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7,701 | paralysis in the B cellimmunodeficient recipi ent may be as much as 6,800 times that in normal persons. HIV infec tion has not been found to result in long term excretion of virus. As of January 2000, the IPV only schedule is recommended for routine polio vaccination in the United States. All children should receive four doses of IPV, at 2 months, 4 months, 6 18 months, and 4 6 years of age. Five combination vaccines (DTaP HepB IPV Pediarix; DTaP IPVHib Pentacel; DTaP IPV Hib HepBVaxelis, and DTaP IPVKinrix and Quadracel) and a single antigen IPV (IPOL; distributed in 10 dose vials) are approved in the United States with different schedules and ages for use. Given the rapid spread of cVPDV (Fig. 296.1) in many countries of the world, the reader is advised to refer to CDC or WHO websites to determine the necessity for accelerated vaccination of chil dren going to identified countries. IPV can be given at a minimum of 6, 10, or 14 weeks of age with a booster at 6 months. In 1988 the World Health Assembly resolved to eradicate poliomy elitis globally by 2000, and remarkable progress had been made toward reaching this target. To achieve this goal, the WHO used four basic strategies: routine immunization, National Immunization Days, acute flaccid paralysis surveillance, and mop up immunization. This strategy has resulted in a 99 decline in poliomyelitis cases; in early 2002, there were only 10 countries in the world endemic for poliomyelitis. In 2012 there were the fewest cases of poliomyelitis ever and the virus was endemic in only three countries (Afghanistan, Pakistan, and Nigeria). The last case of WPV 3 infection occurred in Nigeria in November 2012, leading to certification of global WPV3 eradication. The last case of wild poliovirus type 2 infection occurred in India in October 1999. Polioviruses remain endemic in Pakistan and Afghanistan. The rejec tion of poliovirus vaccine initiatives and campaign quality in security compromised areas in parts of these countries are still the main factors interfering with efforts to eradicate polio. In May 2013 the WHO assembly recommended the development of a Polio Eradication and Endgame Strategic Plan. This plan included the replacement of trivalent OPV (tOPV) with bivalent OPV (bOPV) containing only Sabin types 1 and 3 in all countries by 2016 and the introduction of initially one dose of IPV followed by the replacement of bOPV with IPV in all countries of the world by 2019. As long as the OPV is being used, there is the potential that vaccine derived poliovi rus (VDPV) will acquire the neurovirulent phenotype and transmis sion characteristics of the wild type polioviruses. VDPV emerges from the OPV because of continuous replication in immunodeficient per sons (iVDPV) or by circulation in populations with low vaccine cover age (cVDPVs). The risk was highest with the type 2 strain. Since the world switched from the use of tOPV to bOPV, tOPV is no longer used globally in any routine or supplemental immunization activities. |
7,702 | Recommendations for international travelers to certain countries were made by the WHO and endorsed by the CDC. Continuing spread due to poor herd immunity and now international spread pose a sig nificant threat to the eradication effort. The committee recommended that for countries with WPV1, cVDPV1, or cVDPV2 with potential risk of international spread, all residents and long term visitors (i.e., 4 weeks) of all ages receive a dose of bOPV or IPV between 4 weeks and 12 months before travel to these countries. Such travelers should WPV1 cases (latest onset) Pakistan Afghanistan Mozambique cVDPV1 cases (latest onset) DR Congo Madagascar Mozambique Malawi Congo cVDPV2 cases (latest onset) Cte dIvoire DR Congo CAR Benin Indonesia Israel Chad Somalia Nigeria Niger Cameroon Yemen Algeria Burundi Sudan Mali Togo Ghana USA Endemic country (WPV1) 17 20Feb23 1 29Aug22 7 10Aug22 153 6Mar23 1 22Mar23 311 5Mar23 10 27Feb23 13 23Feb23 4 20Feb23 1 13Feb23 43 13Feb23 4 12Jan23 22 1Jan23 13 25Dec22 3 22Dec22 61 14Dec22 2 13Dec22 1 24Nov22 1 31Oct22 2 26Oct22 1 30Sep22 3 14Sep22 1 20Jun22 18 1Mar23 24 27Feb23 4 1Dec22 1 15Oct22 Fig. 296.1 Global WPV1 and cVDPV cases, previous 12 months. Excludes viruses detected from environmental surveillance. Onset of paralysis: 3 May 2022 to 2 May 2023; data in WHO HQ as of 2 May 2023. (Courtesy Global Polio Eradication Initiative. https:polioeradication.orgpolio todaypolio now. Accessed Jan 26, 2022.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 297 u Nonpolio Enteroviruses 1979 be provided with an International Certificate of Vaccination of Prophy laxis to record their polio vaccination and service proof of vaccination. These countries have been advised to restrict at the point of departure the international travel of any resident lacking documentation of full vaccination, whether by air, sea, or land. For countries infected with cVDPV2 with potential risk of international spread (see Fig. 296.1 and WHO website), visitors should be encouraged to follow these recom mendations (not mandated). The WHO has mandated that infants in all countries still using bOPV should receive a dose of IPV, to offer protection against polio virus type 2. These efforts have been stymied because of the global inability to produce IPV in a large enough volume to cover all the 128 million babies born annually in the world. This problem was a crisis during the global synchronized introduction of bOPV, when several countries (e.g., India) had to use two fractional doses of IPV (15 dose) administered intradermally. To enhance scale up of IPV production in countries such as India, Brazil, and China, IPV using Sabin strains of poliovirus (sIPV) were developed in Japan and China. These mitigate the stringent requirements for wild type poliovirus culture that are normally required for IPV production. Other strategies include devel oping adjuvants for IPV (approved by the Danish Medicines Agency in 2019) and other novel |
7,703 | E.colibased adjuvants that could potentially lower the antigen quantities needed for each dose. Given the ongoing spread of cVDPVs, alternative stable novel Sabin vaccine strains that do not revert to neurovirulence (nOPVs) were developed for all three strains (Bio Farma, Indonesia) and have been shown to be immunogenic, stable, and safe. In countries where bOPV is included in routine immunization, it is best if it follows at least one dose of IPV or two doses of fractional intradermal IPV. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. The genus Enterovirus contains a large number of viruses spread via the gastrointestinal and respiratory routes that produce a broad range of illnesses in patients of all ages. Many of the manifestations predomi nantly affect infants and young children. ETIOLOGY Enteroviruses are nonenveloped, single stranded, positive sense viruses in the Picornaviridae (small RNA virus) family, which also includes the rhinoviruses, hepatitis A virus, and parechoviruses. The original human enterovirus subgroupspolioviruses (see Chap ter 296), coxsackieviruses, and echoviruseswere differentiated by their replication patterns in tissue culture and animals (Table 297.1). Enteroviruses have been reclassified on the basis of genetic similarity into four species, human enteroviruses A D. Specific enterovirus types are distinguished by antigenic and genetic sequence differences, with enteroviruses discovered after 1970 classified by species and number (e.g., enterovirus D68 and A71). Although more than 100 types have been described, 10 15 account for the majority of disease. No disease is uniquely associated with any specific serotype, although certain manifestations are associated with specific serotypes. The closely related human parechoviruses can cause clinical presentations similar to those associated with enteroviruses. Chapter 297 Nonpolio Enteroviruses Kevin B. Messacar and Mark J. Abzug Table 297.1 Classification of Human Enteroviruses Family Picornaviridae Genus Enterovirus Subgroups Poliovirus serotypes 1 3 Coxsackie A virus serotypes 1 22, 24 (23 reclassified as echovirus 9) Coxsackie B virus serotypes 1 6 Echovirus serotypes 1 9, 11 27, 29 33 (echoviruses 10 and 28 reclassified as nonenteroviruses; echovirus 34 reclassified as a variant of coxsackie A virus 24; echoviruses 22 and 23 reclassified within the genus Parechovirus) Numbered enterovirus serotypes (enterovirus 72 reclassified as hepatitis A virus) The human enteroviruses have been alternatively classified on the basis of nucleotide and amino acid sequences into four species (human enteroviruses A D). Epidemiology Enterovirus infections are common, with a worldwide distribution. In temperate climates, annual epidemic peaks occur in summerfall, although some transmission occurs year round. Enteroviruses are responsible for 3365 of acute febrile illnesses and 5565 of hospital izations for suspected sepsis in infants during the summer and fall in the United States. In tropical and semitropical areas, enteroviruses typically circulate year round. In general, only a few serotypes circulate simulta neously. Infections by different serotypes can occur within the same sea son. Factors associated with increased incidence andor severity include young age, male sex, exposure to children, poor hygiene, overcrowding, and low socioeconomic status. More than 25 of symptomatic infec tions occur in children younger than 1 year of age. Breastfeeding reduces |
