexes based on presenting symptoms or signs.

Viral Immunizations

Whereas treatment strategies against most bacterial diseases have focused on eradication of bacteria from the host after disease has developed, the most successful strategies against viral diseases have concentrated on immunization, with the goal of preventing infection or illness. The history of immunization against viral diseases began in 1796, when Jenner injected pustular material from the lesions of cowpox into a child to prevent smallpox.1 The word vaccination is derived from vaccinia, referring to the skin reaction at the site of injection of such material for smallpox immunization, and originally meant “inoculation to render a person immune to smallpox.” Currently, the terms vaccination and immunization are used interchangeably to mean the administration of any vaccine. Immunization is a broader term that includes administration of immunobiologics such as immune globulins.

Viral vaccines are suspensions of live, attenuated, or inactivated whole viruses or parts of viruses that are administered to induce immunity. Some vaccines, such as the surface antigen of hepatitis B, are highly defined; others, such as live, attenuated viruses, are complex. Immune globulin is an antibody preparation obtained from large pools of human blood plasma. It is given intramuscularly for passive immunization against measles and hepatitis A and intravenously as replacement therapy for antibody deficiency disorders. Specific immune globulins are preparations of monoclonal antibodies or are prepared from special donor plasma pools preselected for high antibody titers against specific antigens, such as those presented by the hepatitis B, varicella-zoster, or rabies viruses. None of the immune globulin preparations, when properly prepared, can transmit infectious viruses.

The modern era of immunization began in 1885, when Louis Pasteur and colleagues injected the first of 14 daily doses of rabbit spinal cord suspensions containing progressively inactivated rabies virus into 9-year-old Joseph Meister, who had been bitten by a rabid dog 2 days earlier.2 The introduction of the inactivated poliomyelitis vaccine (IPV) in 1955 and the attenuated live oral polio vaccine (OPV) in 1962 has virtually eliminated the threat of paralytic poliomyelitis in the United States and other developed countries.2,3 Currently, a massive World Health Organization (WHO) campaign to eradicate polio worldwide is under way. As of 2007, in four countries (Pakistan, India, Afghanistan, and Nigeria), polio transmission has never been interrupted, and in several more countries in Asia and Africa, polio has reemerged.4 Vaccines against measles, mumps, rubella, influenza, and hepatitis B have greatly reduced morbidity and mortality associated with these diseases. The worldwide eradication of smallpox in 1977 is a testament to the advances made against viral diseases.

Administration of an immunobiologic agent does not automatically confer adequate immunity. Some preparations require more than one dose to produce an adequate antibody response, or periodic boosters may be needed to maintain protection. The simultaneous administration of immune globulin with a live virus vaccine may result in diminished antibody response to the vaccine. Deviation from the recommended volume or number of doses of any vaccine is strongly discouraged. Significant problems also remain in developing countries that cannot afford vaccines or have problems delivering vaccines to their at-risk populations. Table 130-2 summarizes currently available viral vaccines, their indications, and recommended uses.58 During the past several years, new vaccines have been developed against rotavirus,8 a major cause of diarrheal disease in young children worldwide; human papillomaviruses,9 which are associated with urogenital cancers; and herpes zoster (shingles),10 which is a major cause of morbidity in mostly elderly patients.

Table 130-2

Viral Vaccines

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Antiviral Chemotherapy

Because most viral illnesses are self-limited, treatment generally is targeted at amelioration of symptoms. The revolution in molecular biology has unlocked pathophysiologic mechanisms of viral diseases and opened up the field of viral chemotherapy. The initial therapeutic armamentarium for viral diseases has been aimed at illnesses associated with significant mortality (e.g., ribavirin for Lassa fever, acyclovir for HSV encephalitis) or those associated with significant end-organ damage (e.g., ganciclovir for cytomegalovirus [CMV] retinitis, acyclovir for ophthalmic zoster) (Table 130-3).

Amantadine and Rimantadine

Amantadine (Symmetrel) and rimantadine (Flumadine) are effective in the prevention and treatment of influenza A but have no activity against influenza B. They prevent or greatly reduce the uncoating of the viral RNA of influenza A after attachment and endocytosis by host cells. When it is initiated before exposure to influenza A, amantadine, 200 mg/day orally, is effective in preventing illness in 50 to 90% of subjects. When it is begun within 2 days after the onset of symptoms of influenza A, amantadine has reduced the duration of fever and systemic symptoms by 1 to 2 days. The drug generally is well tolerated; the most common therapy-limiting toxicities are central nervous system (CNS) effects, such as nervousness, lightheadedness, difficulty in concentrating, insomnia, and decreased psychomotor performance. These reactions occur particularly in elders who have impaired renal function; they should receive no more than 100 mg of amantadine daily. Rimantadine is mostly metabolized before renal excretion, and a lower incidence of CNS toxicity is associated with rimantadine than with amantadine. Other side effects include nausea and loss of appetite. Overdose is associated with an anticholinergic syndrome.11

Prophylaxis with daily amantadine or rimantadine is indicated for the duration of the influenza season in persons at high risk for contracting influenza in whom the influenza vaccine is contraindicated. When influenza A is reported in a community, appropriate management is to administer the influenza vaccine and to give amantadine for 2 weeks while antibody production is induced. Adults with acute onset of fever, cough, headache, and myalgias may be treated with 200 mg of amantadine, followed by 100 mg for 5 to 7 days.

