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InternalMed_Harrison. Acyclovir is administered at a dosage of 800 mg five times daily for 7–10 days. However, valacyclovir and famciclovir are superior in terms of pharmacokinetics and pharmacodynamics and should be used preferentially. Famciclovir, the prodrug of penciclovir, is at least as effective as acyclovir and perhaps more so; the dose is 500 mg by mouth three times daily for 7 days. Valacyclovir, the prodrug of acyclovir, accelerates healing and resolution of zosterassociated pain more promptly than acyclovir. The dose is 1 g by mouth three times daily for 5–7 days. Compared with acyclovir, both famciclovir and valacyclovir offer the advantage of less frequent administration. All three of these drugs are now off patent. In severely immunocompromised hosts (e.g., transplant recipients, patients with lymphoproliferative malignancies), both chickenpox and herpes zoster (including disseminated disease) should be treated, at least at the outset, with IV acyclovir, which reduces the occurrence of


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InternalMed_Harrison. lymphoproliferative malignancies), both chickenpox and herpes zoster (including disseminated disease) should be treated, at least at the outset, with IV acyclovir, which reduces the occurrence of visceral complications but has no effect on healing of skin lesions or pain. The dose is 10 mg/kg every 8 h for 7 days. For low-risk immunocompromised hosts, oral therapy with valacyclovir or famciclovir appears beneficial. If medically feasible, it is desirable to decrease immunosuppressive treatment concomitant with the administration of IV acyclovir. Patients with varicella pneumonia often require ventilatory support. Persons with zoster ophthalmicus should be referred immediately to an ophthalmologist. Therapy for this condition consists of the administration of analgesics for severe pain and the use of atropine. Acyclovir, valacyclovir, and famciclovir all accelerate healing. Decisions about the use of glucocorticoids should be made by the ophthalmologist. The management of acute


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InternalMed_Harrison. and the use of atropine. Acyclovir, valacyclovir, and famciclovir all accelerate healing. Decisions about the use of glucocorticoids should be made by the ophthalmologist. The management of acute neuritis and/or postherpetic neuralgia can be particularly difficult. In addition to the judicious use of analgesics ranging from nonnarcotics to narcotic derivatives, drugs such as gabapentin, pregabalin, amitriptyline hydrochloride, lidocaine (patches), and fluphenazine hydrochloride are reportedly beneficial for pain relief. In one study, glucocorticoid therapy administered early in the course of localized herpes zoster significantly accelerated such quality-of-life improvements as a return to usual activity and termination of analgesic medications. The dose of prednisone administered orally was 60 mg/d on days 1–7, 30 mg/d on days 8–14, and 15 mg/d on days 15–21. This regimen is appropriate only for relatively healthy elderly persons with moderate or severe pain at presentation. Patients


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InternalMed_Harrison. 60 mg/d on days 1–7, 30 mg/d on days 8–14, and 15 mg/d on days 15–21. This regimen is appropriate only for relatively healthy elderly persons with moderate or severe pain at presentation. Patients with osteoporosis, diabetes mellitus, glycosuria, or hypertension may not be appropriate candidates. Glucocorticoids should not be used without concomitant antiviral therapy.


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InternalMed_Harrison. Three methods are used for the prevention of VZV infections. First, a live attenuated varicella vaccine (Oka) is recommended for all children >1 year of age (up to 12 years of age) who have not had chickenpox and for adults known to be seronegative for VZV. Two doses are recommended for all children: the first at 12–15 months of age and the second at ~4–6 years of age. VZV-seronegative persons >13 years of age should receive two doses of vaccine at least 1 month apart. The vaccine is both safe and efficacious. Breakthrough cases are mild and may result in spread of the vaccine virus to susceptible contacts. The universal vaccination of children is resulting in a decreased incidence of chickenpox in sentinel communities. Furthermore, inactivation of the vaccine virus significantly decreases the occurrence of herpes zoster after hematopoietic stem-cell transplantation. 1. Exposure to a person with chickenpox or zoster a. Household: residence in the same household b.


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InternalMed_Harrison. 1. Exposure to a person with chickenpox or zoster a. Household: residence in the same household b. Playmate: face-to-face indoor play c. Varicella: same 2to 4-bed room or adjacent beds in large ward, faceto-face contact with infectious staff member or patient, visit by a person deemed contagious Zoster: intimate contact (e.g., touching or hugging) with a person deemed contagious d. Newborn infant: onset of varicella in the mother ≤5 days before delivery or ≤48 h after delivery; VZIG not indicated if the mother has zoster 2. Patient should receive VZIG as soon as possible but not >96 h after exposure Candidates (Provided They Have Significant Exposure) Include: 1. Immunocompromised susceptible children without a history of varicella or varicella immunization 2. 3. Newborn infants whose mother had onset of chickenpox within 5 days before or within 48 h after delivery 4.


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InternalMed_Harrison. 3. Newborn infants whose mother had onset of chickenpox within 5 days before or within 48 h after delivery 4. Hospitalized premature infant (≥28 weeks of gestation) whose mother lacks a reliable history of chickenpox or serologic evidence of protection against varicella 5. Hospitalized premature infant (<28 weeks of gestation or ≤1000-g birth weight), regardless of maternal history of varicella or VZV serologic status In individuals >50 years of age, a VZV vaccine with 18 times the viral content of the Oka vaccine decreased the incidence of shingles by 51%, the burden of illness by 61%, and the incidence of postherpetic neuralgia by 66%. The Advisory Committee on Immunization Practices has therefore recommended that persons in this age group be offered this vaccine in order to reduce the frequency of shingles and the severity of postherpetic neuralgia.


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InternalMed_Harrison. A second approach is to administer varicella-zoster immune globulin (VZIG) to individuals who are susceptible, are at high risk for developing complications of varicella, and have had a significant exposure. This product should be given within 96 h (preferably within 72 h) of the exposure. Indications for administration of VZIG appear in Table 217-1. Lastly, antiviral therapy can be given as prophylaxis to individuals at high risk who are ineligible for vaccine or who are beyond the 96-h window after direct contact. While the initial studies have used acyclovir, similar benefit can be anticipated with either valacyclovir or famciclovir. Therapy is instituted 7 days after intense exposure. At this time, the host is midway into the incubation period. This approach significantly decreases disease severity, if not totally preventing disease. Epstein-Barr virus Infections, 218 Including Infectious Mononucleosis Jeffrey I. Cohen


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InternalMed_Harrison. Epstein-Barr virus Infections, 218 Including Infectious Mononucleosis Jeffrey I. Cohen Epstein-Barr virus (EBV) is the cause of heterophile-positive infectious mononucleosis (IM), which is characterized by fever, sore throat, lymphadenopathy, and atypical lymphocytosis. EBV is also associated with several tumors, including nasopharyngeal and gastric carcinoma, Burkitt’s lymphoma, Hodgkin’s disease, and (in patients with immunodeficiencies) B cell lymphoma. The virus is a member of the family Herpesviridae. The two types of EBV that are widely prevalent in nature are not distinguishable by conventional serologic tests.


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InternalMed_Harrison. EBV infections occur worldwide. These infections are most common in early childhood, with a second peak during late adolescence. By adulthood, more than 90% of individuals have been infected and have antibodies to the virus. IM is usually a disease of young adults. In lower socioeconomic groups and in areas of the world with deficient standards of hygiene (e.g., developing regions), EBV tends to infect children at an early age, and IM is uncommon. In areas with higher standards of hygiene, infection with EBV is often delayed until adulthood, and IM is more prevalent.


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InternalMed_Harrison. EBV is spread by contact with oral secretions. The virus is frequently transmitted from asymptomatic adults to infants and among young adults by transfer of saliva during kissing. Transmission by less intimate contact is rare. EBV has been transmitted by blood transfusion and by bone marrow transplantation. More than 90% of asymptomatic seropositive individuals shed the virus in oropharyngeal secretions. Shedding is increased in immunocompromised patients and those with IM.


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InternalMed_Harrison. EBV is transmitted by salivary secretions. The virus infects the epithelium of the oropharynx and the salivary glands and is shed from these cells. While B cells may become infected after contact with epithelial cells, studies suggest that lymphocytes in the tonsillar crypts can be infected directly. The virus then spreads through the bloodstream. The proliferation and expansion of EBV-infected B cells along with reactive T cells during IM result in enlargement of lymphoid tissue. Polyclonal activation of B cells leads to the production of antibodies to host-cell and viral proteins. During the acute phase of IM, up to 1 in every 100 B cells in the peripheral blood is infected by EBV; after recovery, 1–50 in every 1 million B cells is infected. During IM, there is an inverted CD4+/CD8+ T cell ratio. The percentage of CD4+ T cells decreases, while there are large clonal expansions of CD8+ T cells; up to 40% of CD8+ T cells are directed against EBV antigens during acute infection. Memory


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InternalMed_Harrison. ratio. The percentage of CD4+ T cells decreases, while there are large clonal expansions of CD8+ T cells; up to 40% of CD8+ T cells are directed against EBV antigens during acute infection. Memory B cells, not epithelial cells, are the reservoir for EBV in the body. When patients are treated with acyclovir, shedding of EBV from the oropharynx stops but the virus persists in B cells.


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InternalMed_Harrison. The EBV receptor (CD21) on the surface of B cells is also the receptor for the C3d component of complement. EBV infection of epithelial cells results in viral replication and production of virions. When B cells are infected by EBV in vitro, they become transformed and can proliferate indefinitely. During latent infection of B cells, only the EBV nuclear antigens (EBNAs), latent membrane proteins (LMPs), and small EBV RNAs (EBERs) are expressed in vitro. EBV-transformed B cells secrete immunoglobulin; only a small fraction of these cells produce virus.