7,704 | the risk for infection, likely via enterovirus specific antibodies. Humans are the only known natural reservoir for human enterovi ruses. Virus is primarily spread person to person, by the fecal oral and respiratory routes, although types causing acute hemorrhagic conjunc tivitis may be spread via airborne transmission. Virus can be transmit ted vertically prenatally or in the peripartum period or possibly via breastfeeding. Enteroviruses can survive on environmental surfaces, permitting transmission via fomites. Enteroviruses also can frequently be isolated from water sources, sewage, and wet soil. Although con tamination of drinking water, swimming pools and ponds, and hospital water reservoirs may occasionally be responsible for transmission, such contamination is often considered the result rather than the cause of human infection. Transmission is common within families (50 risk of spread to nonimmune household contacts), daycare centers, play grounds, summer camps, orphanages, and hospital nurseries; severe secondary infections may occur in nursery outbreaks. Transmission risk is increased by diaper changing and decreased by handwashing. Tickborne transmission has been suggested by some authors but is not a predominant route of transmission. Large enterovirus outbreaks have included meningitis epidemics (echoviruses 4, 6, 9, 13, and 30 commonly); epidemics of hand foot and mouth disease with severe central nervous system (CNS) and or cardiopulmonary disease caused by enterovirus A71 in Asia and Australia; outbreaks of atypical, severe hand foot and mouth disease caused by coxsackievirus A6 in the United States and United Kingdom; outbreaks of human enterovirus D68 respiratory illness associated with acute flaccid myelitis in the Americas, Europe, and Asia; out breaks of acute hemorrhagic conjunctivitis caused by enterovirus D70, coxsackievirus A24, and coxsackievirus A24 variant in tropical and temperate regions; and community outbreaks of uveitis. Reverse tran scription polymerase chain reaction (RT PCR) and genomic sequenc ing help identify outbreaks and demonstrate commonality of outbreak strains, differences among epidemic strains and older prototype strains, changes in circulating viral subgroups over time, cocircula tion of multiple genetic lineages, co infections with different entero virus serotypes, and associations between specific genogroups andor Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 297 u Nonpolio Enteroviruses 1979 be provided with an International Certificate of Vaccination of Prophy laxis to record their polio vaccination and service proof of vaccination. These countries have been advised to restrict at the point of departure the international travel of any resident lacking documentation of full vaccination, whether by air, sea, or land. For countries infected with cVDPV2 with potential risk of international spread (see Fig. 296.1 and WHO website), visitors should be encouraged to follow these recom mendations (not mandated). The WHO has mandated that infants in all countries still using bOPV should receive a dose of IPV, to offer protection against polio virus type 2. These efforts have been stymied because of the global inability to produce IPV in a large enough volume to |
7,705 | cover all the 128 million babies born annually in the world. This problem was a crisis during the global synchronized introduction of bOPV, when several countries (e.g., India) had to use two fractional doses of IPV (15 dose) administered intradermally. To enhance scale up of IPV production in countries such as India, Brazil, and China, IPV using Sabin strains of poliovirus (sIPV) were developed in Japan and China. These mitigate the stringent requirements for wild type poliovirus culture that are normally required for IPV production. Other strategies include devel oping adjuvants for IPV (approved by the Danish Medicines Agency in 2019) and other novel E.colibased adjuvants that could potentially lower the antigen quantities needed for each dose. Given the ongoing spread of cVDPVs, alternative stable novel Sabin vaccine strains that do not revert to neurovirulence (nOPVs) were developed for all three strains (Bio Farma, Indonesia) and have been shown to be immunogenic, stable, and safe. In countries where bOPV is included in routine immunization, it is best if it follows at least one dose of IPV or two doses of fractional intradermal IPV. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. The genus Enterovirus contains a large number of viruses spread via the gastrointestinal and respiratory routes that produce a broad range of illnesses in patients of all ages. Many of the manifestations predomi nantly affect infants and young children. ETIOLOGY Enteroviruses are nonenveloped, single stranded, positive sense viruses in the Picornaviridae (small RNA virus) family, which also includes the rhinoviruses, hepatitis A virus, and parechoviruses. The original human enterovirus subgroupspolioviruses (see Chap ter 296), coxsackieviruses, and echoviruseswere differentiated by their replication patterns in tissue culture and animals (Table 297.1). Enteroviruses have been reclassified on the basis of genetic similarity into four species, human enteroviruses A D. Specific enterovirus types are distinguished by antigenic and genetic sequence differences, with enteroviruses discovered after 1970 classified by species and number (e.g., enterovirus D68 and A71). Although more than 100 types have been described, 10 15 account for the majority of disease. No disease is uniquely associated with any specific serotype, although certain manifestations are associated with specific serotypes. The closely related human parechoviruses can cause clinical presentations similar to those associated with enteroviruses. Chapter 297 Nonpolio Enteroviruses Kevin B. Messacar and Mark J. Abzug Table 297.1 Classification of Human Enteroviruses Family Picornaviridae Genus Enterovirus Subgroups Poliovirus serotypes 1 3 Coxsackie A virus serotypes 1 22, 24 (23 reclassified as echovirus 9) Coxsackie B virus serotypes 1 6 Echovirus serotypes 1 9, 11 27, 29 33 (echoviruses 10 and 28 reclassified as nonenteroviruses; echovirus 34 reclassified as a variant of coxsackie A virus 24; echoviruses 22 and 23 reclassified within the genus Parechovirus) Numbered enterovirus serotypes (enterovirus 72 reclassified as hepatitis A virus) The human enteroviruses have been alternatively classified on the basis of nucleotide and amino acid sequences into four species (human enteroviruses A D). Epidemiology Enterovirus infections are common, with a worldwide distribution. In temperate climates, annual epidemic peaks occur in summerfall, |
7,706 | although some transmission occurs year round. Enteroviruses are responsible for 3365 of acute febrile illnesses and 5565 of hospital izations for suspected sepsis in infants during the summer and fall in the United States. In tropical and semitropical areas, enteroviruses typically circulate year round. In general, only a few serotypes circulate simulta neously. Infections by different serotypes can occur within the same sea son. Factors associated with increased incidence andor severity include young age, male sex, exposure to children, poor hygiene, overcrowding, and low socioeconomic status. More than 25 of symptomatic infec tions occur in children younger than 1 year of age. Breastfeeding reduces the risk for infection, likely via enterovirus specific antibodies. Humans are the only known natural reservoir for human enterovi ruses. Virus is primarily spread person to person, by the fecal oral and respiratory routes, although types causing acute hemorrhagic conjunc tivitis may be spread via airborne transmission. Virus can be transmit ted vertically prenatally or in the peripartum period or possibly via breastfeeding. Enteroviruses can survive on environmental surfaces, permitting transmission via fomites. Enteroviruses also can frequently be isolated from water sources, sewage, and wet soil. Although con tamination of drinking water, swimming pools and ponds, and hospital water reservoirs may occasionally be responsible for transmission, such contamination is often considered the result rather than the cause of human infection. Transmission is common within families (50 risk of spread to nonimmune household contacts), daycare centers, play grounds, summer camps, orphanages, and hospital nurseries; severe secondary infections may occur in nursery outbreaks. Transmission risk is increased by diaper changing and decreased by handwashing. Tickborne transmission has been suggested by some authors but is not a predominant route of transmission. Large enterovirus outbreaks have included meningitis epidemics (echoviruses 4, 6, 9, 13, and 30 commonly); epidemics of hand foot and mouth disease with severe central nervous system (CNS) and or cardiopulmonary disease caused by enterovirus A71 in Asia and Australia; outbreaks of atypical, severe hand foot and mouth disease caused by coxsackievirus A6 in the United States and United Kingdom; outbreaks of human enterovirus D68 respiratory illness associated with acute flaccid myelitis in the Americas, Europe, and Asia; out breaks of acute hemorrhagic conjunctivitis caused by enterovirus D70, coxsackievirus A24, and coxsackievirus A24 variant in tropical and temperate regions; and community outbreaks of uveitis. Reverse tran scription polymerase chain reaction (RT PCR) and genomic sequenc ing help identify outbreaks and demonstrate commonality of outbreak strains, differences among epidemic strains and older prototype strains, changes in circulating viral subgroups over time, cocircula tion of multiple genetic lineages, co infections with different entero virus serotypes, and associations between specific genogroups andor Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1980 Part XV u Infectious Diseases genetic substitutions and epidemiologic and clinical characteristics. Genetic analyses have demonstrated recombination and genetic drift that lead to evolutionary |