During the 2005-2006 influenza season, the Centers for Disease Control and Prevention (CDC) recommended that amantadine and rimantadine no longer be used for treatment or prophylaxis of influenza A because of high levels of resistance among H3N2 viruses during that season.12 In 2008 the Advisory Committee on Immunization Practices updated their recommendations that these antivirals not be used for the treatment or chemoprophylaxis of influenza A in the United States until evidence of their effectiveness had been reestablished among circulating influenza A viruses.13 It seems unlikely they will come back into use, given persistent findings of adamantane resistance among influenza A viruses, including pandemic H1N1.14

Zanamivir and Oseltamivir

Zanamivir (Relenza) and oseltamivir (Flumadine) were approved in 1999 for the treatment of influenza A and B. Both medications act by inhibiting the activity of neuraminidase, an enzyme involved in the release of viral progeny from infected cells. They have been shown to decrease the duration of moderate or severe symptoms of influenza by approximately 1 day. Either medication should be started within 2 days of onset of symptoms if efficacy is to be expected. Zanamivir is administered by inhalation through a novel device (Diskhaler) and is approved for use in patients older than 12 years. The dose is two inhalations twice a day for 5 days. Most of the inhaled dose is deposited in the respiratory tract and cleared unchanged in the urine or stool. The most common side effect is bronchospasm in predisposed patients. Such patients should be given a fast-acting inhaled bronchodilator before receiving zanamivir.12,15

Olestamivir is an oral medication approved for patients older than 2 weeks. The dose is 75 mg twice daily for 5 days for adults and children weighing more than 40 kg. For children younger than 1 year, the dose is 3 mg/kg twice daily. For children 1 year or older, the dose varies by weight: 30 mg twice daily for those weighing less than 15 kg, 45 mg twice daily for those weighing 15 to 23 kg, and 60 mg twice daily for those weighing 23 to 40 kg. Initial reports of influenza virus resistance to oseltamivir were followed by a rapid rise in such resistance in H1N1 strains in the United States during the 2008-2009 influenza season.16 This resistance was not seen in the H3N2 strain that was also circulating during the same season. This resulted in the CDC’s issuing interim treatment recommendations in December 2008. If treatment was based on the identification of the infecting virus, zanamivir was recommended as first-line treatment for H1N1 and oseltamivir for H3N2. If such data were not available to the treating physician, the CDC recommended that clinicians review local disease surveillance data to determine which subtype was more likely to be the offending agent and choose treatment accordingly.13 With the onset of pandemic H1N1, there were initial concerns about the need for treatment and prophylaxis of patients at risk for complications from influenza, which prompted the CDC to create interim guidelines recommending that all hospitalized persons confirmed or thought to be infected with novel H1N1 and all patients at risk for complications be treated with antiviral agents.16,17 Because of concerns about the development of resistance to oseltamivir and zanamivir in influenza A viruses, recommendations for their use were limited to the population at risk for complications. To date, 0.5% of novel H1N1 viruses submitted to a United States influenza surveillance system were found to be resistant to olsetamivir.18

Famciclovir and Valacyclovir

Famciclovir (Famvir) and valacyclovir (Valtrex) are analogues of acyclovir that inhibit herpesvirus DNA synthesis.20,21 They are much more bioavailable than acyclovir and can be given less frequently. Both are available only as oral formulations and are effective in prevention of recurrent HSV infection.22,23

Ganciclovir

Ganciclovir (Cytovene) is used to treat life- or sight-threatening CMV infections in immunocompromised patients. Patients with acquired immunodeficiency syndrome (AIDS) and CMV colitis or esophagitis may also improve with ganciclovir. Some CMV isolates in immunocompromised patients have been found to be or may become resistant to ganciclovir.24 Ganciclovir also is effective against HSV, but isolates resistant to acyclovir also are resistant to ganciclovir. The most common therapy-limiting toxic effects of ganciclovir are granulocytopenia and thrombocytopenia, which usually are reversible when therapy ceases.