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InternalMed_Harrison. Cellular immunity is more important than humoral immunity in controlling EBV infection. In the initial phase of infection, suppressor T cells, natural killer cells, and nonspecific cytotoxic T cells are important in controlling the proliferation of EBV-infected B cells. Levels of markers of T cell activation and serum interferon γ are elevated. Later in infection, human leukocyte antigen–restricted cytotoxic T cells that recognize EBNAs and LMPs and destroy EBV-infected cells are generated. If T cell immunity is compromised, EBV-infected B cells may begin to proliferate. When EBV is associated with lymphoma in immunocompetent persons, virus-induced proliferation is but one step in a multi-step process of neoplastic transformation. In many EBV-containing tumors, LMP-1 mimics members of the tumor necrosis factor receptor family (e.g., CD40), transmitting growth-proliferating signals.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Signs and Symptoms Most EBV infections in infants and young children either are asymptomatic or present as mild pharyngitis with or without tonsillitis. In contrast, ~75% of infections in adolescents present as IM. IM in the elderly often presents with nonspecific symptoms, including prolonged fever, fatigue, myalgia, and malaise. In contrast, pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytes are relatively rare in elderly patients. Median Percentage of Manifestation Patients (Range) Sore throat 75 (50–87) Malaise 47 (42–76) Headache 38 (22–67) Abdominal pain, nausea, or vomiting 17 (5–25) Chills 10 (9–11)


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InternalMed_Harrison. The incubation period for IM in young adults is ~4–6 weeks. A prodrome of fatigue, malaise, and myalgia may last for 1–2 weeks before the onset of fever, sore throat, and lymphadenopathy. Fever is usually low-grade and is most common in the first 2 weeks of the illness; however, it may persist for >1 month. Common signs and symptoms are listed along with their frequencies in Table 218-1. Lymphadenopathy and pharyngitis are most prominent during the first 2 weeks of the illness, while splenomegaly is more prominent during the second and third weeks. Lymphadenopathy most often affects the posterior cervical nodes but may be generalized. Enlarged lymph nodes are frequently tender and symmetric but are not fixed in place. Pharyngitis, often the most prominent sign, can be accompanied by enlargement of the tonsils with an exudate resembling that of streptococcal pharyngitis. A morbilliform or papular rash, usually on the arms or trunk, develops in ~5% of cases (Fig. 218-1). Many patients


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InternalMed_Harrison. of the tonsils with an exudate resembling that of streptococcal pharyngitis. A morbilliform or papular rash, usually on the arms or trunk, develops in ~5% of cases (Fig. 218-1). Many patients treated with ampicillin develop a macular rash; this rash is not predictive of future adverse reactions to penicillins. Erythema nodosum and erythema multiforme also have been described (Chap. 72). The severity of the disease correlates with the levels of CD8+ T cells and EBV DNA in the blood. Most patients have symptoms for 2–4 weeks, but nearly 10% have fatigue that persists for ≥6 months.


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InternalMed_Harrison. FIGuRE 218-1 Rash in a patient with infectious mononucleosis due to Epstein-Barr virus. (Courtesy of Maria Turner, MD; with permission.) Epstein-Barr Virus Infections, Including Infectious Mononucleosis FIGuRE 218-2 Atypical lymphocytes from a patient with infectious mononucleosis due to Epstein-Barr virus.


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InternalMed_Harrison. Epstein-Barr Virus Infections, Including Infectious Mononucleosis FIGuRE 218-2 Atypical lymphocytes from a patient with infectious mononucleosis due to Epstein-Barr virus. Laboratory Findings The white blood cell count is usually elevated and peaks at 10,000–20,000/μL during the second or third week of illness. Lymphocytosis is usually demonstrable, with >10% atypical lymphocytes. The latter cells are enlarged lymphocytes that have abundant cytoplasm, vacuoles, and indentations of the cell membrane (Fig. 218-2). CD8+ cells predominate among the atypical lymphocytes. Low-grade neutropenia and thrombocytopenia are common during the first month of illness. Liver function is abnormal in >90% of cases. Serum levels of aminotransferases and alkaline phosphatase are usually mildly elevated. The serum concentration of bilirubin is elevated in ~40% of cases.


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InternalMed_Harrison. Complications Most cases of IM are self-limited. Deaths are very rare and are most often due to central nervous system (CNS) complications, splenic rupture, upper airway obstruction, or bacterial superinfection.


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InternalMed_Harrison. When CNS complications develop, they usually do so during the first 2 weeks of EBV infection; in some patients, especially children, they are the only clinical manifestations of IM. Heterophile antibodies and atypical lymphocytes may be absent. Meningitis and encephalitis are the most common neurologic abnormalities, and patients may present with headache, meningismus, or cerebellar ataxia. Acute hemiplegia and psychosis also have been described. The cerebrospinal fluid contains mainly lymphocytes, with occasional atypical lymphocytes. Most cases resolve without neurologic sequelae. Acute EBV infection has also been associated with cranial nerve palsies (especially those involving cranial nerve VII), Guillain-Barré syndrome, acute transverse myelitis, and peripheral neuritis.


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InternalMed_Harrison. Autoimmune hemolytic anemia occurs in ~2% of cases during the first 2 weeks. In most cases, the anemia is Coombs-positive, with cold agglutinins directed against the red blood cell antigen. Most patients with hemolysis have mild anemia that lasts for 1–2 months, but some patients have severe disease with hemoglobinuria and jaundice. Nonspecific antibody responses may also include rheumatoid factor, antinuclear antibodies, anti–smooth muscle antibodies, antiplatelet antibodies, and cryoglobulins. IM has been associated with red-cell aplasia, severe granulocytopenia, thrombocytopenia, pancytopenia, and hemophagocytic lymphohistiocytosis. The spleen ruptures in <0.5% of cases. Splenic rupture is more common among male than female patients and may manifest as abdominal pain, referred shoulder pain, or hemodynamic compromise.


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InternalMed_Harrison. Hypertrophy of lymphoid tissue in the tonsils or adenoids can result in upper airway obstruction, as can inflammation and edema of the epiglottis, pharynx, or uvula. About 10% of patients with IM develop streptococcal pharyngitis after their initial sore throat resolves. Other rare complications associated with acute EBV infection include hepatitis (which can be fulminant), myocarditis or pericarditis, pneumonia with pleural effusion, interstitial nephritis, genital ulcerations, and vasculitis.


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InternalMed_Harrison. EBV-Associated Diseases Other Than IM EBV-associated lymphoproliferative disease has been described in patients with congenital or acquired immunodeficiency, including those with severe combined immunodeficiency, patients with AIDS, and recipients of bone marrow or organ transplants who are receiving immunosuppressive drugs (especially cyclosporine). Proliferating EBV-infected B cells infiltrate lymph nodes and multiple organs, and patients present with fever and lymphadenopathy or gastrointestinal symptoms. Pathologic studies show B cell hyperplasia or polyor monoclonal lymphoma.


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InternalMed_Harrison. X-linked lymphoproliferative disease is a recessive disorder of young boys who have a normal response to childhood infections but develop fatal lymphoproliferative disorders after infection with EBV. The protein associated with most cases of this syndrome (SAP) binds to a protein that mediates interactions of B and T cells. Most patients with this syndrome die of acute IM. Others develop hypogammaglobulinemia, malignant B cell lymphomas, aplastic anemia, or agranulocytosis. Disease resembling X-linked lymphoproliferative disease has also been associated with mutations in XIAP. Mutations in ITK, MagT1, or CD27 are associated with inability to control EBV and lymphoma. Moreover, IM has proved fatal to some patients with no obvious preexisting immune abnormality.


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InternalMed_Harrison. Oral hairy leukoplakia (Fig. 218-3) is an early manifestation of infection with HIV in adults (Chap. 226). Most patients present with raised, white corrugated lesions on the tongue (and occasionally on the buccal mucosa) that contain EBV DNA. Children infected with HIV can develop lymphoid interstitial pneumonitis; EBV DNA is often found in lung tissue from these patients.


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InternalMed_Harrison. Patients with chronic fatigue syndrome may have titers of antibody to EBV that are elevated but are not significantly different from those in healthy EBV-seropositive adults. While some patients have malaise and fatigue that persist for weeks or months after IM, persistent EBV infection is not a cause of chronic fatigue syndrome. Chronic active EBV infection is very rare and is distinct from chronic fatigue syndrome. The affected patients have an illness lasting >6 months, with elevated levels of EBV DNA in the blood, high titers of antibody to EBV, and evidence of organ involvement, including hepatosplenomegaly, lymphadenopathy, and pneumonitis, uveitis, or neurologic disease.


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InternalMed_Harrison. EBV is associated with several malignancies. About 15% of cases of Burkitt’s lymphoma in the United States and ~90% of those in Africa are associated with EBV (Chap. 134). African patients with Burkitt’s lymphoma have high levels of antibody to EBV, and their tumor tissue usually contains viral DNA. Malaria in African patients may impair cellular immunity to EBV and induce polyclonal B cell activation with an expansion of EBV-infected B cells. These changes may enhance the proliferation of B cells with elevated EBV DNA in the bloodstream, thereby increasing the likelihood of a c-myc translocation—the hallmark of Burkitt’s lymphoma. EBV-containing Burkitt’s lymphoma also occurs in patients with AIDS.


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InternalMed_Harrison. Anaplastic nasopharyngeal carcinoma is common in southern China and is uniformly associated with EBV; the affected tissues contain viral DNA and antigens. Patients with nasopharyngeal carcinoma often have elevated titers of antibody to EBV (Chap. 106). High levels of EBV plasma DNA before treatment or detectable levels of EBV DNA after radiation therapy correlate with lower rates of overall survival and relapse-free survival among patients with nasopharyngeal carcinoma. FIGuRE 218-3 Oral hairy leukoplakia often presents as white plaques on the lateral surface of the tongue and is associated with Epstein-Barr virus infection. Worldwide, the most common EBV-associated malignancy is gastric carcinoma. About 9% of these tumors are EBV-positive.


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InternalMed_Harrison. Worldwide, the most common EBV-associated malignancy is gastric carcinoma. About 9% of these tumors are EBV-positive. EBV has been associated with Hodgkin’s disease, especially the mixed-cellularity type (Chap. 134). Patients with Hodgkin’s disease often have elevated titers of antibody to EBV. In about half of cases in the United States, viral DNA and antigens are found in Reed-Sternberg cells. The risk of EBV-positive Hodgkin’s disease is significantly increased in young adults for several years after EBV-seropositive IM. About 50% of non-Hodgkin’s lymphomas in patients with AIDS are EBV-positive.


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InternalMed_Harrison. EBV is present in B cells of lesions from patients with lymphomatoid granulomatosis. In some cases, EBV DNA has been detected in tumors from immunocompetent patients with angiocentric nasal NK/T cell lymphoma, T cell lymphoma, and CNS lymphoma. Studies have demonstrated viral DNA in leiomyosarcomas from AIDS patients and in smooth-muscle tumors from organ transplant recipients. Virtually all CNS lymphomas in AIDS patients are associated with EBV. Studies have found that a history of IM and higher levels of antibodies to EBV before the onset of disease is more common in persons with multiple sclerosis than in the general population; additional research on a possible causal relationship is needed.