7,707 | changes in genomic sequence and antigenicity and extensive genetic diversity. For example, emergence of new sub genotypes and genetic lineages of enterovirus A71 may contribute to sequential outbreaks and increases in circulation. The incubation period is typically 3 6 days, except for a 1 3 day incu bation period for acute hemorrhagic conjunctivitis. Symptomatic and asymptomatic infected children typically shed cultivable virus from the respiratory tract for 1 3 weeks. In contrast, fecal shedding of cultivat able virus continues for as long as 7 11 weeks for acid stabile strains (e.g., poliovirus, enterovirus A71). Enterovirus RNA can be shed from mucosal sites for comparable and possibly longer periods. PATHOGENESIS Cell surface macromolecules, including poliovirus receptor, integ rin very late activation antigen (VLA) 2, decay accelerating factor complement regulatory protein (DAFCD55), intercellular adhesion molecule 1 (ICAM 1), ICAM 5, and coxsackievirus adenovirus recep tor, serve as viral receptors. In addition, respiratory epithelial cell sialic acids serve as receptors for enterovirus D68, enterovirus D70, and coxsackievirus A24 variants, and human scavenger receptor class B2 (SCARB2), human P selectin glycoprotein ligand 1, and DC SIGN are receptors for enterovirus A71. After virus attaches to a cell surface receptor, a conformational change in surface capsid proteins expels a hydrophobic pocket factor, facilitating penetration and uncoating with release of viral RNA in the cytoplasm. Translation of the positive sense RNA produces a polyprotein that undergoes cleavage by proteases encoded in the polyprotein. Several proteins resulting from cleavage of the polyprotein guide synthesis of negative sense RNA that serves as a template for replication of new positive sense RNA. The genome is approximately 7,500 nucleotides long and includes a highly conserved 5 noncoding region important for replication efficiency and a highly conserved 3 polyA region; these regions flank a continuous region encoding viral proteins. The 5 end is covalently linked to a small viral protein (VPg) necessary for initiation of RNA synthesis. There is significant variation within genomic regions encoding the structural proteins, leading to variability in antigenicity. Replication is followed by further cleavage of proteins and assembly into 30 nm icosahedral virions. Of the four structural proteins (VP1 VP4) in the capsid, VP1 is the most important determinant of serotype specificity. Additional reg ulatory proteins such as an RNA dependent RNA polymerase and pro teases are also present in the virion. Approximately 104 105 virions are released from an infected cell by lysis within 5 10 hours of infection. Following oral or respiratory acquisition, initial replication for most enteroviruses occurs in the pharynx and intestine, possibly within mucosal M cells. The acid stability of most enteroviruses favors survival in the gastrointestinal tract. Two or more enteroviruses may invade and replicate in the gastrointestinal tract simultaneously, but interference due to replication of one type often hinders growth of the heterolo gous type. Initial replication of most enteroviruses in the pharynx and intestine is followed within days by multiplication in lymphoid tissue, such as tonsils, Peyer patches, and regional lymph nodes. A primary, transient viremia (minor viremia) |
7,708 | results in spread to distant parts of the reticuloendothelial system, including the liver, spleen, bone marrow, and distant lymph nodes. Host immune responses may limit replication and progression beyond the reticuloendothelial system, resulting in subclinical infection. Clinical infection occurs if replica tion proceeds in the reticuloendothelial system and virus spreads via a secondary, sustained viremia (major viremia) to target organs such as the CNS, heart, and skin. Tropism to target organs is determined in part by the infecting serotype. Some enteroviruses, such as enterovirus D68, can be acid labile and bind sialic acid receptors on respiratory epithe lial cells in the upper and lower respiratory tract and primarily produce respiratory illness. Cytokine responses may contribute to development of respiratory disease by these viruses. Enterovirus D68 RNA has also been transiently detected by PCR in the blood of young children with enterovirus D68 pneumonia when drawn soon after illness onset. Enteroviruses can damage a wide variety of organs and systems, including the CNS, heart, liver, lungs, pancreas, kidneys, muscle, and skin. Damage is mediated by necrosis and the inflammatory response. CNS infections are often associated with pleocytosis in the cerebrospi nal fluid (CSF), composed of macrophages and activated T lympho cytes, and a mixed meningeal inflammatory response. Parenchymal involvement may affect the cerebral white and gray matter, cerebellum, basal ganglia, brainstem, and spinal cord with perivascular and paren chymal mixed or lymphocytic inflammation, gliosis, cellular degen eration, and neuronophagocytosis. Encephalitis during enterovirus A71 epidemics has been characterized by severe involvement of the brainstem, spinal cord gray matter, hypothalamus, and subthalamic and dentate nuclei, and can be complicated by pulmonary edema, pul monary hemorrhage, andor interstitial pneumonitis, presumed sec ondary to brainstem damage; sympathetic hyperactivity; myoclonus; ataxia; autonomic dysfunction; and CNS and systemic inflammatory responses (including cytokine and chemokine overexpression). Immu nologic cross reactivity with brain tissue has been postulated as one mechanism responsible for neurologic damage and sequelae following enterovirus A71 infection. Enterovirus myocarditis is characterized by perivascular and inter stitial mixed inflammatory infiltrates and myocyte damage, possi bly mediated by viral cytolytic (e.g., cleavage of dystrophin or serum response factor) and innate and adaptive immune mediated mecha nisms. Chronic inflammation may persist after viral clearance. The potential for enteroviruses to cause persistent infection is contro versial. Persistent infection in dilated cardiomyopathy and in myocar dial infarction has been suggested, but enterovirus RNA sequences and or antigens have been demonstrated in cardiac tissues in some, but not other, series. Infections with enteroviruses such as coxsackievirus B4, during gestation or subsequently, have been implicated as a trigger for development of cell autoantibodies andor type 1 diabetes in geneti cally susceptible hosts. Persistent infection in the pancreas, intestine, or peripheral blood mononuclear cells, with downstream immunomodula tory effects, has been suggested, but data are inconsistent. Similarly, per sistent infection has been implicated in a variety of conditions, including amyotrophic lateral sclerosis, Sjgren syndrome, chronic fatigue syn drome, and gastrointestinal tumors. Early enterovirus infection was associated with reduced risk of developing lymphocytic and myeloid |