Foscarnet

Foscarnet (Foscavir, trisodium phosphonoformate hexahydrate, phosphonoformic acid) is an antiviral agent with activity against the human herpesviruses and HIV-1. It has been shown to be effective against CMV retinitis in AIDS patients and in acyclovir-resistant HSV and VZV infections.25 The main limiting form of toxicity with foscarnet is renal insufficiency, which usually is reversible after the drug is discontinued. Other side effects include malaise, headache, fatigue, nausea, vomiting, anemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia, and hypocalcemia.

Interferon Alfa, Recombinant

Interferons are naturally occurring proteins with both antiviral and immunomodulating properties that are produced by host cells in response to an inducer. Injected intralesionally, recombinant preparations of interferon-alpha (interferon alfa-2a [Roferon-A], interferon alfa-2b [Intron A], peginterferon alfa-2b [PegIntron]) are effective in treatment of refractory condyloma acuminatum.26 Patients with chronic hepatitis B who have lost hepatitis B e antigen with interferon therapy have better long-term outcome with lower rates of end-stage liver disease and its complications.27 Newer agents for treatment of hepatitis B infection include lamivudine, adefovir, entecavir, and telbivudine. Interferon alfa-2b combined with ribavirin has been shown to induce virologic and histologic response in patients with chronic hepatitis C infection. Therapy is discontinued because of side effects in approximately 20% of patients. The side effects of interferon therapy include fever, malaise, headache, fatigue, alopecia, and bone marrow suppression. Use of newer pegylated interferons is now standard therapy for hepatitis C.28,29

Therapy for HIV Infection

More than 30 antiretroviral drugs are currently available for the treatment of HIV infection (see Table 130-3). Treatment regimens usually include at least three of the recommended antiretroviral agents. Treatment of HIV infection is covered in Chapter 132.

Vaccine-Preventable Infections of Childhood

Mumps Virus

Clinical Features.: Nonsuppurative parotid swelling is the hallmark of mumps; the swelling may be unilateral. Trismus sometimes is a feature. In the first 3 days, the patient’s temperature may range between normal and 40° C. The most important but less common manifestations are epididymo-orchitis and meningitis. Orchitis occurs in 15 to 25% of postpubertal male patients and usually is unilateral. Although some degree of testicular atrophy is usual, the incidence of sterility is low, especially when the orchitis is unilateral. More than 50% of patients with mumps have a lymphocytic pleocytosis in the cerebrospinal fluid (CSF), and hypoglycorrhachia is common; symptomatic meningitis occurs in less than 10% of cases. Encephalitis is uncommon, occurring in 1 in 6000 cases, and is the major determinant of mortality. Congenital infection is rare but may result in fetal loss if it occurs in the first trimester. Rare complications of mumps include hydrocephalus, deafness, transverse myelitis, Guillain-Barré syndrome, pancreatitis, mastitis, oophoritis, myocarditis, and arthritis.

Differential Considerations.: In children, the diagnosis of mumps is made by a history of infectious exposure and the presence of parotid swelling and tenderness in association with constitutional symptoms. Laboratory confirmation generally is not required. Considerations in the differential diagnosis include other viral infections and other causes of parotid swelling and tenderness, such as bacterial parotitis or sarcoidosis.

A multistate outbreak of mumps was reported in the United States in 2006, with almost 6000 reported cases.30 Because the likelihood of infection was five times higher in persons who had received only one dose of mumps vaccine as opposed to those who had received two doses of the vaccine, updated recommendations that all persons receive two doses of mumps vaccine were introduced by the CDC’s Advisory Committee on Immunization Practices.31

Measles Virus (Rubeola)

Principles of Disease.: Measles is a highly communicable viral illness acquired as an infection of the respiratory tract. In general, all susceptible people exposed to an active case will acquire infection. After multiplication in the respiratory mucosa, the virus spreads to regional lymphoid cells and then travels in the bloodstream to leukocytes in the reticuloendothelial system. The clinical manifestations appear after a second viremic phase.

Before the availability of an effective vaccine in 1963, measles was a ubiquitous disease. In 2006, measles accounted for approximately 240,000 deaths globally; in view of higher death rates in previous years, it is clear that great strides have been made to decrease measles deaths in many areas of the world. Measles continues to be a leading cause of death in young children, especially those living in developing countries.32 Endemic measles in the United States has been eradicated, although the disease continues to occur among inadequately vaccinated persons who, in most instances, have been exposed to the disease by someone who has been infected abroad. A recent increase in the number of reported measles cases has been linked to travel abroad and unvaccinated status.33,34 Measles is a reportable disease, and the local health authority should be contacted. Children should be kept out of school for at least 4 days after the appearance of the rash.