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InternalMed_Harrison. DIAGNOSIS Serologic Testing (Fig. 218-4) The heterophile test is used for the diagnosis of IM in children and adults. In the test for this antibody, human serum is absorbed with guinea pig kidney, and the heterophile titer is defined as the greatest serum dilution that agglutinates sheep, horse, or cow erythrocytes. The heterophile antibody does not interact with EBV proteins. A titer of ≥40 is diagnostic of acute EBV infection in a patient who has symptoms compatible with IM and atypical lymphocytes. Tests for heterophile antibodies are positive in 40% of patients with IM during the first week of illness and in 80–90% during the third week. Therefore, repeated testing may be necessary, especially if the initial test is performed early. Tests usually remain positive for 3 months after the onset of illness, but heterophile antibodies can persist for up to 1 year. These antibodies usually are not detectable in children <5 years of age, in the elderly, or in patients presenting with


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InternalMed_Harrison. the onset of illness, but heterophile antibodies can persist for up to 1 year. These antibodies usually are not detectable in children <5 years of age, in the elderly, or in patients presenting with symptoms not typical of IM. The commercially available monospot test for heterophile antibodies is somewhat more sensitive than the classic heterophile test. The monospot test is ~75% sensitive and ~90% specific compared with EBV-specific serologies (see below). False-positive monospot results are more common among persons with connective tissue disease, lymphoma, viral hepatitis, and malaria.


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InternalMed_Harrison. EBV-specific antibody testing is used for patients with suspected acute EBV infection who lack heterophile antibodies and for patients with atypical infections. Titers of IgM and IgG antibodies to viral capsid antigen (VCA) are elevated in the serum of more than 90% of patients at the onset of disease. IgM antibody to VCA is most useful for the diagnosis of acute IM because it is present at elevated titers only 1189 during the first 2–3 months of the disease; in contrast, IgG antibody to VCA is usually not useful for diagnosis of IM but is often used to assess past exposure to EBV because it persists for life. Seroconversion to EBNA positivity also is useful for the diagnosis of acute infection with EBV. Antibodies to EBNA become detectable relatively late (3–6 weeks after the onset of symptoms) in nearly all cases of acute EBV infection and persist for the lifetime of the patient. These antibodies may be lacking in immunodeficient patients and in those with chronic active EBV


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InternalMed_Harrison. of symptoms) in nearly all cases of acute EBV infection and persist for the lifetime of the patient. These antibodies may be lacking in immunodeficient patients and in those with chronic active EBV infection.


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InternalMed_Harrison. Titers of other antibodies also may be elevated in IM; however, these elevations are less useful for diagnosis. Antibodies to early antigens are detectable 3–4 weeks after the onset of symptoms in patients with IM. About 70% of individuals with IM have early antigen diffuse (EA-D) antibodies during the illness; the presence of EA-D antibodies is especially likely in patients with relatively severe disease. These antibodies usually persist for only 3–6 months. Levels of EA-D antibodies are also elevated in patients with nasopharyngeal carcinoma or chronic active EBV infection. Early antigen restricted (EA-R) antibodies are only occasionally detected in patients with IM but are often found at elevated titers in patients with African Burkitt’s lymphoma or chronic active EBV infection. IgA antibodies to EBV antigens have proved useful for the identification of patients with nasopharyngeal carcinoma and of persons at high risk for the disease.


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InternalMed_Harrison. Other Studies Detection of EBV DNA, RNA, or proteins has been valuable in demonstrating the association of the virus with various malignancies. The polymerase chain reaction has been used to detect EBV DNA in the cerebrospinal fluid of some AIDS patients with lymphomas and to monitor the amount of EBV DNA in the blood of patients with lymphoproliferative disease. Detection of high levels of EBV DNA in blood for a few days to several weeks after the onset of IM may be useful if serologic studies yield equivocal results. Culture of EBV from throat washings or blood is not helpful in the diagnosis of acute infection, since EBV persists in the oropharynx and in B cells for the lifetime of the infected individual.


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InternalMed_Harrison. Differential Diagnosis Whereas ~90% of cases of IM are due to EBV, 5–10% of cases are due to cytomegalovirus (CMV) (Chap. 219). CMV is the most common cause of heterophile-negative mononucleosis; less common causes of IM and differences from IM due to EBV are shown in Table 218-2. Therapy for IM consists of supportive measures, with rest and analgesia. Excessive physical activity during the first month should be avoided to reduce the possibility of splenic rupture, which often necessitates splenectomy. Glucocorticoid therapy is not indicated for uncomplicated IM and in fact may predispose to bacterial superinfection. Prednisone (40–60 mg/d for 2–3 days, with subsequent tapering of the dose over 1–2 weeks) has been used for the prevention of airway obstruction in patients with severe tonsillar hypertrophy, for Epstein-Barr Virus Infections, Including Infectious Mononucleosis Time of symptoms


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InternalMed_Harrison. Epstein-Barr Virus Infections, Including Infectious Mononucleosis Time of symptoms FIGuRE 218-4 Pattern of Epstein-Barr virus (EBV) serology during acute infection. EBNA, Epstein-Barr nuclear antigen; VCA, viral capsid antigen. (From JI Cohen, in NS Young et al [eds]: Clinical Hematology. Philadelphia, Mosby, 2006.) aMost commonly phenytoin, carbamazepine, sulfonamides, or minocycline. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus. autoimmune hemolytic anemia, for hemophagocytic lymphohistiocytosis, and for severe thrombocytopenia. Glucocorticoids have also been administered to rare patients with severe malaise and fever and to patients with severe CNS or cardiac disease. Acyclovir has had no significant clinical impact on IM in controlled trials. In one study, the combination of acyclovir and prednisolone had no significant effect on the duration of symptoms of IM.


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InternalMed_Harrison. Acyclovir, at a dosage of 400–800 mg five times daily, has been effective for the treatment of oral hairy leukoplakia (despite common relapses). The posttransplantation EBV lymphoproliferative syndrome (Chap. 169) generally does not respond to antiviral therapy. When possible, therapy should be directed toward reduction of immunosuppression. Antibody to CD20 (rituximab) has been effective in some cases. Infusions of donor lymphocytes are often effective for stem cell transplant recipients, although graftversus-host disease can occur. Infusions of EBV-specific cytotoxic T cells have been used to prevent EBV lymphoproliferative disease in high-risk settings as well as to treat the disease. Interferon α administration, cytotoxic chemotherapy, and radiation therapy (especially for CNS lesions) also have been used. Infusion of autologous EBV-specific cytotoxic T lymphocytes has shown promise in small studies of patients with nasopharyngeal carcinoma and Hodgkin’s disease. Treatment of


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InternalMed_Harrison. also have been used. Infusion of autologous EBV-specific cytotoxic T lymphocytes has shown promise in small studies of patients with nasopharyngeal carcinoma and Hodgkin’s disease. Treatment of several cases of X-linked lymphoproliferative disease with antibody to CD20 resulted in a successful outcome of what otherwise would probably have been fatal acute EBV infection.


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InternalMed_Harrison. The isolation of patients with IM is unnecessary. A vaccine directed against the major EBV glycoprotein reduced the frequency of IM but did not affect the rate of asymptomatic infection in a phase 2 trial. Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8 Camille Nelson Kotton, Martin S. Hirsch CYTOMEGALOVIRuS DEFINITION 219


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InternalMed_Harrison. Cytomegalovirus (CMV), which was initially isolated from patients with congenital cytomegalic inclusion disease, is now recognized as an important pathogen in all age groups. In addition to inducing severe birth defects, CMV causes a wide spectrum of disorders in older chil-dren and adults, ranging from an asymptomatic subclinical infection + Older age at presentation, longer duration of fever ± Diffuse rash, oral/genital ulcers, aseptic meningitis ± Less splenomegaly, exposure to cats or raw meat − No splenomegaly, less fatigue ± Maculopapular rash, no splenomegaly + Fixed, nontender lymph nodes to a mononucleosis syndrome in healthy individuals to disseminated disease in immunocompromised patients. Human CMV is one of several related species-specific viruses that cause similar diseases in various animals. All are associated with the production of characteristic enlarged cells—hence the name cytomegalovirus.


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InternalMed_Harrison. CMV, a β-herpesvirus, has double-stranded DNA, four species of mRNA, a protein capsid, and a lipoprotein envelope. Like other herpesviruses, CMV demonstrates icosahedral symmetry, replicates in the cell nucleus, and can cause either a lytic and productive or a latent infection. CMV can be distinguished from other herpesviruses by certain biologic properties, such as host range and type of cytopathology. Viral replication is associated with the production of large intra-nuclear inclusions and smaller cytoplasmic inclusions. CMV appears to replicate in a variety of cell types in vivo; in tissue culture it grows preferentially in fibroblasts. Although there is little evidence that CMV is oncogenic in vivo, it does transform fibroblasts in rare instances, and genomic transforming fragments have been identified.


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InternalMed_Harrison. CMV has a worldwide distribution. In many regions of the world, the vast majority of adults are seropositive for CMV, whereas only half of adults in the United States and Canada are seropositive. In regions where the prevalence of CMV antibody is high, immunocompromised adults are more likely to undergo reactivation disease rather than primary infection. Data generated in specific regions should be considered in the context of local seropositivity rates, when appropriate.


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InternalMed_Harrison. Of newborns in the United States, ∼1% are infected with CMV; the percentages are higher in many less-developed countries. Communal living and poor personal hygiene facilitate spread. Perinatal and early childhood infections are common. CMV may be present in breast milk, saliva, feces, and urine. Transmission has occurred among young children in day-care centers and has been traced from infected toddler to pregnant mother to developing fetus. When an infected child introduces CMV into a household, 50% of susceptible family members seroconvert within 6 months.


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InternalMed_Harrison. CMV is not readily spread by casual contact but rather requires repeated or prolonged intimate exposure for transmission. In late adolescence and young adulthood, CMV is often transmitted sexually, and asymptomatic carriage in semen or cervical secretions is common. Antibody to CMV is present at detectable levels in a high proportion of sexually active men and women, who may harbor several strains simultaneously. Transfusion of blood products containing viable leukocytes may transmit CMV, with a frequency of 0.14–10% per unit transfused. Transfusion of leukocyte-reduced or CMV-seronegative blood significantly decreases the risk of CMV transmission.


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InternalMed_Harrison. Once infected, an individual generally carries CMV for life. The infection usually remains silent. CMV reactivation syndromes develop more frequently, however, when T lymphocyte–mediated immunity is compromised—for example, after organ transplantation, with lymphoid neoplasms and certain acquired immunodeficiencies (in particular, HIV infection; Chap. 226), or during critical illness in intensive care units. Most primary CMV infections in organ transplant recipients (Chap. 169) result from transmission via the graft. In CMV-seropositive transplant recipients, infection results from reactivation of latent virus or from infection by a new strain. CMV infection may also be associated with diseases as diverse as coronary artery stenosis and malignant gliomas, but these associations require further validation.