7,709 | leukemia in a large retrospective Taiwanese cohort study. Severe neonatal infections can produce hepatic necrosis, hemor rhage, inflammation, endotheliitis, and venoocclusive disease; myocar dial mixed inflammatory infiltrates, edema, and necrosis; meningeal and brain inflammation, hemorrhage, gliosis, necrosis, and white mat ter damage; inflammation, hemorrhage, thrombosis, and necrosis in the lungs, pancreas, and adrenal glands; and disseminated intravascu lar coagulation. In utero infections are characterized by placentitis and infection of multiple fetal organs such as heart, lung, and brain. Development of type specific neutralizing antibodies appears to be the most important immune defense, mediating prevention against and recovery from infection. Immunoglobulin (Ig) M antibodies, fol lowed by long lasting IgA and IgG antibodies, and secretory IgA, medi ating mucosal immunity, are produced. Although local reinfection of the gastrointestinal tract can occur, replication is usually limited and not associated with disease. In vitro and animal experiments suggest that heterotypic antibody may enhance disease caused by a different serotype. Evidence also suggests that subneutralizing concentrations of serotype specific antibody may lead to antibody dependent enhance ment of enterovirus A71 infection. Innate and cellular defenses (mac rophages and cytotoxic T lymphocytes) may play important roles in recovery from infection. Altered cellular responses to enterovirus A71, including T lymphocyte and natural killer cell depletion, have been associated with severe meningoencephalitis and pulmonary edema. Hypogammaglobulinemia and agammaglobulinemia predispose to severe, often chronic enterovirus infections. Similarly, perinatally infected neonates lacking maternal type specific antibody to the infecting virus are at risk for severe disease. Enterovirus A71 disease increases after 6 months of age, when maternal serotype specific antibody levels have Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 297 u Nonpolio Enteroviruses 1981 declined. Other risk factors for significant illness include young age, immune suppression (posttransplantation and lymphoid malignancy), and, according to animal models andor epidemiologic observations, exercise, cold exposure, malnutrition, and pregnancy. Specific human leukocyte antigen genes, immune response gene (e.g., interleukin 10 and interferon ) polymorphisms, and low vitamin A levels have been linked to enterovirus A71 susceptibility and severe disease. CLINICAL MANIFESTATIONS Manifestations are protean, ranging from asymptomatic infection to undifferentiated febrile or respiratory illnesses, often in association with exanthems andor enanthems, to, less frequently, severe diseases such as meningoencephalitis, myocarditis, and neonatal sepsis. A majority of individuals are asymptomatic or have very mild illness, yet may serve as important sources for spread of infection. Symptomatic disease is generally more common in young children. Nonspecific Febrile Illness Nonspecific febrile illnesses are the most common symptomatic mani festations, especially in infants and young children. These are difficult to differentiate clinically from serious infections such as urinary tract infection, bacteremia, and bacterial meningitis, often necessitating hospitalization with diagnostic testing and presumptive antibiotic therapy for suspected bacterial infection in young infants. Illness usually begins abruptly with fever of 38.540C (101.3 104F), malaise, and irritability. Associated symptoms may include lethargy, anorexia, |
7,710 | diarrhea, nausea, vomiting, abdominal discomfort, rash, sore throat, and respiratory symptoms. Older children may have headaches and myalgias. Findings are generally nonspecific and may include mild conjunctivitis, pharyngeal injection, and cervical lymph adenopathy. Meningitis may be present, but specific clinical features such as meningeal findings or bulging anterior fontanelle distinguish ing those with meningitis are often lacking in infants. Fever lasts a mean of 3 days and occasionally is biphasic. Duration of illness is usually 4 7 days but can range from 1 day to 1 week. White blood cell (WBC) count, inflammatory biomarkers (e.g., C reactive protein, erythrocyte sedimentation rate), and results of routine laboratory tests are gener ally normal, although transient neutropenia can be seen. Concomitant enterovirus and bacterial infection is rare but has been observed in a small number of infants, most commonly with urinary tract infections. Enterovirus illnesses may be associated with a wide variety of skin manifestations, including macular, maculopapular, urticarial, vesicu lar, and petechial eruptions. Rare cases of idiopathic thrombocytopenic purpura have been reported. Enteroviruses have also been implicated in cases of pityriasis rosea. In general, the frequency of cutaneous man ifestations is inversely related to age. Serotypes commonly associated with rashes are echoviruses 9, 11, 16, and 25; coxsackie A viruses 2, 4, 6, 9, and 16; coxsackie B viruses 3 5; and enterovirus A71. Virus can occasionally be recovered from vesicular skin lesions. Hand Foot and Mouth Disease Hand foot and mouth disease, one of the more distinctive rash syn dromes, is most frequently caused by coxsackievirus A16, sometimes in large outbreaks, and can also be caused by enterovirus A71; coxsackie A viruses 5, 6, 7, 9, and 10; coxsackie B viruses 2 and 5; and some echovi ruses. It is usually a mild illness, with or without low grade fever. When the mouth is involved, the oropharynx is inflamed and often contains scattered, painful vesicles on the tongue, buccal mucosa, posterior phar ynx, palate, gingiva, andor lips (Fig. 297.1). These lesions may ulcerate, leaving 4 8 mm shallow lesions with surrounding erythema. Maculo papular, vesicular, andor pustular lesions may occur on the hands and fingers, feet, and buttocks and groin (see Figs. 297.1 and 297.2). Skin lesions occur more commonly on the hands than feet and are more com mon on dorsal surfaces, but frequently also affect palms and soles. Hand and foot lesions are usually tender, 3 7mm vesicles that resolve in about 1 week. Buttock lesions do not usually progress to vesiculation. Dissemi nated vesicular rashes described as eczema coxsackium may complicate preexisting eczema. Coxsackievirus A6, in particular, is responsible for relatively severe, atypical hand foot and mouth disease (and herpan gina) affecting adults and children that is characterized by fever, general ized rash (face, proximal extremities, and trunk, in addition to hands, feet, and buttocks), pain, dehydration, and desquamation of palms and soles (see Fig. 297.2). Onychomadesis (nail shedding) has been observed following coxsackievirus A6 and other coxsackievirus infections. Hand foot and mouth disease caused by enterovirus A71 |
7,711 | can be associated with neurologic and cardiopulmonary involvement, especially in young children (see Neurologic Manifestations, later). Hand foot and mouth disease caused by coxsackievirus A16 also can occasionally be associated with complications such as encephalitis, acute flaccid paralysis, myocar ditis, pericarditis, and shock. Herpangina Herpangina is characterized by sudden onset of fever, sore throat, dysphagia, and painful lesions in the posterior pharynx. Tempera tures range from normal to 41C (105.8F); fever tends to be higher in younger patients. Headache and backache may occur in older children, and vomiting and abdominal pain occur in 25 of cases. Characteristic lesions, present on the anterior tonsillar pillars, soft palate, uvula, ton sils, posterior pharyngeal wall, and, occasionally, the posterior buccal surfaces, are discrete 1 2mm vesicles and ulcers that enlarge over 2 3 days to 3 4 mm and are surrounded by erythematous rings that vary in size up to 10 mm. The number of lesions can range from 1 to 15 but is most commonly around 5. The remainder of the pharynx appears normal or minimally erythematous. Most cases are mild and have no complications. However, dehydration as a result of decreased oral intake may occur with more severe illness; meningitis can also some times occur. Fever generally lasts 1 4 days, and resolution of symptoms occurs in 3 7 days. A variety of enteroviruses cause herpangina, includ ing enterovirus A71, but coxsackie A viruses are implicated most often. A CB Fig. 297.1 A, Oval blisters of the palms in a child with hand foot and mouth disease (coxsackievirus A16 infection). B, Oval blisters on the feet of a child with hand foot and mouth disease. C, Erosion of the tongue in a child with hand foot and mouth disease. (From Weston WL, Lane AT, Morelli JG. Color Textbook of Pediatric Dermatology, 3rd ed. St. Louis: Mosby; 2002:109.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1982 Part XV u Infectious Diseases Respiratory Manifestations Symptoms such as sore throat and coryza frequently accompany and sometimes dominate enterovirus illnesses. Other respiratory findings may include wheezing, exacerbation of asthma, apnea, pneumonia, otitis media, bronchiolitis, croup, parotitis, and pharyngotonsillitis, which may occasionally be exudative. Lower respiratory tract infec tion may be significant in immunocompromised patients. Clusters and outbreaks of cases of severe respiratory disease, including pneumonia and wheezing (both in children with a history of asthma and those unaffected by asthma), have been increasingly recognized in associa tion with multiple lineages of enterovirus D68. Pleurodynia (Bornholm disease), caused most frequently by cox sackie B viruses 3, 5, 1, and 2 and echoviruses 1 and 6, is an epidemic or sporadic illness characterized by paroxysmal thoracic pain, as a result of myositis involving chest and abdominal wall muscles and, possibly, pleural inflammation. In epidemics, which occur every 10 20 years, children and adults are affected, but most cases occur in |