Clinical Features.: The incubation period of measles is 10 to 14 days. Cough, coryza, conjunctivitis, and fever precede development of the characteristic rash by 2 to 4 days (Fig. 130-1A). Pinpoint grayish spots surrounded by bright red inflammation (Koplik’s spots) typically are found on the lateral buccal mucosa before the appearance of the rash and are considered pathognomonic for measles (Fig. 130-1B). Discrete red macular and papular lesions begin on the head and progress downward during a period of 3 days to cover the entire body. Laryngitis, tracheobronchitis, bronchiolitis, and pneumonitis may accompany the disease. Bacterial superinfections occasionally delay recovery. A rare acute encephalomyelitis, associated with a mortality rate of 25%, can complicate recovery. Unlike rubella, measles acquired during pregnancy is not teratogenic but may result in stillbirth or premature delivery.

Among infants and malnourished children, more severe illness is usual. Deaths from pneumonia and diarrhea occur in up to 10% of cases. Measles can exacerbate vitamin A deficiency and lead to blindness.

Measles may be manifested with atypical findings in people who were vaccinated with the inactivated vaccine before its removal from the market in the United States in 1968. An atypical rash, predominantly on the extremities, can accompany pneumonitis, pleural effusion, and peripheral edema. The current vaccine is a live, attenuated strain available as a single antigen or in combination with rubella vaccine or with mumps and rubella vaccines.

Subacute Sclerosing Panencephalitis

Rubella Virus (German Measles)

Clinical Features.: Rubella is a mild febrile illness associated with a diffuse maculopapular rash, fever, malaise, headache, and postauricular, occipital, and posterior cervical lymphadenopathy (Fig. 130-2).

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Figure 130-2 Rubella.

Transmission of rubella is through contact with respiratory secretions. The incubation period of rubella ranges from 12 to 23 days. Accompanied by viremia, the rash usually lasts 3 to 5 days. The disease is highly communicable from approximately 1 week before to 4 days after the onset of the rash. The most common complications of rubella are arthropathies, or frank arthritis, predominantly affecting the fingers, wrists, and knees; the arthropathies may persist for several months. Encephalitis and thrombocytopenia are rare complications.

Although the disease generally is a mild, febrile illness in children and adults, the consequences of rubella occurring during pregnancy (congenital rubella syndrome) may be tragic. Severe consequences include fetal death, premature delivery, and a variety of congenital defects, including hearing loss, cataracts, retinopathy, mental retardation, and a variety of cardiac abnormalities. The younger the fetus is at the time of a maternal infection, the more likely it is that the fetus will be affected. During the first 2 months of pregnancy, the fetus has an approximately 90% chance of being affected. The risk decreases to approximately 80% during the third month and to 66% during the fourth month, with no congenital defects reported from infection after the 17th week of pregnancy.

Management.: Rubella control is required to prevent birth defects in the offspring of women who have the disease during pregnancy. In the United States, vaccination to prevent rubella is recommended for all children at the age of 15 months. Vaccination results in a greater than 95% seroconversion rate. Because of the production of a transient viremia, pregnancy should be delayed for 3 months after a susceptible woman has been vaccinated. No cases of the congenital rubella syndrome attributable to rubella vaccine occurred in more than 300 women inadvertently vaccinated during pregnancy who carried their infants to term.35 There is no evidence of decreasing immunity with age. Persons with rubella should be cautioned to avoid contact with susceptible women. Because of an increasing failure to vaccinate susceptible persons, a moderate resurgence of rubella and a major increase in the congenital rubella syndrome in the United States occurred in 1990. Since then, a general decline in rubella incidence has been observed, but outbreaks continue to occur, especially among foreign-born adults.

Specific Viral Diseases by Presenting Clinical Syndrome

Viral Diseases with Significant Dermatologic Manifestations

Poxviridae

Perspective.: The elimination from the natural environment of variola virus, the virus that causes smallpox, at one time the most devastating worldwide pestilence, is one of the great medical and public health accomplishments of the past century.5 The elimination of smallpox from the natural environment was possible because of the lack of nonhuman reservoirs or human carriers of variola and the availability of rapid diagnostic techniques and an effective vaccine. Global eradication was certified by the WHO in 1980. Other human poxvirus diseases include monkeypox, vaccinia virus infection, molluscum contagiosum, orf, and paravaccinia virus infection. The poxviruses are the largest pathogenic viruses, consisting of complex, brick-shaped capsids and double-stranded DNA.

Variola (Smallpox), Monkeypox, Vaccinia, and Cowpox Viruses.: Within the Poxviridae family, the Orthopoxvirus genus contains at least nine homogeneous viruses, including variola, vaccinia, cowpox, and monkeypox viruses. The last naturally acquired case of smallpox occurred in Somalia in October 1977. Two cases occurred in 1978 in Birmingham, England, related to a research laboratory accident.