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InternalMed_Harrison. Congenital CMV infection can result from either primary or reactivation infection of the mother. However, clinical disease in the fetus or newborn is related almost exclusively to primary maternal infection (Table 219-1). The factors determining the severity of congenital infection are unknown; a deficient capacity to produce precipitating antibodies and to mount T cell responses to CMV is associated with relatively severe disease. Primary infection with CMV in late childhood or adulthood is often associated with a vigorous T lymphocyte response that may contribute to the development of a mononucleosis syndrome similar to that which follows infection with Epstein-Barr virus (Chap. 218). The hallmark of such infection is the appearance of atypical lymphocytes in the peripheral blood; these cells are predominantly activated CD8+ T lymphocytes. Polyclonal activation of B cells by CMV contributes to the development of rheumatoid factors and other autoantibodies during mononucleosis.


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InternalMed_Harrison. Once acquired, CMV persists indefinitely in host tissues. The sites of persistent infection probably include multiple cell types and various organs. Transmission via blood transfusion or organ transplantation is due primarily to latent infections in these tissues. If the host’s T cell responses become compromised by disease or by iatrogenic immunosuppression, latent virus can reactivate to cause a variety of syndromes. Chronic antigenic stimulation in the presence of immunosuppression (for example, after organ transplantation) appears to be an ideal setting for CMV activation and CMV disease. Certain particularly potent suppressants of T cell immunity (e.g., antithymocyte globulin, alemtuzumab) are associated with a high rate of clinical CMV syndromes. CMV may itself contribute to further T lymphocyte hyporesponsiveness, which often precedes superinfection with other opportunistic pathogens such as bacteria, molds, and Pneumocystis.


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InternalMed_Harrison. Cytomegalic cells in vivo (presumed to be infected epithelial cells) are two to four times larger than surrounding cells and often contain an 8to 10-μm intranuclear inclusion that is eccentrically placed and is surrounded by a clear halo, producing an “owl’s eye” appearance. Smaller granular cytoplasmic inclusions are demonstrated occasionally. Cytomegalic cells are found in a wide variety of organs, including the salivary gland, lung, liver, kidney, intestine, pancreas, adrenal gland, and central nervous system. The cellular inflammatory response to infection consists of plasma 1191 cells, lymphocytes, and monocyte-macrophages. Granulomatous reactions occasionally develop, particularly in the liver. Immunopathologic reactions may contribute to CMV disease. Immune complexes have been detected in infected infants, sometimes in association with CMV-related glomerulopathies. Immune-complex glomerulopathy has also been observed in some CMV-infected patients after renal transplantation.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Congenital CMV Infection Fetal infections range from subclinical to severe and disseminated. Cytomegalic inclusion disease develops in ∼5% of infected fetuses and is seen almost exclusively in infants born to mothers who develop primary infections during pregnancy. Petechiae, hepatosplenomegaly, and jaundice are the most common presenting features (60–80% of cases). Microcephaly with or without cerebral calcifications, intrauterine growth retardation, and prematurity are reported in 30–50% of cases. Inguinal hernias and chorioretinitis are less common. Laboratory abnormalities include elevated alanine aminotransferase levels in serum, thrombocytopenia, conjugated hyperbilirubinemia, hemolysis, and elevated protein levels in cerebrospinal fluid. The prognosis for severely infected infants is poor; the mortality rate is 20–30%, and few survivors escape intellectual or hearing difficulties later in childhood. The differential diagnosis of cytomegalic inclusion


InternalMed_Harrison

InternalMed_Harrison. severely infected infants is poor; the mortality rate is 20–30%, and few survivors escape intellectual or hearing difficulties later in childhood. The differential diagnosis of cytomegalic inclusion disease in infants includes syphilis, rubella, toxoplasmosis, infection with herpes simplex virus or enterovirus, and bacterial sepsis.


InternalMed_Harrison

InternalMed_Harrison. Most congenital CMV infections are clinically inapparent at birth. Of asymptomatically infected infants, 5–25% develop significant psychomotor, hearing, ocular, or dental abnormalities over the next several years. Perinatal CMV Infection The newborn may acquire CMV at delivery by passage through an infected birth canal or by postnatal contact with infected breast milk or other maternal secretions. Of infants who are breast-fed for >1 month by seropositive mothers, 40–60% become infected. Iatrogenic transmission can result from blood transfusion; use of leukocyte-reduced or CMV-seronegative blood products for transfusion into low-birth-weight seronegative infants or seronegative pregnant women decreases risk.


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InternalMed_Harrison. The great majority of infants infected at or after delivery remain asymptomatic. However, protracted interstitial pneumonitis has been associated with perinatally acquired CMV infection, particularly in premature infants, and occasionally has been accompanied by infection with Chlamydia trachomatis, Pneumocystis, or Ureaplasma urealyticum. Poor weight gain, adenopathy, rash, hepatitis, anemia, and atypical lymphocytosis may also be found, and CMV excretion often persists for months or years. CMV Mononucleosis The most common clinical manifestation of CMV infection in immunocompetent hosts beyond the neonatal period is a heterophile antibody–negative mononucleosis syndrome, which may develop spontaneously or follow transfusion of leukocyte-containing blood products. Although the syndrome occurs at all ages, it most Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8


InternalMed_Harrison

InternalMed_Harrison. Person with AIDS <100 CD4+ T cells/μL; CMV seropositivity Retinitis; gastrointestinal Ganciclovir, valganciclovir, Oral valganciclovir disease; neurologic disease foscarnet, or cidofovir 1192 often involves sexually active young adults. With incubation periods of 20–60 days, the illness generally lasts for 2–6 weeks. Prolonged high fevers, sometimes with chills, profound fatigue, and malaise, characterize this disorder. Myalgias, headache, and splenomegaly are common, but in CMV (as opposed to Epstein-Barr virus) mononucleosis, exudative pharyngitis and cervical lymphadenopathy are rare. Occasional patients develop rubelliform rashes, often after exposure to ampicillin or certain other antibiotics. Less common are interstitial or segmental pneumonia, myocarditis, pleuritis, arthritis, and encephalitis. In rare cases, Guillain-Barré syndrome complicates CMV mononucleosis. The characteristic laboratory abnormality is relative lymphocytosis in peripheral blood, with >10% atypical


InternalMed_Harrison

InternalMed_Harrison. and encephalitis. In rare cases, Guillain-Barré syndrome complicates CMV mononucleosis. The characteristic laboratory abnormality is relative lymphocytosis in peripheral blood, with >10% atypical lymphocytes. Total leukocyte counts may be low, normal, or markedly elevated. Although significant jaundice is uncommon, serum aminotransferase and alkaline phosphatase levels are often moderately elevated. Heterophile antibodies are absent; however, transient immunologic abnormalities are common and may include the presence of cryoglobulins, rheumatoid factors, cold agglutinins, and antinuclear antibodies. Hemolytic anemia, thrombocytopenia, and granulocytopenia complicate recovery in rare instances. Most patients recover without sequelae, although postviral asthenia may persist for months. The excretion of CMV in urine, genital secretions, and/or saliva often continues for months or years. Rarely, CMV infection is fatal in immunocompetent hosts; survivors can have recurrent episodes of


InternalMed_Harrison

InternalMed_Harrison. The excretion of CMV in urine, genital secretions, and/or saliva often continues for months or years. Rarely, CMV infection is fatal in immunocompetent hosts; survivors can have recurrent episodes of fever and malaise, sometimes associated with autonomic nervous system dysfunction (e.g., attacks of sweating or flushing).


InternalMed_Harrison

InternalMed_Harrison. CMV Infection in the Immunocompromised Host (Table 219-1) CMV is the viral pathogen most commonly complicating organ transplantation (Chap. 169). In recipients of kidney, heart, lung, liver, pancreas, and vascularized composite (hand, face, other) transplants, CMV induces a variety of syndromes, including fever and leukopenia, hepatitis, colitis, pneumonitis, esophagitis, gastritis, and retinitis. CMV disease is an independent risk factor for both graft loss and death. Without prophylaxis, the period of maximal risk is between 1 and 4 months after transplantation. Disease likelihood and viral replication levels generally are greater after primary infection than after reactivation. Molecular studies indicate that seropositive transplant recipients are susceptible to infection with donor-derived, genotypically variant CMV, and such infection often results in disease. Reactivation infection, although common, is less likely than primary infection to be important clinically. The risk of


InternalMed_Harrison

InternalMed_Harrison. genotypically variant CMV, and such infection often results in disease. Reactivation infection, although common, is less likely than primary infection to be important clinically. The risk of clinical disease is related to various factors, such as degree of immunosuppression, use of antilymphocyte antibodies, lack of anti-CMV prophylaxis, and co-infection with other pathogens. The transplanted organ is particularly vulnerable as a target for CMV infection; thus there is a tendency for CMV hepatitis to follow liver transplantation and for CMV pneumonitis to follow lung transplantation.


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InternalMed_Harrison. CMV viremia occurs in roughly one-third of hematopoietic stem cell transplant recipients; the risk of severe disease may be reduced by prophylaxis or preemptive therapy with antiviral drugs. The risk is greatest 5–13 weeks after transplantation, and identified risk factors include certain types of immunosuppressive therapy, an allogeneic (rather than an autologous) graft, acute graft-versus-host disease, older age, and pretransplantation recipient seropositivity.


InternalMed_Harrison

InternalMed_Harrison. CMV is an important pathogen in patients with advanced HIV infection (Chap. 226), in whom it may cause retinitis or disseminated disease, particularly when peripheral-blood CD4+ T cell counts fall below 50–100/μL. As treatment for underlying HIV infection has improved, the incidence of serious CMV infections (e.g., retinitis) has decreased. However, during the first few weeks after institution of highly active antiretroviral therapy, acute flare-ups of CMV retinitis may occur secondary to an immune reconstitution inflammatory syndrome.


InternalMed_Harrison

InternalMed_Harrison. Syndromes produced by CMV in immunocompromised hosts often begin with prolonged fatigue, fever, malaise, anorexia, night sweats, and arthralgias or myalgias. Liver function abnormalities, leukopenia, thrombocytopenia, and atypical lymphocytosis may be observed during these episodes. The development of tachypnea, hypoxemia, and unproductive cough signals respiratory involvement. Radiologic examination of the lung often shows bilateral interstitial or reticulonodular infiltrates that begin in the periphery of the lower lobes and spread centrally and superiorly; localized segmental, nodular, or alveolar patterns are less common. The differential diagnosis includes Pneumocystis infection; other viral, bacterial, or fungal infections; pulmonary hemorrhage; and injury secondary to irradiation or to treatment with cytotoxic drugs.


InternalMed_Harrison

InternalMed_Harrison. Gastrointestinal CMV involvement may be localized or extensive and almost exclusively affects immunocompromised hosts. Colitis is the most common clinical manifestation in organ transplant recipients. Ulcers of the esophagus, stomach, small intestine, or colon may result in bleeding or perforation. CMV infection may lead to exacerbations of underlying ulcerative colitis. Hepatitis occurs frequently, particularly after liver transplantation. Acalculous cholecystitis and adrenalitis also have been described.