7,712 | per sons younger than age 30 years. Malaise, myalgias, and headache are followed by sudden onset of fever and spasmodic, pleuritic pain in the chest or upper abdomen aggravated by coughing, sneezing, deep breathing, or other movement. During spasms, which last from a few minutes to several hours, pain may be severe, and respirations are usu ally rapid, shallow, and grunting, suggesting pneumonia or pleural inflammation. A pleural friction rub is noted during pain episodes in 10 of patients. Chest radiographs are generally normal but can dem onstrate pulmonary infiltrates or pleural effusions. Pain localized to the abdomen may suggest colic, intestinal obstruction, appendicitis, or peritonitis. Pain usually subsides within 3 6 days but may persist for up to weeks. Symptoms may occur in a biphasic or, rarely, recurrent pat tern, with less prominent fever during recurrences. Pleurodynia may be associated with meningitis, orchitis, myocarditis, or pericarditis. Life threatening noncardiogenic pulmonary edema, hemorrhage, andor interstitial pneumonitis may occur in patients with enterovirus A71 brainstem encephalitis. Ocular Manifestations Epidemics of acute hemorrhagic conjunctivitis, primarily caused by enterovirus D70 and coxsackievirus A24A24 variant, are explosive and marked by high contagiousness, with spread mainly via eye hand fomite eye transmission. School age children, teenagers, and adults 20 50 years of age have the highest attack rates. Sudden onset of severe eye pain is associated with photophobia, blurred vision, lacrima tion, conjunctival erythema and congestion, lid edema, preauricular lymphadenopathy, and, in some cases, subconjunctival hemorrhages and superficial punctate keratitis. Subconjunctival hemorrhage is the hallmark of enterovirus D70 cases (70) but is more rare with cox sackievirus infections. Eye discharge is initially serous but becomes mucopurulent with secondary bacterial infection. Systemic symptoms, including fever and headache, occur in up to 20 of cases; manifes tations suggestive of pharyngoconjunctival fever occasionally occur. Recovery is usually complete within 1 2 weeks. Polyradiculoneu ropathy or acute flaccid paralysis following enterovirus D70 infection occurs occasionally. Other enteroviruses have occasionally been impli cated as causes of keratoconjunctivitis. Epidemic and sporadic uveitis in infants caused by subtypes of enteroviruses 11 and 19 can be associated with severe complications, including destruction of the iris, cataracts, and glaucoma. Enterovi ruses have been implicated in cases of chorioretinitis, uveoretinitis, optic neuritis, and unilateral acute idiopathic maculopathy. Myocarditis and Pericarditis Enteroviruses account for approximately 2535 of cases of myocardi tis and pericarditis of proven etiology (see Chapters 488 and 489). Cox sackie B viruses are most commonly implicated, although coxsackie A viruses and echoviruses also may be causative. Adolescents and young adults (especially physically active males) are disproportionately affected. Myopericarditis may be the dominant feature, or it may be one manifestation of disseminated disease, as in neonates. Disease ranges from relatively mild to severe. Upper respiratory tract symptoms fre quently precede fatigue, dyspnea, chest pain, congestive heart failure, and dysrhythmias. Presentations may mimic myocardial infarction; sudden death may also occur (including apparent sudden infant death syndrome). A pericardial friction rub indicates pericardial involve ment. Chest radiography often demonstrates cardiac enlargement, and echocardiography may confirm ventricular |
7,713 | dilation, reduced con tractility, andor pericardial effusion. Electrocardiography frequently reveals ST segment, T wave, andor rhythm abnormalities, and serum myocardial enzyme concentrations are often elevated. The acute mortality of enterovirus myocarditis is 04. Recovery is complete without residual disability in the majority of patients. Occasionally, chronic cardiomyopathy, inflammatory ventricular microaneurysms, or constrictive pericarditis may result. The role of persistent infection in chronic dilated cardiomyopathy is controversial. Enteroviruses have also been implicated in late adverse cardiac events following heart transplantation and in acute cardiac events such as myocardial infarc tion, endocarditis, and peripartum cardiomyopathy. Cardiopulmonary dysfunction observed in enterovirus A71 epidemics most commonly occurs without evidence of myocarditis and may be of neurogenic ori gin; however, true myocarditis has also been described. Gastrointestinal and Genitourinary Manifestations Gastrointestinal symptoms such as emesis (especially with meningitis), diarrhea (rarely severe), and abdominal pain are frequent but generally not dominant. Diarrhea, hematochezia, pneumatosis intestinalis, and necrotizing enterocolitis have occurred in premature infants during nursery outbreaks. Enterovirus infection has been implicated in acute and chronic gastritis, intussusception, chronic intestinal inflamma tion in hypogammaglobulinemic patients, sporadic hepatitis in nor mal children, severe hepatitis in neonates, and pancreatitis, which may result in transient exocrine pancreatic insufficiency. Coxsackie B viruses are second only to mumps as causes of orchi tis, most commonly presenting in adolescents. The illness is fre quently biphasic; fever and pleurodynia or meningitis are followed approximately 2 weeks later by orchitis, often with epididymitis. Enteroviruses have also been implicated in cases of nephritis and IgA nephropathy. Fig. 297.2 Atypical hand foot and mouth disease. Vesiculobullous rash on the right buttock and posterior thigh. (From Waldman A, Thom as L, Thacker S, et al. Vesiculobullous eruption as an atypical hand, foot, and mouth presentation. J Pediatr. 2016;179:273. Fig. B.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 297 u Nonpolio Enteroviruses 1983 Neurologic Manifestations Enteroviruses are the most common cause of viral meningitis in mumps immunized populations, accounting for up to 90 or more of cases in which a cause is identified. Meningitis is particularly com mon in infants, especially in those younger than 3 months of age, often during community epidemics. Frequently implicated serotypes include coxsackie B viruses 2 5; echoviruses 4, 6, 7, 9, 11, 13, 16, and 30; and enteroviruses D70 and A71. Most cases in infants and young children are mild and lack specific meningeal signs, whereas nuchal rigidity is apparent in more than half of children older than 1 2 years of age. Fever is present in 50100 and may be accompanied by irritability, malaise, headache, photophobia, nausea, emesis, anorexia, lethargy, hypotonia, rash, cough, rhinorrhea, pharyngitis, diarrhea, andor myalgia. Some cases are biphasic, with fever and nonspecific symptoms lasting a few days and followed by return of fever with meningeal signs several days later. Fever usually resolves in 3 5 days, and other symptoms in |
7,714 | infants and young children usually resolve within 1 week. In adults, symptoms tend to be more severe and of longer duration. CSF findings include pleocytosis (generally 500 but occasionally as high as 1,000 8,000 WBCsL; often predominantly polymorphonuclear cells in the first 48 hours before becoming mostly mononuclear); normal or slightly low glucose content (10 40 mgdL); and normal or mildly increased protein content (generally 100 mgdL). CSF parameters are normal in up to half of young infants despite detection of enterovirus in CSF and may also be normal in older children early after illness onset. Acute complications occur in approximately 10 of young children, includ ing simple and complex seizures, obtundation, increased intracranial pressure, syndrome of inappropriate antidiuretic hormone secretion, ventriculitis, transient cerebral arteriopathy, and coma. The long term prognosis for most children, even in those with acute complications, is good. Enteroviruses are also responsible for 1020 of cases of encepha litis with an identified cause. Frequently implicated serotypes include echoviruses 3, 4, 6, 9, and 11; coxsackie B viruses 2, 4, and 5; coxsackie A virus 9; and enterovirus A71. After initial nonspecific symptoms, there is progression to encephalopathy characterized by confusion, weakness, lethargy, andor irritability. Symptoms are most commonly generalized, although focal findings, including focal motor seizures, hemichorea, acute cerebellar ataxia, aphasia, extrapyramidal symp toms, andor focal imaging abnormalities, may occur. Meningeal signs and CSF indices similar to those of enteroviral meningitis are com monly present, leading to characterization of most cases as meningo encephalitis. Severity ranges from mild alteration in mental status to coma and decerebrate status. Long term sequelae, including epilepsy, weakness, cranial nerve palsy, spasticity, psychomotor retardation, and hearing loss, or death may follow severe disease. Persistent or recurrent cases have been observed rarely. Neurologic manifestations have been prominent in epidemics in Asia and Australia of enterovirus A71, and, to a lesser extent, cox sackievirus A16 disease. Many affected children have had hand foot and mouth disease, some have had herpangina, and others have had no mucocutaneous manifestations. Neurologic syndromes in a frac tion of children have included meningitis, meningoencephalomy elitis, acute flaccid paralysis, Guillain Barr syndrome, transverse myelitis, acute disseminated encephalomyelitis, cerebellar ataxia, opsoclonus myoclonus syndrome, benign intracranial hyperten sion, and brainstem encephalitis (rhombencephalitis involving the midbrain, pons, and medulla). Enterovirus A71 rhombencephalitis is characterized by altered consciousness, myoclonus, vomiting, ataxia, nystagmus, tremor, cranial nerve abnormalities, autonomic dysfunc tion, and MRI demonstrating lesions in the brainstem, thalamus, and cerebellum. Although the disease has been mild and reversible in some children, others have had rapid progression to noncardio genic (presumed neurogenic) pulmonary edema and hemorrhage, cardiopulmonary failure, shock, and coma. High mortality rates have been reported in children younger than 5 years of age, especially in those younger than 1 year of age. Deficits such as central hypoven tilation, bulbar dysfunction, neurodevelopmental delay, cerebellar defects, attention deficithyperactivityrelated symptoms, persistent limb weakness, and muscle atrophy have been observed among sur vivors, especially those who experienced cardiopulmonary failure or acute flaccid paralysis during their acute illness. |