Clinical Features.: Smallpox is transmitted by infected droplets or close contact with a patient in any stage of illness. The most common manifestation in the unvaccinated host is variola major, which has a fatality rate of approximately 30%. The illness is characterized by a short prodrome of headache, backache, and fever. An ensuing enanthem progresses from small macules to papules and then vesicles during a few days. Lesions begin on the face and limbs and spread in a centrifugal pattern. These develop into 4- to 6-mm firm, deep-seated vesicles or pustules that umbilicate, crust, and then desquamate in the next several weeks (Fig. 130-3). All lesions are at the same stage of development. Modified, milder forms of smallpox can appear in previously vaccinated patients and, more rarely, in nonimmune hosts. There are also two more rare but almost uniformly fatal forms of smallpox: a fulminant, “hemorrhagic” form and “flat type” smallpox, characterized by plaquelike lesions.36

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Figure 130-3 Smallpox.

Management.: The CDC guidelines classify suspected cases of smallpox into categories of high, moderate, and low risk. Cases with high or moderate risk should prompt appropriate isolation and consultation with an infectious disease specialist or local health care authority. Quarantine, contact tracing, and immunization efforts are a priority for public health officials, and prompt involvement of the appropriate agencies will be crucial to containment efforts in the event of an outbreak.

Immunization with vaccinia virus was the cornerstone of smallpox containment and eradication efforts. Vaccinia virus immunization has been associated with morbidity and death in vaccinated persons and their close contacts. The decision to vaccinate must balance the risk of smallpox infection against the risk of vaccine-related injury. Pre-event vaccination is contraindicated in several groups of patients, including those who are pregnant, are breast-feeding, have significant immunosuppression, or have eczema. Close household contacts of persons at risk for serious side effects from vaccine should not be vaccinated. There are no absolute contraindications to vaccination for persons who have been exposed to smallpox.

Vaccinia Virus:

Perspective.: The origin of the vaccinia virus is not well established, but it is the poxvirus that is used to produce the smallpox vaccine. Although primary infection (through live virus vaccination) or secondary infection (from virus shed from an immunized patient) with vaccinia virus is usually well tolerated, severe local reactions from immunization as well as disseminated severe manifestations of primary or secondary infection have been well described. The normal reaction to vaccinia vaccine is a localized inflammatory reaction with scar formation. Viremia is possible, but manifestations are of a mild viral illness. In immunocompromised hosts, such as some young infants or persons with aberrant cell-mediated immunity, a syndrome of multiplying and aggressive necrotic skin lesions called progressive vaccinia can lead to death.

Cowpox Virus:

Perspective.: Edward Jenner, in his An Inquiry into the Causes and Effects of the Variolae Vaccinae in 1798, observed that on inoculation into humans, the pustular material from the lesions of cowpox protected them from infection with smallpox.1 Cowpox virus is similar to vaccinia virus and is found mostly in Europe, countries of the former Soviet Union, and Central Asia. It has natural reservoirs in wild animals but can also cause infection in domesticated animals, including cattle and cats.

Monkeypox Virus:

Clinical Features.: The disease of monkeypox is clinically similar to that of smallpox. Most cases have occurred in west and central Africa, with a case fatality rate of 1 to 10% and higher death rates among children. An outbreak of 72 cases in the Midwest United States in spring 2003 was traced to contact with prairie dogs housed with Gambian giant rats that were imported from Ghana.39 No deaths were associated with this outbreak. There seems to be an increase in monkeypox cases that could be attributable to decreased cross-immunity from the cessation of smallpox vaccination as well as to increased human exposure to rainforest wildlife from hunting “bush meat.” Monkeypox has also been seen as a potential biowarfare agent, but the greater threat for global spread of the disease comes from the illegal international trade of exotic animals.40

Parapoxviruses, Molluscum Contagiosum, and Tanapox Viruses:

Clinical Features.: The milker’s node virus, or paravaccinia virus, produces vesicular lesions on the udders or teats in cattle and is transmitted to humans by direct contact. Milker’s nodules, which develop on the fingers or hands, are small, watery, painless nodules occasionally associated with lymphadenopathy. The lesions generally resolve completely within 3 to 8 weeks.

Bovine pustular stomatitis, ecthyma contagiosum, and orf viruses cause papillomatous lesions on the mucous membranes and corneas of sheep. Single lesions generally develop in infected persons at the site of an abrasion.

Molluscum contagiosum is a generally benign human disease characterized by multiple small, painless, pearly, umbilicated nodules. They appear on epithelial surfaces, commonly in anogenital regions, and may be spread through close contact or autoinoculation. In immunocompetent persons, the lesions may clear rapidly or persist for up to 18 months. The infection often is seen in patients with HIV infection, in whom the lesions often are not restricted to the genital area and may increase in size and number.41 Curettage or other forms of local ablation may be helpful in such recalcitrant cases.