InternalMed_Harrison

InternalMed_Harrison. CMV rarely causes meningoencephalitis in otherwise healthy individuals. Two forms of CMV encephalitis are seen in patients with AIDS. One resembles HIV encephalitis and presents as progressive dementia; the other is a ventriculoencephalitis characterized by cranial-nerve deficits, nystagmus, disorientation, lethargy, and ventriculomegaly. In immunocompromised patients, CMV can also cause subacute progressive polyradiculopathy, which is often reversible if recognized and treated promptly. CMV retinitis is an important cause of blindness in immunocompromised patients, particularly patients with advanced AIDS (Chap. 226). Early lesions consist of small, opaque, white areas of granular retinal necrosis that spread in a centrifugal manner and are later accompanied by hemorrhages, vessel sheathing, and retinal edema (Fig. 219-1). CMV retinopathy must be distinguished from that due to other conditions, including toxoplasmosis, candidiasis, and herpes simplex virus infection.


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InternalMed_Harrison. Fatal CMV infections are often associated with persistent viremia and the involvement of multiple organ systems. Progressive pulmonary infiltrates, pancytopenia, hyperamylasemia, and hypotension are characteristic features that are frequently found in conjunction with a terminal bacterial, fungal, or protozoan superinfection. Extensive adrenal necrosis with CMV inclusions is often documented at autopsy, as is CMV involvement of many other organs.


InternalMed_Harrison

InternalMed_Harrison. CMV infection usually cannot be diagnosed reliably on clinical grounds alone. Isolation of CMV or detection of its antigens or DNA in appropriate clinical specimens is the preferred approach. The most common method of detection is quantitative nucleic acid testing (QNAT) for CMV by polymerase chain reaction (PCR) technology, for which blood or other specimens can be used; some centers use a CMV antigenemia test, an immunofluorescence assay that detects CMV antigens (pp65) in peripheral-blood leukocytes. Such assays may yield a positive result several days earlier than culture methods. QNAT may predict the risk for disease progression, particularly in immunocompromised hosts. CMV DNA in cerebrospinal fluid is useful in the diagnosis of CMV encephalitis or polyradiculopathy. Considerable variation exists among assays and laboratories; a recently introduced international testing standard should help reduce variation in PCR test results.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 219-1 Cytomegalovirus infection in a patient with AIDS may appear as an arcuate zone of retinitis with hemorrhages and optic disk swelling. Often CMV is confined to the retinal periphery, beyond view of the direct ophthalmoscope.


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InternalMed_Harrison. Virus excretion or viremia is readily detected by culture of appropriate specimens on human fibroblast monolayers. If CMV titers are high, as is common in congenital disseminated infection and in AIDS, characteristic cytopathic effects may be detected within a few days. However, in some situations (e.g., CMV mononucleosis), viral titers are low, and cytopathic effects may take several weeks to appear. Many laboratories expedite diagnosis with an overnight tissue-culture method (shell vial assay) involving centrifugation and an immunocytochemical detection technique employing monoclonal antibodies to an immediate-early CMV antigen. Isolation of virus from urine or saliva does not, by itself, constitute proof of acute infection, since excretion from these sites may continue for months or years after illness. Detection of viremia is a better predictor of acute infection.


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InternalMed_Harrison. A variety of serologic assays detect antibody to CMV. An increased level of IgG antibody to CMV may not be detectable for up to 4 weeks after primary infection. Detection of CMV-specific IgM is sometimes useful in the diagnosis of recent or active infection; however, circulating rheumatoid factors may result in occasional false-positive IgM tests. Serology is especially helpful when used to predict risk of CMV infection and disease in transplant recipients.


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InternalMed_Harrison. Prevention of CMV in organ and hematopoietic stem cell transplant recipients is usually based on one of two methods: universal prophylaxis or preemptive therapy. With universal prophylaxis, antiviral drugs are used for a defined period, often 3 or 6 months. One clinical trial demonstrated that, in CMV-seronegative recipients with seropositive donors, prophylaxis was more effective at prevention when given for 200 days rather than 100 days. With preemptive therapy, patients are monitored weekly for CMV viremia, and antiviral treatment is initiated once viremia is detected. Because of the bone marrow–suppressive effects of universal prophylaxis, preemptive therapy is more commonly employed in hematopoietic stem cell transplant recipients. For patients with advanced HIV infection (CD4+ T cell counts of <50/μL), some experts have advocated prophylaxis with valganciclovir (see below). However, side effects, lack of proven benefit, possible induction of viral resistance, and high cost have


InternalMed_Harrison

InternalMed_Harrison. counts of <50/μL), some experts have advocated prophylaxis with valganciclovir (see below). However, side effects, lack of proven benefit, possible induction of viral resistance, and high cost have precluded the wide acceptance of this practice. Preemptive therapy is under study in HIV-infected patients.


InternalMed_Harrison

InternalMed_Harrison. Several additional measures are useful for the prevention of CMV transmission to CMV-naïve, high-risk patients. The use of CMVseronegative or leukocyte-depleted blood greatly decreases the rate of transfusion-associated transmission. In a placebo-controlled trial, a CMV glycoprotein B vaccine reduced infection rates among 464 CMV-seronegative women; this outcome raises the possibility that this experimental vaccine will reduce rates of congenital infection, but further studies must validate this approach. A CMV glycoprotein B vaccine with MF59 adjuvant appeared effective in reducing the risk and duration of viremia in both seropositive and seronegative renal transplant recipients at risk for CMV infection. CMV immune globulin has been reported to prevent congenital CMV infection in infants of women with primary infection during pregnancy. Studies in hematopoietic stem cell transplant recipients have produced conflicting results.


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InternalMed_Harrison. Prophylactic acyclovir or valacyclovir may reduce rates of CMV infection and disease in renal transplant recipients, although neither drug is effective in the treatment of active CMV disease.


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InternalMed_Harrison. Ganciclovir is a guanosine derivative that has considerably more activity against CMV than its congener acyclovir. After intracellular conversion by a viral phosphotransferase encoded by CMV gene region UL97, ganciclovir triphosphate is a selective inhibitor of CMV DNA polymerase. Several clinical studies have indicated response rates of 70–90% among patients with AIDS who are given ganciclovir for the treatment of CMV retinitis or colitis. In severe infections (e.g., CMV pneumonia in hematopoietic stem cell transplant recipients), ganciclovir is often combined with CMV immune globulin. Prophylactic or suppressive ganciclovir may be useful in high-risk hematopoietic stem cell or organ transplant recipients (e.g., those who are CMV-seropositive before transplantation). In many patients with AIDS, persistently low CD4+ T cell counts, and CMV disease, clinical and virologic relapses occur promptly if treatment with ganciclovir is discontinued. Therefore, prolonged maintenance regimens


InternalMed_Harrison

InternalMed_Harrison. AIDS, persistently low CD4+ T cell counts, and CMV disease, clinical and virologic relapses occur promptly if treatment with ganciclovir is discontinued. Therefore, prolonged maintenance regimens are recommended for such patients. Resistance to ganciclovir is more common among patients treated for >3 months and is usually related to mutations in the CMV UL97 gene (or, less commonly, the UL54 gene).


InternalMed_Harrison

InternalMed_Harrison. Valganciclovir is an orally bioavailable prodrug that is rapidly metabolized to ganciclovir in intestinal tissues and the liver. Approximately 60–70% of an oral dose of valganciclovir is absorbed. An oral valganciclovir dose of 900 mg results in ganciclovir blood levels similar to those obtained with an IV ganciclovir dose of 5 mg/kg. Valganciclovir appears to be as effective as IV ganciclovir for both CMV induction (treatment) and maintenance regimens, while providing the ease of oral dosing. Furthermore, the adverse-event profiles and rates of resistance for the two drugs are similar.


InternalMed_Harrison

InternalMed_Harrison. Ganciclovir or valganciclovir therapy for CMV disease consists of a 14-to 21-day induction course (5 mg/kg IV twice daily for ganciclovir or 900 mg PO twice daily for valganciclovir), sometimes followed by maintenance therapy (e.g., valganciclovir, 900 mg/d). Peripheral-blood neutropenia develops in roughly one-quarter of treated patients but may be ameliorated by granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. Whether to use maintenance therapy should depend on the overall level of immunocompromise and the risk of recurrent disease. Discontinuation of maintenance therapy should be considered in patients with AIDS who, while receiving antiretroviral therapy, have a sustained (3to 6-month) increase in CD4+ T cell counts to >100/μL.


InternalMed_Harrison

InternalMed_Harrison. For treatment of CMV retinitis, ganciclovir may also be administered via a slow-release pellet sutured into the eye. Although this intraocular device provides good local protection, contralateral eye disease and disseminated disease are not affected, and early retinal detachment is possible. A combination of intraocular and systemic therapy may be better than the intraocular implant alone.


InternalMed_Harrison

InternalMed_Harrison. Foscarnet (sodium phosphonoformate) inhibits CMV DNA polymerase. Because this agent does not require phosphorylation to be active, it is also effective against most ganciclovir-resistant isolates. Foscarnet is less well tolerated than ganciclovir and causes considerable toxicity, including renal dysfunction, hypomagnesemia, hypokalemia, hypocalcemia, genital ulcers, dysuria, nausea, and paresthesia. Moreover, foscarnet administration requires the use of an infusion pump and close clinical monitoring. With aggressive hydration and dose adjustments for renal dysfunction, the toxicity of foscarnet can be reduced. The use of foscarnet should be avoided when a saline load cannot be tolerated (e.g., in cardiomyopathy). The approved induction regimen is 60 mg/kg every 8 h for 2 weeks, although 90 mg/kg every 12 h is equally effective and no more toxic. Maintenance infusions should deliver 90–120 mg/ kg once daily. No oral preparation is available. Foscarnet-resistant virus may emerge during


InternalMed_Harrison

InternalMed_Harrison. mg/kg every 12 h is equally effective and no more toxic. Maintenance infusions should deliver 90–120 mg/ kg once daily. No oral preparation is available. Foscarnet-resistant virus may emerge during extended therapy. This drug is used more frequently after hematopoietic stem cell transplantation than in other situations to avoid the myelosuppressive effects of ganciclovir; in


InternalMed_Harrison

InternalMed_Harrison. Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8 11 general, foscarnet is also the first choice for infections with ganciclovir-resistant CM Cidofovir is a nucleotide analogue with a long intracellular half-life that allows intermittent Iadministration. Induction regimens of 5 mgkg weekly for 2 weeks are followed by maintenance regimens of –5 mgkg every 2 weeks. Cidofovir can cause severe nephrotoxicity through dose-dependent proximal tubular cell injuryhowever, this adverse effect can be tempered somewhat by saline hydration and probenecid. Cidofovir is used primarily for ganciclovir-resistant virus. HUMAN HERPESVIRUS (HHV) TYPES 6, 7, ANd 8


InternalMed_Harrison

InternalMed_Harrison. HUMAN HERPESVIRUS (HHV) TYPES 6, 7, ANd 8 HHV-6 and -7 seropositivity rates are generally high throughout the world. HHV-6 was first isolated in 1986 from peripheral- blood leukocytes of six persons with various lymphoproliferative disorders. Two genetically distinct variants (HHV-6A and HHV-6B) are now recognized. HHV-6 appears to be transmitted by saliva and possibly by genital secretions.