7,715 | Although the most severe cases have been associated with enterovirus A71, similar clini cal pictures have been produced by other enterovirus serotypes (e.g., coxsackieviruses A16 and B5, echovirus 7). Patients with antibody or combined immunodeficiencies (includ ing human immunodeficiency virus infection, acute lymphocytic leu kemia, and transplantation) and patients receiving anti CD20 antibody therapy are at risk for acute or, more commonly, chronic enterovirus meningoencephalitis. The latter is characterized by persistent CSF abnormalities, viral detection in CSF or brain tissue for years, and recurrent encephalitis andor progressive neurologic deterioration, including insidious intellectual or personality deterioration, altered mental status, seizures, motor weakness, and increased intracranial pressure. Although disease may wax and wane, deficits generally become progressive and ultimately are frequently fatal or lead to long term sequelae. A dermatomyositis like syndrome, hepatitis, arthritis, myocarditis, or disseminated infection may also occur. Chronic entero virus meningoencephalitis has become less common with prophylactic high dose intravenous immunoglobulin replacement in agammaglob ulinemic patients. A variety of nonpoliovirus enteroviruses, including enteroviruses D68, D70, A71, coxsackie A viruses 7 and 24, coxsackie B viruses, and several echoviruses, have been associated with acute flaccid paraly sis with motor weakness as a result of spinal cord anterior horn cell involvement. Acute flaccid myelitis is used to designate the clinical syndrome of acute flaccid limb weakness with longitudinal MRI abnor malities in the spinal cord gray matter. Neurologic abnormalities are commonly preceded by a febrile respiratory or gastrointestinal prodro mal illness around 1 week before onset. Limb involvement tends to be asymmetric and varies from one to all four limbs, with severity ranging from mild weakness to complete paralysis. Cranial nerve dysfunction, including bulbar paralysis, and respiratory failure requiring ventila tor support, similar to poliovirus poliomyelitis, have been described in acute flaccid myelitis cases associated with enterovirus D68 and enterovirus A71. Sensory involvement, encephalopathy, seizures, and supratentorial imaging changes are uncommon with enterovirus D68 infection. Functional improvements may be seen over time, but muscle atrophy with limb weakness and some degree of disability persist in the vast majority of cases. A proportion of children with acute flac cid myelitis will have a need for long term tracheostomy, ventilation, and enteral feeding tubes as a result of persistent bulbar or respiratory paralysis, and scoliosis requiring spinal fusion, limb deformity requir ing orthotics and assistive devices, and low bone density predispos ing to fractures are common. Nerve transfer surgical procedures that involve splitting and moving functioning nerves to completely dener vated muscles have been used to improve functional outcomes in select cases. Other neurologic syndromes include cerebellar ataxia; transverse myelitis; Guillain Barr syndrome (including Miller Fisher variant) and axonal polyneuropathy; acute disseminated encephalomyeli tis; peripheral neuritis; optic neuritis; sudden hearing loss, tinnitus, and inner ear disorders such as vestibular neuritis; and other cranial neuropathies. Myositis and Arthritis Although myalgia is common, direct evidence of muscle involvement, including rhabdomyolysis, muscle swelling, focal myositis, and poly myositis, has uncommonly been reported. A dermatomyositis like syn drome and arthritis can be seen in enterovirus infected |
7,716 | patients with hypogammaglobulinemia. Enteroviruses are a rare cause of arthritis in normal hosts. Neonatal Infections Neonatal infections are relatively common, with a disease incidence comparable to or greater than that of symptomatic neonatal herpes simplex virus, cytomegalovirus, and group B streptococcus infec tions. Infection frequently is caused by coxsackie B viruses 2 5 and Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1984 Part XV u Infectious Diseases echoviruses 6, 9, 11, and 19, although many serotypes have been impli cated, including coxsackie B virus 1 and echovirus 30 in more recent years. Enteroviruses may be acquired vertically before, during, or after delivery, including possibly via breast milk; horizontally from family members; or by sporadic or epidemic transmission in nurseries. In utero infection can lead to fetal demise, nonimmune hydrops fetalis, or neonatal illness. Additionally, maternal and intrauterine infections have been speculatively linked to congenital anomalies; prematurity, low birthweight, and intrauterine growth restriction; neurodevelop mental sequelae; unexplained neonatal illness and death; and increased risk of type 1 diabetes and schizophrenia. The majority of neonatal infections are asymptomatic, and symp tomatic presentations range from benign febrile illness to severe mul tisystem disease. Most affected newborns are full term and previously well. Maternal history often reveals a recent viral illness preceding or immediately following delivery, which may include fever and abdomi nal pain. Neonatal symptoms may occur as early as day 1 of life, with onset of severe disease generally within the first 2 weeks of life. Fre quent findings include fever or hypothermia, irritability, lethargy, anorexia, rash (usually maculopapular, occasionally petechial or papu lovesicular), jaundice, respiratory symptoms, apnea, hepatomegaly, abdominal distention, emesis, diarrhea, and decreased perfusion. Most patients have benign courses, with resolution of fever in an average of 3 days and of other symptoms in about 1 week. A biphasic course may occur occasionally. A minority have severe disease dominated by any combination of sepsis, meningoencephalitis, myocarditis, hepatitis, coagulopathy, andor pneumonitis. Meningoencephalitis may be man ifested by focal or complex seizures, bulging fontanelle, nuchal rigidity, andor reduced level of consciousness. Myocarditis, most often associ ated with coxsackie B virus infection, may be suggested by tachycardia, dyspnea, cyanosis, and cardiomegaly. Hepatitis and pneumonitis are most often associated with echovirus infection, although they may also occur with coxsackie B viruses. Gastrointestinal manifestations may be prominent in premature neonates. Laboratory and radiographic evalu ation may reveal leukocytosis, thrombocytopenia, CSF pleocytosis, CNS white matter damage, elevations of serum transaminases and bili rubin, coagulopathy, pulmonary infiltrates, and electrocardiographic changes. Complications of severe neonatal disease include CNS necrosis and generalized or focal neurologic compromise; arrhythmias, congestive heart failure, myocardial infarction, and pericarditis; hepatic necrosis and failure; coagulopathy with intracranial or other bleeding; adrenal necrosis and hemorrhage; and rapidly progressive pneumonitis and pulmonary hypertension. Myositis, arthritis, necrotizing enterocoli tis, inappropriate antidiuretic hormone secretion, hemophagocytic lymphohistiocytosis like presentation, bone marrow failure, and |
7,717 | sud den death are rare events. Mortality with severe disease is significant and is most often associated with hepatitis and bleeding complications, myocarditis, andor pneumonitis. Survivors of severe neonatal disease may have gradual resolution of hepatic and cardiac dysfunction, although persistent hepatic dysfunc tion and residual cardiac impairment, chronic calcific myocarditis, and ventricular aneurysm may occur. Meningoencephalitis may be associated with speech and language impairment; cognitive deficits; spasticity, hypotonicity, or weakness; seizure disorders; microcephaly or hydrocephaly; and ocular abnormalities. However, many survivors appear to have no long term sequelae. Risk factors for severe disease include illness onset in the first few days of life; maternal illness just before or after delivery; prematurity; male sex; infection by echovirus 11 or a coxsackie B virus; positive serum viral culture; absence of neu tralizing antibody to the infecting virus; and evidence of severe hepati tis, myocarditis, andor multisystem disease. Transplant Recipients and Patients with Malignancies Enterovirus infections in stem cell and solid organ transplant recipi ents may be severe andor prolonged, causing progressive pneumonia, severe diarrhea, pericarditis, heart failure, meningoencephalitis, and disseminated disease. Enterovirus associated hemophagocytic lym phohistiocytosis, meningitis, encephalitis, acute flaccid myelitis, and myocarditis have been reported in children with malignancies and patients treated