Herpesviridae

Principles of Disease.: At least eight human herpesviruses are known. Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are the agents of herpes genitalis, labialis, and encephalitis. Varicella-zoster virus (VZV) is the etiologic agent of chickenpox and herpes zoster. Epstein-Barr virus (EBV) is the agent of infectious mononucleosis and also is associated with nasopharyngeal carcinoma, Burkitt’s lymphoma, and other lymphoproliferative syndromes. Cytomegalovirus (CMV) is associated with heterophil-negative infectious mononucleosis and invasive disease in immunocompromised patients. Human herpesvirus 6 (HHV-6) is associated with roseola infantum.42 The role of human herpesvirus 7 (HHV-7) has not been completely elucidated. Human herpesvirus 8 (HHV-8) is associated with Kaposi’s sarcoma,43 body cavity–based lymphomas, and multicentric Castleman’s disease. In addition, a closely related monkey virus, herpesvirus simiae or herpes B virus, has been shown to cause fatal encephalitis in humans.

Herpes Simplex Virus:

Principles of Disease.: A localized primary lesion, latency, and a tendency for local recurrence characterize infections with HSV-1 and HSV-2 (herpesvirus hominis). The primary lesion with HSV-1 may be mild and inapparent; the first outbreak may occur during childhood. Reactivation of latent HSV-1 infection usually results in herpes labialis (cold sores, fever blisters). Neurologic involvement is not uncommon with HSV-1. Although such involvement usually occurs in association with a primary infection, neurologic signs may appear after a recrudescence and may be manifested as encephalitis. Although it is uncommon, HSV-1 encephalitis is one of the most common causes of encephalitis in the United States, with estimates of several hundred to several thousand cases occurring yearly. HSV-2 most commonly is associated with genital herpes, although either HSV-1 or HSV-2 may infect any mucous membrane, depending on the route of inoculation. HSV-2 is commonly associated with aseptic meningitis rather than with meningoencephalitis. The incubation period for primary herpes infection is 2 to 12 days.44

On contact with abraded skin or mucous membranes, HSV replicates locally in epithelial cells, which lyse and cause a local inflammatory response. Thin-walled vesicles on an erythematous base are the characteristic lesions of superficial HSV infection. Multinucleated giant cells with ballooning degeneration and intranuclear inclusions may be seen on a Tzanck preparation of a smear of material obtained from the base of these vesicles. After primary infection, HSV can become latent within sensory nerve ganglia. Emotional stress, sunlight, fever, or local trauma can trigger reactivation of the virus. HSV encephalitis usually involves the temporal lobes, resulting in a necrotizing, hemorrhagic encephalitis.

Clinical Features.: Primary HSV-1 often is asymptomatic but may appear as pharyngitis and gingivostomatitis in children younger than 5 years. Associated with fever, pharyngeal edema, erythema, cervical adenopathy, and multiple small vesicles that ulcerate and multiply, the disease generally lasts 10 to 14 days. Recurrences develop in 60 to 90% of people after primary infection but generally are milder than the primary infection. Vesicles generally recur on the vermilion border, usually are small, and crust within 48 hours.

Herpes simplex infections of the eye most often are caused by HSV-1. Primary infections are manifested as follicular conjunctivitis, blepharitis, or corneal epithelial opacities, which usually heal completely within 2 to 3 weeks. Recurrences may result in keratitis. Branching dendritic ulcers, detectable with fluorescein staining, are diagnostic and may result in diminished visual acuity. Deep stromal involvement may result in corneal scarring.

Primary herpetic finger infections (i.e., herpetic whitlow) generally are caused by HSV-1 among medical or dental personnel and by HSV-2 among the general population. The lesions are associated with intense pain and itching but generally resolve in 2 to 3 weeks. Recurrent whitlow with severe local neuralgia may occur.

Primary genital herpes generally is seen in the sexually active population and is caused by HSV-2 in 70 to 95% of cases. The lesions usually involve the shaft or glans of the penis in men and the vulva, perineum, buttocks, cervix, and vagina in women. Primary perianal and anal herpes can be seen in persons who have had receptive anal intercourse. Primary infection may be associated with fever, malaise, anorexia, and inguinal adenopathy. Vaginal discharge is common, and urethral involvement can result in urinary retention. Herpetic sacral radiculomyelitis is uncommon but is associated with urinary retention, myalgias, and obstipation. The lesions of primary genital herpes can last for several weeks before completely clearing. Recurrences of genital herpes generally are shorter and milder than the primary episodes and may be preceded by a prodrome of tenderness, itching, or tingling. Healing of recurrent lesions generally is complete in 6 to 10 days. Minimally symptomatic lesions are often overlooked as recurrent episodes by the patient. Over time, symptomatic recurrences can be expected to diminish in frequency, intensity, and duration, but persons who have diminished immunity, such as those infected with HIV, may suffer with prolonged, frequent, or atypical recurrences.