InternalMed_Harrison

InternalMed_Harrison. Infection with HHV-6 frequently occurs during infancy as maternal antibody wanes. The peak age of acquisition is 9–21 months; by 24 months, seropositivity rates approach 80%. Older siblings appear to serve as a source of transmission. Congenital infection also may occur, and 1% of newborns are infected with HHV-6; placental infection with HHV-6 has been described. Most postnatally infected children develop symptoms (fever, fussiness, and diarrhea). A minority develop exanthem subitum (roseola infantum; see Fig. 25e-5), a common illness characterized by fever with subsequent rash. In addition, ~10–20% of febrile seizures without rash during infancy are caused by HHV-6. After initial infection, HHV-6 persists in peripheral-blood mononuclear cells as well as in the central nervous system, salivary glands, and female genital tract.


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InternalMed_Harrison. In older age groups, HHV-6 has been associated with mononucleosis syndromes; in immunocompromised hosts, encephalitis, pneumonitis, syncytial giant-cell hepatitis, and disseminated disease are seen. In transplant recipients, HHV-6 infection may also be associated with graft dysfunction. Acute HHV-6-associated limbic encephalitis has been reported in hematopoietic stem cell transplant recipients and is characterized by memory loss, confusion, seizures, hyponatremia, and abnormal electroencephalographic and MRI results. High plasma loads of HHV-6 DNA in hematopoietic stem cell transplant recipients are associated with allelic-mismatched donors, use of glucocorticoids, delayed monocyte and platelet engraftment, development of limbic encephalitis, and increased all-cause mortality rates. Like many other viruses, HHV-6 has been implicated in the pathogenesis of multiple sclerosis, although further study is needed to distinguish between association and etiology.


InternalMed_Harrison

InternalMed_Harrison. HHV-7 was isolated in 1990 from T lymphocytes from the peripheral blood of a healthy 26-year-old man. The virus is frequently acquired during childhood, albeit at a later age than HHV-6. HHV-7 is commonly present in saliva, which is presumed to be the principal source of infection; breast milk also can carry the virus. Viremia can be associated with either primary or reactivation infection. The most common clinical manifestations of childhood HHV-7 infections are fever and seizures. Some children present with respiratory or gastrointestinal signs and symptoms. An association has been made between HHV-7 and pityriasis rosea, but evidence is insufficient to indicate a causal relationship.


InternalMed_Harrison

InternalMed_Harrison. Clustering of HHV-6, HHV-7, and CMV infections in transplant recipients can make it difficult to sort out the roles of the various agents in individual clinical syndromes. HHV-6 and HHV-7 appear to be susceptible to ganciclovir and foscarnet, although definitive evidence of clinical response is lacking.


InternalMed_Harrison

InternalMed_Harrison. Unique herpesvirus-like DNA sequences were reported during 1994 and 1995 in tissues derived from Kaposi’s sarcoma (KS) and body cavity–based lymphoma occurring in patients with AIDS. The virus from which these sequences were derived is designated HHV-8 or Kaposi’s sarcoma–associated herpesvirus (KSHV). HHV-8, which infects B lymphocytes, macrophages, and both endothelial and epithelial cells, appears to be causally related not only to KS and a subgroup of AIDS-related B cell body cavity–based lymphomas (primary effusion lymphomas) but also to multicentric Castleman’s disease, a lymphoproliferative disorder of B cells. The association of HHV-8 with several other diseases has been reported but not confirmed.


InternalMed_Harrison

InternalMed_Harrison. HHV-8 seropositivity occurs worldwide, with areas of high endemicity influencing rates of disease. Unlike other herpes- virus infections, HHV-8 infection is much more common in some geographic areas (e.g., central and southern Africa) than in others (North America, Asia, northern Europe). In high-prevalence areas, infection occurs in childhood, seropositivity is associated with having a seropositive mother or (to a lesser extent) older sibling, and HHV-8 may be transmitted in saliva. In low-prevalence areas, infections typically occur in adults, probably with sexual transmission. Concurrent epidemics of HIV-1 and HHV-8 infections among certain populations (e.g., men who have sex with men) in the late 1970s and early 1980s appear to have resulted in the frequent association of AIDS and KS. Transmission of HHV-8 may also be associated with organ transplantation, injection drug use, and blood transfusion; however, transmission via blood transfusion in the United States appears to be


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InternalMed_Harrison. KS. Transmission of HHV-8 may also be associated with organ transplantation, injection drug use, and blood transfusion; however, transmission via blood transfusion in the United States appears to be quite rare.


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InternalMed_Harrison. Primary HHV-8 infection in immunocompetent children may manifest as fever and maculopapular rash. Among individuals with intact immunity, chronic asymptomatic infection is the rule, and neoplastic disorders generally develop only after subsequent immunocompromise. Immunocompromised persons with primary infection may present with fever, splenomegaly, lymphoid hyperplasia, pancytopenia, or rapid-onset KS. uantitative analysis of HHV-8 DNA suggests a predominance of latently infected cells in KS lesions and frequent lytic replication in multicentric Castleman’s disease.


InternalMed_Harrison

InternalMed_Harrison. Effective antiretroviral therapy for HIV-infected individuals has led to a marked reduction in rates of KS among persons dually infected with HHV-8 and HIV in resource-rich areas. HHV-8 itself is susceptible in vitro to ganciclovir, foscarnet, and cidofovir. A small, randomized, double-blind, placebo-controlled, crossover trial suggested that oral valganciclovir administered once daily reduced HHV-8 replication. However, clinical benefits of valganciclovir or other drugs in HHV-8 infection have not yet been demonstrated. Sirolimus has been shown to inhibit the progression of dermal KS in kidney transplant recipients while providing effective immunosuppression.


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InternalMed_Harrison. Molluscum Contagiosum, Monkeypox, and Other Poxvirus Infections Fred Wang The poxvirus family includes a large number of related DNA viruses 220e that infect various vertebrate hosts. The poxviruses responsible for infections in humans, the geographic locations in which these infections are found, the host reservoirs, and the main manifestations are listed in Table 220e-1. Infections with orthopoxviruses—e.g., smallpox (variola major) virus (Chap. 261e) or the zoonotic monkeypox virus—can result in systemic, potentially lethal human disease. Other poxvirus infections cause primarily localized skin disease in humans.


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InternalMed_Harrison. Molluscum contagiosum virus is an obligate human pathogen that causes distinctive proliferative skin lesions. These lesions measure 2–5 mm in diameter and are pearly, flesh-colored, and umbilicated, with a characteristic dimple at the center (Fig. 220e-1). A relative lack of inflammation and necrosis distinguishes these proliferative lesions from other poxvirus lesions. Lesions may be found—singly or in clusters—anywhere on the body except on the palms and soles and may be associated with an eczematous rash.


InternalMed_Harrison

InternalMed_Harrison. Molluscum contagiosum is highly prevalent among children and is the most common human disease resulting from poxvirus infection. Swimming pools are a common vector for transmission. Atopy and compromise of skin integrity increase the risk of infection. Genital lesions are more common in adults, to whom the virus may be transmitted by sexual contact. The incubation period ranges from 2 weeks to 6 months, with an average of 2–7 weeks. In most cases, the disease is self-limited and regresses spontaneously after 3–4 months in immunocompetent hosts. There are no systemic complications, but skin lesions may persist for 3–5 years. Molluscum contagiosum can be associated with immunosuppression and is frequently seen among HIV-infected patients (Chap. 226). The disease can be more generalized, severe, and persistent in AIDS patients than in other groups. Moreover, molluscum contagiosum can be exacerbated in the immune reconstitution inflammatory syndrome (IRIS) associated with the initiation


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InternalMed_Harrison. and persistent in AIDS patients than in other groups. Moreover, molluscum contagiosum can be exacerbated in the immune reconstitution inflammatory syndrome (IRIS) associated with the initiation of antiretroviral therapy.


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InternalMed_Harrison. The diagnosis of molluscum contagiosum is typically based on its clinical presentation and can be confirmed by histologic demonstration of the cytoplasmic eosinophilic inclusions (molluscum bodies) that are characteristic of poxvirus replication. Molluscum contagiosum FIGUrE 220e-1 Molluscum contagiosum is a cutaneous poxvirus infection characterized by multiple umbilicated flesh-colored or hypopigmented papules. virus cannot be propagated in vitro, but electron microscopy and molecular studies can be used for its identification. There is no specific systemic treatment for molluscum contagiosum, but a variety of techniques for physical ablation have been used. Cidofovir displays in vitro activity against many poxviruses, and case reports suggest that parenteral or topical cidofovir may have some efficacy in the treatment of recalcitrant molluscum contagiosum in immunosuppressed hosts.


InternalMed_Harrison

InternalMed_Harrison. Although monkeypox virus was named after the animal from which it was originally isolated, rodents are the primary viral reservoir. Human infections with monkeypox virus typically occur in Africa when humans come into direct contact with infected animals. Human-to-human propagation of monkeypox infection is rare. Human disease is characterized by a systemic illness and vesicular rash similar to those of variola. The clinical presentation of monkey-pox can be confused with that of the more common varicella-zoster virus infection (Chap. 217). Compared with the lesions of this herpes-virus infection, monkeypox lesions tend to be more uniform (i.e., in the same stage of development), diffuse, and peripheral in distribution. Lymphadenopathy is a prominent feature of monkeypox infection.


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InternalMed_Harrison. The first outbreak of human monkeypox infection in the Western Hemisphere occurred during 2003, when more than 70 cases were reported in the midwestern United States. The outbreak was linked to contact with pet prairie dogs that had become infected while being housed with rodents imported from Ghana. Patients presented most CHAPTER 220e Molluscum Contagiosum, Monkeypox, and Other Poxvirus Infections frequently with fever, rash, and lymphadenopathy ~12 days after exposure. Nine patients were hospitalized, but there were no deaths. Smallpox vaccination can provide cross-reactive immunity to monkeypox infection; studies of people exposed in the outbreak detected subclinical infection in a few vaccinated individuals—an observation suggesting the possibility of long-term vaccine protection. The risk of human disease from animal orthopoxvirus infections may increase as smallpox immunity wanes in the general population and the popularity of exotic animals as household pets grows.