with anti CD20 monoclonal antibody. Infections in these groups are associated with high fatality rates. DIAGNOSIS Clues to enterovirus infection include characteristic findings such as hand foot and mouth disease or herpangina lesions, consistent sea sonality, known community outbreak, and exposure to enterovirus compatible disease. Acute flaccid myelitis due to enterovirus should be considered in the differential diagnosis of any child presenting with acute onset limb weakness, particularly in the summer to fall during enterovirus outbreaks and when following a febrile illness. In the neo nate, history of maternal fever, malaise, andor abdominal pain near delivery during enterovirus season is suggestive. Traditionally, enterovirus infection has been confirmed with viral cul ture using a combination of cell lines. Sensitivity of culture ranges from 50 to 75 and can be increased by sampling of multiple sites (e.g., CSF plus oropharynx and rectum in children with meningitis). In neonates, yields of 3070 are achieved when blood, urine, CSF, and mucosal swabs are cultured. A major limitation is the inability of most coxsackie A viruses to grow in culture. Yield may also be limited by neutralizing antibody in patient specimens, improper specimen handling, or insensi tivity of the cell lines used. Culture is relatively slow, with 3 8 days usually required to detect growth. Although cultivation of an enterovirus from any site can generally be considered evidence of recent infection, isola tion from the rectum or stool can reflect more remote shedding. Simi larly, recovery from a mucosal site may suggest an association with an illness, whereas recovery from a normally sterile site (e.g., CSF, blood, or tissue) is more conclusive evidence of causation. Serotype identification by type specific antibody staining or neutralization of a viral isolate is generally required only for investigation of an outbreak or an unusual disease manifestation, for |
7,718 | surveillance, or to distinguish nonpoliovirus enteroviruses from vaccine or wild type polioviruses. Direct testing for nucleic acid has replaced culture because of increased sensitivity and more rapid turnaround. RT PCR detection of highly conserved areas of the enterovirus genome can detect the majority of enteroviruses in CSF; serum; urine; conjunctival, naso pharyngeal, oropharyngeal, tracheal, rectal, and stool specimens; dried blood spots; and tissues such as myocardium, liver, and brain. However, the closely related parechoviruses are not detected by most enterovirus RT PCR primers. Sensitivity and specificity of RT PCR are high, with results available in as short as 1 hour. Real time, quantita tive PCR assays and nested PCR assays with enhanced sensitivity have been developed, as have enterovirus containing multiplex PCR assays, nucleic acid sequencebased amplification assays, reverse transcrip tion loop mediated isothermal amplification, culture enhanced PCR assays, and PCR based microarray assays. PCR testing of CSF from children with meningitis and from hypogammaglobulinemic patients with chronic meningoencephalitis is frequently positive despite nega tive cultures. Routine PCR testing of CSF in infants and young children with suspected meningitis during enterovirus season decreases the number of diagnostic tests, duration of hospital stay, antibiotic use, and overall costs. Enterovirus RNA may not be detected in CSF by the time of clinical presentation with neurologic syndromes associated with cer tain enteroviruses (e.g., enterovirus A71 and D68), but shedding may still be detectable in nonsterile sites (stoolrectal for enterovirus A71; respiratory for enterovirus D68). PCR testing of tracheal aspirates of children with myocarditis has good concordance with testing of myo cardial specimens. In ill neonates and young infants, PCR testing of serum and urine has higher yields than culture. Viral load in blood of neonates is correlated with disease severity; viral nucleic acid may persist in blood of severely ill newborns for up to 2 months. Sequence analysis of amplified nucleic acid can be used for serotype identification and phylogenetic analysis and to establish a transmission link among cases. Serotype specific (e.g., enterovirus A71, enterovi rus D68, and coxsackievirus A16) PCR assays have been developed. For enterovirus A71, the yield of specimens other than CSF and blood (oropharyngeal, nasopharyngeal, rectal, vesicle swabs, and CNS tis sue) is greater than the yield of CSF and blood, which are infrequently Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 297 u Nonpolio Enteroviruses 1985 positive. Enterovirus D68 is more readily detected in respiratory spec imens (i.e., nasal wash or nasopharyngeal swab) compared to stool rectal or CSF specimens. Routine collection and testing of respiratory and stoolrectal specimens, in addition to CSF, is warranted in neuro logic presentations potentially associated with these viruses. Of note, commercially available multiplex respiratory PCR assays generally are unable to distinguish enteroviruses (including enterovirus D68) from rhinoviruses. Antigen detection assays that target specific serotypes such as enterovirus A71 with monoclonal antibodies have also been developed. |
7,719 | Enterovirus infections can be detected serologically by a rise in serum or CSF of neutralizing, complement fixation, enzyme linked immunosorbent assay, or other type specific antibody or by detec tion of serotype specific IgM antibody. However, serologic testing requires presumptive knowledge of the infecting serotype or an assay with sufficiently broad cross reactivity. Sensitivity and specificity may be limiting, and cross reactivity among serotypes may occur. Except for epidemiologic studies or cases characteristic of specific serotypes (e.g., enterovirus A71 or enterovirus D68), serology is generally less useful than culture or nucleic acid detection. Enterovirus antibodies have been detected in CSF of children with acute flaccid myelitis when viral RNA was not detectable. DIFFERENTIAL DIAGNOSIS The differential diagnosis of enterovirus infections varies with the clin ical presentation (Table 297.2). Human parechoviruses, members of the Picornaviridae family, produce many manifestations similar to the nonpolio enteroviruses. They are small RNA viruses that were originally classified as echo viruses. Nineteen parechoviruses have been identified that infect humans; serotypes 1 and 3 are the most common causes of symp tomatic infection. Parechovirus epidemics occur in the same season as enterovirus infections, with a biennial pattern of circulation noted in Europe. Outbreaks have been described in the nursery setting. In young infants, parechoviruses can cause a sepsis like illness similar to enterovirus illness and are a common, underrecognized cause of viral meningoencephalitis. More frequently than with enteroviruses, infants with parechovirus CNS infection often have no CSF pleocytosis. There is also a higher incidence of white matter MRI abnormalities and long term neurodevelopmental deficits with parechovirus encephalitis com pared with enterovirus encephalitis. Rarely, parechoviruses have been identified in cases of hepatitis or myocarditis. Infections in older chil dren are often unrecognized or cause acute, benign febrile, respiratory, or gastrointestinal illnesses with few specific findings. Infants suspected of having an enterovirus infection should also be considered as possibly having a parechovirus infection, because the two may be indistinguishable. A distinctive rash involving the extremities with palm and sole erythema or peripheral leukopenia in the setting of high fever during the summer fall season are clinical findings that should also prompt consideration of parechovirus infec tion. The diagnosis of parechovirus infection is confirmed by human parechovirus specific PCR on CSF, blood, stool, and oropharyngeal or nasopharyngeal specimens. TREATMENT In the absence of a proven antiviral agent for enterovirus infections, supportive care is the mainstay of treatment. Newborns and young infants with nonspecific febrile illnesses and children with meningitis frequently require diagnostic evaluation and hospitalization for pre sumptive treatment of bacterial and herpes simplex virus infection. Neonates with severe disease and infants and children with concerning disease manifestations (e.g., myocarditis, enterovirus A71 neurologic and cardiopulmonary disease, enterovirus D68 respiratory failure, and acute flaccid myelitis) may require intensive cardiorespiratory support. Table 297.2 Differential Diagnosis of Nonpolio Enterovirus Infections CLINICAL MANIFESTATION BACTERIAL PATHOGENS VIRAL PATHOGENS NONINFECTIOUS Nonspecific febrile illness Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis Influenza viruses, human herpesviruses 6 and 7, human parechoviruses Rheumatologic disorders, oncologic diseases, drug reaction |