Neonatal herpes infection occurs in 8 to 60 in 100,000 births, depending on the population of patients studied, and is caused by the transmission of the virus at the time of delivery. Most babies with neonatal herpes infection are born to asymptomatic mothers, but there appears to be a much higher risk of transmission by a mother who experiences the first genital herpes infection during pregnancy. It is estimated that 50 to 80% of infants with neonatal herpes are born to mothers who acquire genital herpes infection near term. This might indicate that women with long-standing infection transmit antibody to the fetus that decreases disease manifestation after exposure to virus during birth.45 The use of invasive monitoring and premature delivery also are associated with an increased risk of infection.46 Infection may be manifested after several days to weeks with vesicles or conjunctivitis; neurologic involvement, with seizures, cranial nerve palsies, lethargy, and coma, is common. Untreated disseminated or CNS disease is fatal in more than 70% of patients.

Encephalitis caused by HSV is uncommon, but it is the most common acute, nonepidemic encephalitis in the United States. Cases do not have a seasonal distribution. Other than in the neonate, HSV-1 is the usual pathogen. The clinical disease begins acutely, with fever and focal neurologic signs, often localized to the temporal lobe. The patient may complain of a bad odor not perceived by anyone else (temporal lobe hallucination). Common clinical manifestations include headache, meningeal signs, lethargy, confusion, stupor, and coma. The mortality rate among untreated patients with CNS disease approaches 80%, and less than 10% of patients are left with no neurologic sequelae. Treatment with acyclovir appears to reduce mortality and to decrease the neurologic sequelae more effectively than treatment with vidarabine.

Management.: Oral acyclovir (400 mg three times daily), oral valacyclovir (1 g twice daily), or intravenous acyclovir (5 mg/kg three times daily) is recommended for treatment of primary genital herpes or mucocutaneous herpes in the immunocompromised host, although some authorities use higher dosages in these patients despite no clear evidence.47 Because of the safety and efficacy of oral acyclovir, there is little indication for use of acyclovir ointment. In people with severe or frequent recurrences, acyclovir, ranging in doses from 200 mg five times daily to 800 mg once daily, can be used as an effective suppressive regimen. Both famciclovir and valacyclovir also are approved for suppressive therapy and daily dosing of the affected partner in an HSV-discordant couple; a 500-mg dose of valacyclovir yielded about a 50% reduction in transmission to the unaffected partner in a recent study.45

In the immunocompromised host, acyclovir is effective for both treatment and prophylaxis of recurrent mucocutaneous herpes. Foscarnet has been shown to be effective for the treatment of mucocutaneous herpes that is resistant to acyclovir. Intravenous acyclovir, 10 mg/kg every 8 hours, is the treatment of choice for HSV encephalitis in adults and children. Vidarabine, 30 mg/kg/day intravenously, also is effective in neonatal encephalitis but is rarely used.

Several vaccines against HSV have reached differing phases of development and testing, but none has shown enough promise to become clinically available.48 Research in this area is ongoing.

Disposition.: Patients with cutaneous HSV infections generally can be managed easily. The diagnosis often carries with it a great deal of stigma that should be addressed. Assurance of the generally benign nature of the infection is helpful. Counseling should include cautions about the transmissibility of the virus, even during asymptomatic periods. Women of childbearing age should discuss management of HSV infection during pregnancy and delivery with their obstetricians. It is clear that shedding of HSV occurs when there is no clinical outbreak in persons with a history of recurrent lesions and that persons who have never had recognizable lesions but who have antibody to HSV can also shed virus. With the advent of dependable commercialized serologic tests for HSV-1 and HSV-2, it is hoped that clinicians will be better able to identify persons with asymptomatic infection and to provide counseling on ways to decrease transmission. There are no clear current guidelines for how to decrease such transmission, but the routine use of condoms and suppressive therapy with antiviral medications are reasonable until more research in the field is conducted.

Encephalitis caused by HSV constitutes a treatable medical emergency. Prompt recognition and institution of appropriate therapy in the emergency department (ED) before a definitive diagnosis has been made may decrease the high mortality rate and neurologic sequelae associated with this disease. When HSV encephalitis is suspected, empirical initiation of intravenous acyclovir is indicated in the ED. This approach has minimal toxicity and demonstrable efficacy.