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InternalMed_Harrison. Cowpox and buffalopox are rare zoonotic infections characterized by cutaneous poxlike lesions and mild systemic illness. Outbreaks of similar poxlike lesions among cattle and farm workers in Brazil have been due to Cantagalo and Araçatuba viruses, which are virtually identical to vaccinia virus and may have become established in cattle during smallpox vaccination programs. Parapoxviruses are widely scattered among animal species, but only a few are known to cause human disease via direct contact with infected animals. Parapoxviruses are antigenically distinct from orthopoxviruses and share no cross-immunity. Tanapox virus belongs to a separate, antigenically distinct genus and usually causes a single nodular lesion on the exposed area after contact with infected monkeys.


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InternalMed_Harrison. Parvovirus Infections Kevin E. Brown Parvoviruses, members of the family Parvoviridae, are small (diameter, ~22 nm), nonenveloped, icosahedral viruses with a linear single-strand DNA genome of ~5000 nucleotides. These viruses are dependent on either rapidly dividing host cells or helper viruses for replication. At 221 women, the estimated annual seroconversion rate is ~1%. Within 1195 households, secondary infection rates approach 50%. Detection of high-titer B19V in blood is not unusual (see “Pathogenesis,” below). Transmission can occur as a result of transfusion, most commonly of pooled components. To reduce the risk of transmission, plasma pools are screened by nucleic acid amplification technology, and high-titer pools are discarded. B19V is resistant to both heat and solvent-detergent inactivation.


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InternalMed_Harrison. least four groups of parvoviruses infect humans: parvovirus B19 (B19V), dependoparvoviruses (adeno-associated viruses; AAVs), PARV4/5 virus, and human bocaviruses (HBoVs). Human dependoparvoviruses are nonpathogenic and will not be considered further in this chapter. B19V is the type member of the genus Erythroparvovirus. On the basis of viral sequence, B19V is divided into three genotypes (designated 1, 2, and 3), but only a single B19V antigenic type has been described. Genotype 1 is predominant in most parts of the world; genotype 2 is rarely associated with active infection; and genotype 3 appears to predominate in parts of western Africa. B19V exclusively infects humans, and infection is endemic in virtually all parts of the world. Transmission occurs predominantly via the respiratory route and is followed by the onset of rash and arthralgia. By the age of 15 years, ~ 50% of children have detectable IgG; this figure rises to >90% among the elderly. In pregnant


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InternalMed_Harrison. B19V replicates primarily in erythroid progenitors. This specificity is due in part to the limited tissue distribution of the primary B19V receptor, blood group P antigen (globoside). Infection leads to high-titer viremia, with >1012 virus particles (or IU)/mL detectable in the blood at the apex (Fig. 221-1), and virus-induced cytotoxicity results in cessation of red cell production. In immunocompetent individuals, viremia and arrest of erythropoiesis are transient and resolve as the IgM and IgG antibody response is mounted. In individuals with normal erythropoiesis, there is only a minimal drop in hemoglobin levels; however, in those with increased erythropoiesis (especially with hemolytic anemia), this cessation of red cell production can induce a transient crisis with severe anemia (Fig. 221-1). Similarly, if an individual (or, after maternal infection, a fetus) does not mount a neutralizing antibody response and halt the lytic infection, erythroid production is compromised and


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InternalMed_Harrison. (Fig. 221-1). Similarly, if an individual (or, after maternal infection, a fetus) does not mount a neutralizing antibody response and halt the lytic infection, erythroid production is compromised and chronic anemia develops (Fig. 221-1).


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InternalMed_Harrison. The immune-mediated phase of illness, which begins 2–3 weeks after infection as the IgM response peaks, manifests as the rash of fifth disease together with arthralgia and/or frank arthritis. Low-level B19V DNA can be detected by polymerase chain reaction (PCR) in blood and tissues for months to years after acute infection. The B19V 1.0 0.2 manifestations Fever, chills, headache, myalgia Rash, arthralgia FIGuRE 221-1 Schematic of the time course of parvovirus B19V infection in (A) normals (erythema infectiosum), (B) transient aplastic crisis (TAC), and (C) chronic anemia/pure red-cell aplasia (PRCA). (Reprinted with permission from NS Young, KE Brown: N Engl J Med 350:586, 2004. © 2004 Massachusetts Medical Society. All rights reserved.) FIGuRE 221-2 Young child with erythema infectiosum, or fifth dis-ease, showing typical “slapped-cheek” appearance.


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InternalMed_Harrison. FIGuRE 221-2 Young child with erythema infectiosum, or fifth dis-ease, showing typical “slapped-cheek” appearance. receptor is found in a variety of other cells and tissues, including megakaryocytes, endothelial cells, placenta, myocardium, and liver. Infection of these tissues by B19V may be responsible for some of the more unusual presentations of the infection. Rare individuals who lack P antigen are naturally resistant to B19V infection.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Erythema Infectiosum Most B19V infections are asymptomatic or are associated with only a mild nonspecific illness. The main manifestation of symptomatic B19V infection is erythema infectiosum, also known as fifth disease or slapped-cheek disease (Fig. 221-2 and Fig. 25e-1A). Infection begins with a minor febrile prodrome ~7–10 days after exposure, and the classic facial rash develops several days later; after 2–3 days, the erythematous macular rash may spread to the extremities in a lacy reticular pattern. However, its intensity and distribution vary, and B19V-induced rash is difficult to distinguish from other viral exanthems. Adults typically do not exhibit the “slapped-cheek” phenomenon but present with arthralgia, with or without the macular rash.


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InternalMed_Harrison. Polyarthropathy Syndrome Although uncommon among children, arthropathy occurs in ~50% of adults and is more common among women than among men. The distribution of the affected joints is often symmetrical, with arthralgia affecting the small joints of the hands and occasionally the ankles, knees, and wrists. Resolution usually occurs within a few weeks, but recurring symptoms can continue for months. The illness may mimic rheumatoid arthritis, and rheumatoid factor can often be detected in serum. B19V infection may trigger rheumatoid disease in some patients and has been associated with juvenile idiopathic arthritis.


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InternalMed_Harrison. Transient Aplastic Crisis Asymptomatic transient reticulocytopenia occurs in most individuals with B19V infection. However, in patients who depend on continual rapid production of red cells, infection can cause transient aplastic crisis (TAC). Affected individuals include those with hemolytic disorders, hemoglobinopathies, red cell enzymopathies, and autoimmune hemolytic anemias. Patients present with symptoms of severe anemia (sometimes life-threatening) and a low reticulocyte count, and bone marrow examination reveals an absence of erythroid precursors and characteristic giant pronormoblasts. As its name indicates, the illness is transient, and anemia resolves with the cessation of cytopathic infection in the erythroid progenitors.


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InternalMed_Harrison. Pure Red-Cell Aplasia/Chronic Anemia Chronic B19V infection has been reported in a wide range of immunosuppressed patients, including those with congenital immunodeficiency, AIDS (Chap. 226), lymphoproliferative disorders (especially acute lymphocytic leukemia), and transplantation (Chap. 169). Patients have persistent anemia with reticulocytopenia, absent or low levels of B19V IgG, high titers of B19V DNA in serum, and—in many cases—scattered giant pronormoblasts in bone marrow. Rarely, nonerythroid hematologic lineages are also affected. Transient neutropenia, lymphopenia, and thrombocytopenia (including idiopathic thrombocytopenic purpura) have been observed. B19V occasionally causes a hemophagocytic syndrome.


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InternalMed_Harrison. Recent studies in Papua New Guinea and Ghana, where malaria is endemic, suggest that co-infection with Plasmodium and B19V plays a major role in the development of severe anemia in young children. Further studies must determine whether B19V infection contributes to severe anemia in other malarial regions. Hydrops Fetalis B19V infection during pregnancy can lead to hydrops fetalis and/or fetal loss. The risk of transplacental fetal infection is ~30%, and the risk of fetal loss (predominantly early in the second trimester) is ~9%. The risk of congenital infection is <1%. Although B19V does not appear to be teratogenic, anecdotal cases of eye damage and central nervous system (CNS) abnormalities have been reported. Cases of congenital anemia have also been described. B19V probably causes 10–20% of all cases of nonimmune hydrops.


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InternalMed_Harrison. unusual Manifestations B19V infection may rarely cause hepatitis, vasculitis, myocarditis, glomerulosclerosis, or meningitis. A variety of other cardiac manifestations, CNS diseases, and autoimmune infections have also been reported. However, B19V DNA can be detected by PCR for years in many tissues; this finding is of no known clinical significance, but its interpretation may cause confusion regarding B19V disease association. Diagnosis of B19V infection in immunocompetent individuals is generally based on detection of B19V IgM antibodies (Table 221-1). IgM can be detected at the time of rash in erythema infectiosum and Abbreviations: IU, international units (1 IU equals ~1 genome); n/a, not applicable; PCR, polymerase chain reaction.


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InternalMed_Harrison. Abbreviations: IU, international units (1 IU equals ~1 genome); n/a, not applicable; PCR, polymerase chain reaction. by the third day of TAC in patients with hematologic disorders; these antibodies remain detectable for ~3 months. B19V IgG is detectable by the seventh day of illness and persists throughout life. Quantitative detection of B19V DNA should be used for the diagnosis of early TAC or chronic anemia. Although B19V levels fall rapidly with the development of the immune response, DNA can be detectable by PCR for months or even years after infection, even in healthy individuals; therefore, quantitative PCR should be used. In acute infection at the height of viremia, >1012 B19V DNA IU/mL of serum can be detected; however, titers fall rapidly within 2 days. Patients with aplastic crisis or B19V-induced chronic anemia generally have >105 B19V DNA IU/mL.


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InternalMed_Harrison. No antiviral drug effective against B19V is available, and treatment of B19V infection often targets symptoms only. TAC precipitated by B19V infection frequently necessitates symptom-based treatment with blood transfusions. In patients receiving chemotherapy, temporary cessation of treatment may result in an immune response and resolution. If this approach is unsuccessful or not applicable, commercial immune globulin (IVIg; Gammagard, Sandoglobulin) from healthy blood donors can cure or ameliorate persistent B19V infection in immunosuppressed patients. Generally, the dose used is 400 mg/kg daily for 5–10 days. Like patients with TAC, immunosuppressed patients with persistent B19V infection should be considered infectious. Administration of IVIg is not beneficial for erythema infectiosum or B19V-associated polyarthropathy. Intrauterine blood transfusion can prevent fetal loss in some cases of fetal hydrops.


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InternalMed_Harrison. No vaccine has been approved for the prevention of B19V infection, although vaccines based on B19V virus-like particles expressed in insect cells are known to be highly immunogenic. Phase 1 trials of a putative vaccine were discontinued because of adverse side effects. The PARV4 viral sequence was initially detected in a patient with an acute viral syndrome. Similar sequences, including the related PARV5 sequence, have been detected in pooled plasma collections. The DNA sequence of PARV4/5 is distinctly different from that of all other parvoviruses, and this virus is now classified as a member of the newly described genus Tetraparvovirus.


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InternalMed_Harrison. PARV4 DNA is commonly found in plasma pools but at lower concentrations than levels of B19V DNA found before in plasma pools prior to screening. The higher levels of PARV4 DNA and IgG antibody in tissues (bone marrow and lymphoid tissue) and sera from IV drug users than in the corresponding specimens from control patients suggest that the virus is transmitted predominantly by parenteral means in the United States and Europe. Evidence for non-parenteral transmission in other parts of the world is limited. To date, PARV4/5 infection has been associated only with mild clinical disease (rash and/or transient aminotransferase elevation). Animal bocaviruses are associated with mild respiratory symptoms and enteritis in young animals. HBoV1 was originally identified in the respiratory tract of young children with lower respiratory tract infections. More recently, HBoV1 and the related viruses HBoV2, HBoV3, and HBoV4 have all been identified in human fecal samples.


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InternalMed_Harrison. Seroepidemiologic studies with HBoV virus-like particles suggest that human bocavirus infection is common. Worldwide, most individuals are infected before the age of 5 years. HBoV1 DNA is found in respiratory secretions from 2–20% of children with acute respiratory infection, often in the presence of other pathogens; in these circumstances, the role of HBoV1 in disease pathogenesis is unknown. Clinical disease due to HBoV1 is associated with evidence of primary infection (IgG seroconversion or the presence of IgM), HBoV1 DNA in serum, or high-titer HBoV1 DNA (>104 genome copies/mL) in respiratory secretions. Symptoms are not dissimilar from those of other viral respiratory infections, and cough and wheezing are commonly reported. There is no specific treatment for bocavirus infection. The role of human bocaviruses in childhood gastroenteritis remains to be established. Aaron C. Ermel, Darron R. Brown


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InternalMed_Harrison. Aaron C. Ermel, Darron R. Brown Investigation of human papillomavirus (HPV) infection began in earnest in the 1980s after Harold zur Hausen postulated that infection with these viruses was associated with cervical cancer. It is now recognized that HPV infection of the human genital tract is extremely common and causes clinical states ranging from asymptomatic infection to genital warts (condylomata acuminata); dysplastic lesions or invasive cancers of the anus, penis, vulva, vagina, and cervix; and a subset of oropharyngeal cancers. This chapter describes the epidemiology of HPV in general and as a pathogen, the natural history of HPV infections and associated cancers, strategies to prevent HPV infection and HPV-associated disease, and treatment modalities.


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InternalMed_Harrison. Molecular Overview HPV is an icosahedral, nonenveloped, 8000-base-pair, double-stranded DNA virus with a diameter of 55 nm. Like those of other papillomaviruses, HPV’s genome consists of an early (E) gene region, a late (L) gene region, and a noncoding region that contains regulatory elements. The E1, E2, E5, E6, and E7 proteins are expressed early in the growth cycle and are necessary for viral replication and cellular transformation. The E6 and E7 proteins cause malignant transformation by targeting the human cell cycle– regulatory molecules p53 and Rb (retinoblastoma protein), respectively, for degradation. Translation of the L1 and L2 transcripts and splicing of an E1^E4 transcript occur later. The L1 gene encodes the 54-kDa major capsid protein that makes up the majority of the virus shell; the 77-kDa L2 minor protein constitutes a smaller percentage of the capsid mass.


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InternalMed_Harrison. More than 125 HPV types have been identified and are numerically designated according to a unique L1 gene sequence. Approximately 40 HPV types are regularly found in the anogenital tract and are subdivided into high-risk and low-risk categories on the basis of the associated risk of cervical cancer. For example, HPV-6 and HPV-11 cause genital warts and ~10% of low-grade cervical lesions and are thus designated low risk. HPV-16 and HPV-18 cause dysplastic lesions and invasive cancers of the cervix and are considered high risk. HPV targets basal keratinocytes after microtrauma has exposed these cells to the virus. The HPV replication cycle is completed as keratinocytes undergo differentiation. Virions are assembled in the nuclei of differentiated keratinocytes and can be detected by electron microscopy. Infection is transmitted by contact with virus contained in these desquamated keratinocytes (or with free virus) from an infected individual.


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InternalMed_Harrison. 1198 Immune Response to HPV Infection A cell-mediated immune response plays an important role in controlling the progression of natural HPV infection. Histologic examination of lesions in individuals who experience regression of genital warts demonstrates infiltration of T cells and macrophages. CD4+ T cell regulation is particularly important in controlling HPV infections, as evidenced by the higher rates of infection and disease among immunosuppressed individuals, particularly those who are infected with HIV. Specific T-cell responses may be measured against HPV proteins, the most important of which appear to be the E2 and E6 proteins. In women with HPV-16 cervical infection, a strong T-cell response to HPV-16-derived E2 protein is associated with a lack of progression of cervical disease. Natural HPV infection of the genital tract gives rise to a serum antibody response in only 60–70% of individuals because there is no viremic phase during infection. Significant, although


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InternalMed_Harrison. disease. Natural HPV infection of the genital tract gives rise to a serum antibody response in only 60–70% of individuals because there is no viremic phase during infection. Significant, although incomplete, protection against type-specific reinfection is associated with the presence of neutralizing antibodies. Serum antibodies likely reach the cervical epithelium and secretions by transudation and exudation. Therefore, protection against infection is related to the amount of neutralizing antibody at the site of infection and lasts as long as levels of neutralizing antibodies are sufficient.


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InternalMed_Harrison. EPIDEMIOLOGY AND NATuRAL HISTORY OF HPV-ASSOCIATED MALIGNANCY General Population HPV is transmitted by sexual intercourse, by oral sex, and possibly by touching of a partner’s genitalia. In cross-sectional and longitudinal studies, ~40% of young women have evidence of HPV infection, with peaks during the teens and early twenties—soon after first coitus. The number of lifetime sexual partners correlates with the likelihood of HPV infection and the subsequent risk of HPV-associated malignancy. HPV infection may develop in a monogamous person whose partner is infected. Most HPV infections become undetectable after 6–9 months. However, with prolonged follow-up and frequent sampling, the same HPV types may again be detected weeks or months after becoming undetectable. Whether such episodic detection indicates viral latency followed by reactivation or reinfection with an identical HPV type is still debated.


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InternalMed_Harrison. Although HPV is the causative agent of several cancers, most attention has focused on cervical cancer—the second most common cancer among women worldwide, which affects more than 500,000 women and kills more than 275,000 women annually. More than 85% of all cervical cancer cases and deaths occur in women living in low-income countries, especially in sub-Saharan Africa, Asia, and South and Central America. A quarter-century of evidence shows that HPV causes nearly 100% of cervical cancers. HPV infection is the most significant risk factor for cervical cancer; relative risks range from 10 to 20 and exceed 100 in prospective and case-control studies, respectively. The time from HPV infection to cervical cancer diagnosis may exceed 20 years. Cervical cancer peaks in the fifth and sixth decades of life among women living in developed countries but as much as a decade earlier among women living in resource-poor countries. Persistent carriers of oncogenic HPV types are at greatest risk for


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InternalMed_Harrison. of life among women living in developed countries but as much as a decade earlier among women living in resource-poor countries. Persistent carriers of oncogenic HPV types are at greatest risk for high-grade cervical dysplasia and cancer. Why only certain HPV infections eventually lead to malignancy is not clear. Biomarkers that can predict which women will develop cervical cancer are not available. Immunosuppression in general plays a significant role in re-detection/reactivation of HPV infections, while other factors such as smoking, hormonal changes, Chlamydia infection, and nutritional deficits promote viral persistence and cancer.


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InternalMed_Harrison. The International Agency for Research on Cancer concludes that HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 are carcinogenic in the uterine cervix. HPV-16 is particularly virulent and causes 50% of cervical cancers. Worldwide, HPV-16 and HPV-18 cause 70% of cervical squamous cell carcinomas and 85% of cervical adenocarcinomas. Oncogenic types other than HPV-16 and HPV-18 cause the remaining 30% of cervical cancers. HPV-16 and HPV-18 also cause nearly 90% of anal cancers worldwide. Although oncogenic HPV infection is necessary for the development of cervical malignancy, only ~3–5% of infected women will ever develop this cancer, even in the absence of cytologic screening.


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InternalMed_Harrison. In addition to cervical and anal cancer, other HPV-associated cancers include vulvar and vaginal cancer, which are associated with HPV in 50–70% of cases; penile cancer, which is caused by HPV in 50% of cases; and oropharyngeal squamous cell carcinoma (OPSCC). Over the past two decades, an epidemic of OPSCC related to oncogenic infection with HPV (primarily HPV-16) has developed. Annual rates of OPSCC among men in the United States have been increasing from a low of 0.27 case/100,000 in 1973 to 0.57 case/100,000 as of 2004; rates in women have remained relatively stable at ~0.17 case/100,000 per year. The increase in the incidence of OPSCC is greatest among white men 40–50 years of age. Nearly 14,000 new cases were diagnosed in the United States in 2013. Annual rates of OPSCCs of the base of the tongue and the tonsil have increased dramatically—i.e., by 1.3% and 0.6%, respectively. Fewer data are available from developing countries about OPSCCs.


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InternalMed_Harrison. Effects of HIV on HPV-Associated Disease HIV infection accelerates the natural progression of HPV infections. HIV-infected persons are more likely than other individuals to develop genital warts and to have lesions that are more recalcitrant to treatment. HIV infection has been consistently associated with precancerous cervical lesions, including low-grade cervical intraepithelial neoplasia (CIN) and CIN 3, the immediate precursor to cervical cancer. Women with HIV/AIDS have significantly higher rates of cervical cancer and of subsets of some vulvar, vaginal, and oropharyngeal tumors than women in the general population. Studies indicate a direct relation between low CD4+ T lymphocyte counts and the risk of cervical cancer. Some studies show a reduced likelihood of HPV infection and precancerous lesions of the cervix in HIV-infected women receiving antiretroviral therapy (ART). The incidence of cervical cancer among HIV-infected women has not changed significantly since ART was


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InternalMed_Harrison. precancerous lesions of the cervix in HIV-infected women receiving antiretroviral therapy (ART). The incidence of cervical cancer among HIV-infected women has not changed significantly since ART was introduced, possibly because of preexisting oncogenic HPV infections.