Varicella-Zoster Virus:

Clinical Features.: Chickenpox is an acute, generalized viral disease characterized by sudden onset of fever, malaise, and a skin eruption that initially is maculopapular and then becomes vesiculated for several days before a granular scab is left (Fig. 130-4). Lesions occur in crops, with several stages present at the same time. Lesions can appear anywhere on the skin and mucous membranes. There may be few lesions and mild, inapparent infections. Most cases occur in children younger than 9 years; adults with the disease may have high fevers and severe constitutional symptoms. Children with acute leukemia are at increased risk for disseminated disease, which carries a case fatality rate of greater than 5%. Neonates in whom varicella develops before 10 days of age and mothers who contract the disease in the perinatal period are at increased risk for generalized infection. Fatal disease in adults, although uncommon, usually is associated with pneumonic involvement. In children, fatal disease usually is associated with septic complications and encephalitis.

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Figure 130-4 Chickenpox.

Herpes zoster is due to reactivation of VZV that has been latent in a dorsal root ganglion after an episode of chickenpox; it occurs predominantly in older adults and those with an immunocompromised state, such as HIV infection.49 There are about 1 million cases in the United States annually.50 The rash is often preceded by tingling or hypesthesia; multiple vesicles on an erythematous base appear in crops along nerve pathways supplied by sensory nerves of a single dorsal root ganglion or an associated group of dorsal root ganglia. The distribution usually is unilateral and dermatomal (Fig. 130-5). The lesions often are extremely painful. Postherpetic neuralgia, which is defined as continued pain for 6 months after lesions have healed, is more likely to occur in elders with larger and more painful rashes. It can last for months or years and is refractory to treatment. Ophthalmic infection, which can occur without other cutaneous lesions, can lead to corneal ulceration. Two relatively rare but often cited facial zoster infections are Hutchinson’s sign, which is the appearance of a blister on the tip of the nose with herpes ophthalmicus, and Ramsey Hunt syndrome, which is characterized by localized pain, facial weakness, and a rash of the face or ear canal that can be subtle.51

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Figure 130-5 Herpes zoster.

Management.: Use of acyclovir for uncomplicated chickenpox in children is safe but only modestly effective. Parents of children with chickenpox should be cautioned not to give their children aspirin or aspirin-containing compounds because of the strong association between this practice and the development of Reye’s syndrome.52 Acetaminophen can be used as an antipyretic. Adults experience increased morbidity and mortality from chickenpox, so treatment of otherwise healthy adults with acyclovir, famciclovir, or valacyclovir frequently is indicated. Patients with pneumonitis or other severe illness should be treated with intravenous acyclovir. In immunocompromised patients, varicella-zoster immune globulin and intravenous acyclovir have been shown to decrease morbidity.

A live, attenuated vaccine that shows a high degree of protection for both normal children and children with leukemia was licensed in the United States in 1995. It is recommended for immunocompetent people older than 12 months. In those older than 12 years, two doses of vaccine are to be administered 4 to 8 weeks apart. It also is recommended for use as postexposure prophylaxis in the nonimmune host. The vaccine is most effective in preventing or attenuating illness in these circumstances if it is administered within the first 3 to 5 days after exposure.53 The vaccine is a live attenuated virus and not recommended for use in immunocompromised patients.

Uncomplicated herpes zoster generally is treated with supportive measures, especially pain control, and antivirals (acyclovir, famciclovir, or valacyclovir). The currently recommended dosages are 800 mg five times a day for acyclovir, 500 mg three times a day for famciclovir, and 1 g three times a day for valacyclovir. Both famciclovir and valacyclovir are preferred to acyclovir because of increased compliance. In addition, there are data that valacyclovir 1.5 g twice a day yields equivalent therapeutic effect, and one might guess that compliance may be improved with dosing twice a day compared with three times a day, but this regimen is not currently approved for the treatment of herpes zoster.54 There is good evidence that treatment with antivirals reduces the incidence and severity of postherpetic neuralgia, and treatment should be considered for those most at risk for this complication, such as those with large painful rashes and those 50 years of age or older.54 Treatment with intravenous acyclovir should be considered for patients with disseminated disease and complicated zoster (involving more than one dermatome). Susceptible immunocompromised patients exposed to infected persons should receive varicella-zoster immune globulin within 72 hours to prevent or to modify clinical illness. Foscarnet is useful for treatment of infections due to acyclovir-resistant VZV in immunocompromised patients.

The use of corticosteroids to decrease the incidence of postherpetic neuralgia is controversial. A recent Cochrane review could not support the practice.55 Nevertheless, the use of corticosteroids in conjunction with antivirals in persons who are at highest risk for postherpetic neuralgia and do not have contraindications to systemic steroid therapy is condoned by reliable sources. Herpes zoster is estimated to eventually occur in approximately 30% of the population; the introduction of an effective vaccine led to the recommendation that immunocompetent persons older than 60 years be vaccinated with one dose of varicella-zoster vaccine.

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