7,720 | Exanthemsenanthems Group A Streptococcus, Staphylococcus aureus, N. meningitidis, T. pallidum, M. pneumoniae Herpes simplex virus, adenoviruses, varicella zoster virus, Epstein Barr virus, measles virus, rubella virus, human herpesviruses 6 and 7, human parechoviruses Drug reaction, Stevens Johnson syndrome, toxic epidermal necrolysis, Kawasaki syndrome, vasculitis Respiratory illness conjunctivitis S. pneumoniae, H. influenzae (nontypeable and type b), N. meningitidis, Mycoplasma pneumoniae, Chlamydophila pneumoniae Adenoviruses, influenza viruses, respiratory syncytial virus, parainfluenza viruses, rhinoviruses, human metapneumovirus, coronaviruses Asthma exacerbation, rheumatologic uveitis, Kawasaki syndrome Myocarditispericarditis S. aureus, H. influenzae type b, M. pneumoniae Adenoviruses, influenza virus, parvovirus, cytomegalovirus Drugs, Kawasaki syndrome, rheumatic fever Meningitisencephalitis S. pneumoniae, H. influenzae type b, N. meningitidis, Mycobacterium tuberculosis, Borrelia burgdorferi, M. pneumoniae, Bartonella henselae, Listeria monocytogenes Herpes simplex virus, West Nile virus, influenza viruses, adenoviruses, Epstein Barr virus, mumps virus, lymphocytic choriomeningitis virus, arboviruses, human parechoviruses Drugs, intravenous immunoglobulin, Kawasaki syndrome, autoimmune encephalitis (e.g., anti NMDA receptor), acute disseminated encephalomyelitis (ADEM), demyelinating disorders Acute flaccid myelitis C. botulinum Poliovirus, West Nile virus, Japanese encephalitis virus, rabies virus, adenovirus Spinal cord infarction, antimyelin oligodendrocyte glycoprotein (MOG) myelitis, neuromyelitis optica (NMO), Guillain Barr syndrome, ADEM, transverse myelitis, lupus, tick paralysis Neonatal infections Group B Streptococcus, gram negative enteric bacilli, L. monocytogenes, Enterococcus Herpes simplex virus, adenoviruses, cytomegalovirus, rubella virus, human parechoviruses Neonatal lupus, Aicardi Goutires syndrome Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1986 Part XV u Infectious Diseases Milrinone has been suggested as a useful agent in severe enterovirus A71 cardiopulmonary disease. Liver and cardiac transplantation have been performed for neonates with progressive end organ failure. Immunoglobulin has been used to treat enterovirus infections based on the importance of the humoral immune response to enterovirus infection and the observation that absence of neutralizing antibody is a risk factor for symptomatic infection. Immunoglobulin products contain neutralizing antibodies to many commonly circulating sero types, although titers vary with serotype and among products and lots. Anecdotal and retrospective, uncontrolled use of intravenous immu noglobulin or infusion of maternal convalescent plasma to treat new borns with severe disease has been associated with varying outcomes. The one randomized controlled trial was too small to demonstrate significant clinical benefits, although neonates who received immu noglobulin containing high neutralizing titers to their own isolates had shorter periods of viremia and viruria. Immunoglobulin has been administered intravenously and intraventricularly to treat hypogam maglobulinemia in patients with chronic enterovirus meningoen cephalitis and intravenously in transplant and oncology patients with severe infections, with variable success. Intravenous immunoglobulin and corticosteroids have been used for patients with neurologic disease caused by enterovirus A71, enterovirus D68, and other enteroviruses. Modulation of cytokine profiles after administration of intravenous immunoglobulin for enterovirus A71associated brainstem encephali tis has been demonstrated. High titer enterovirus A71 immunoglobu lin appeared promising in animal models, and clinical trials in regions with epidemic enterovirus A71 disease are ongoing. Antienterovirus A71 and D68 monoclonal antibodies |
7,721 | have also been generated and evaluated in vitro and in animal models. A retrospective study sug gested that treatment of presumed viral myocarditis with immuno globulin was associated with improved outcome; however, virologic diagnoses were not made. Evaluation of corticosteroids and cyclospo rine and other immunosuppressive therapy for myocarditis has been inconclusive. Successful treatment of enterovirus myocarditis with interferon has been reported anecdotally, and interferon treat ment was associated with viral clearance, improved cardiac function, and survival in chronic cardiomyopathy associated with persistence of enterovirus (or adenovirus) genome. Activity of interferon against enterovirus A71 has been demonstrated with in vitro and animal mod els, but potency varies with interferon type. Antiviral agents that act at various steps in the enterovirus life cycle attachment, penetration, uncoating, translation, polyprotein processing, protease activity, replication, and assemblyare being evaluated. Candi dates include pharmacologically active chemical compounds, small inter fering RNAs and DNA like antisense agents, purine nucleoside analogs, synthetic peptides, enzyme inhibitors of signal transduction pathways, interferon inducers, and herbal compounds. Pleconaril, an inhibitor of attachment and uncoating, was associated with benefit in some controlled studies of enterovirus meningitis and picornavirus upper respiratory tract infections, and uncontrolled experience suggested possible benefits in high risk infections. A randomized controlled trial of pleconaril in neo nates with severe hepatitis, coagulopathy, andor myocarditis suggested possible virologic and clinical benefits of treatment. Pocapavir, an agent with a similar mechanism of action that is in development for treatment of poliovirus infections, has been used in a small number of cases of severe neonatal enterovirus sepsis. Vapendavir is another attachment inhibitor that is in clinical trials for rhinovirus infections and has in vitro activity against enteroviruses (including enterovirus A71) but has not entered clin ical trials for enterovirus infections. Pleconaril, pocapavir, and vapendavir are not currently available for clinical use. Design and evaluation of candidate agents active against enterovirus A71 and enterovirus D68 are high priorities. Challenges for therapies of enterovirus A71 include limited cross genotypic activity of candi date compounds and high viral mutagenicity that favors emergence of resistance. Lactoferrin and ribavirin have demonstrated activity with in vitro andor animal models. The investigational agents rupin trivir and V 7404, which inhibit the 3C protease conserved among many enteroviruses and essential for infectivity, have broad activity in vitro, including against both enterovirus A71 and enterovirus D68. DAS181 is an investigational, inhaled drug with sialidase activity that has in vitro activity against recently circulating strains of enterovirus D68. The antidepressant fluoxetine interacts with the enterovirus 2C protein and has in vitro activity against group B and D enteroviruses; it has been used anecdotally for chronic enterovirus encephalitis associ ated with agammaglobulinemia and enterovirus D68 associated acute flaccid myelitis. A retrospective study did not demonstrate a signal of efficacy in the latter condition. COMPLICATIONS AND PROGNOSIS The prognosis in the majority of enterovirus infections is excellent. Morbidity and mortality are associated primarily with myocarditis, neurologic disease, severe neonatal infections, and infections in immu nocompromised hosts. Prevention The first line of defense is |
7,722 | prevention of transmission through good hygiene, such as handwashing, avoidance of sharing utensils and drinking containers and other potential fomites, disinfection of con taminated surfaces, and avoiding community settings where exposures are likely to occur. The paucity of enterovirus circulation and associ ated hand foot mouth disease and respiratory and neurologic disease in 2020 during the COVID 19 pandemic provides indirect evidence of the efficacy of nonpharmaceutical interventions targeted to decrease SARS CoV 2 spread (masking, distancing, school mitigation strate gies) against enteroviruses. Chlorination of drinking water and swim ming pools also may be an important preventative strategy. Contact precautions should be used for all patients with enterovirus infections in the hospital setting; droplet precautions should also be included for patients with respiratory syndromes and, possibly, enterovirus A71 and D68 infection. Infection control techniques such as cohorting have proven effective in limiting nursery outbreaks. Prophylactic adminis tration of immunoglobulin or convalescent plasma has been used in nursery epidemics; simultaneous use of infection control interventions makes it difficult to determine efficacy. Pregnant women near term should avoid contact with individuals ill with possible enterovirus infections. If a pregnant woman experiences a suggestive illness, it is advisable not to proceed with emergency deliv ery unless there is concern for fetal compromise or obstetric emer gencies cannot be excluded. Rather, it may be advantageous to extend pregnancy, allowing the fetus to passively acquire protective antibod ies. A strategy of prophylactically administering immunoglobulin (or maternal convalescent plasma) to neonates born to mothers with enterovirus infections is untested. Maintenance antibody replacement with high dose intravenous immunoglobulin for patients with hypogammaglobulinemia has reduced the incidence of chronic enterovirus meningoencephalitis, although breakthrough infections occur. Inactivated vaccines to pre vent enterovirus A71 infections, given to children 6 35 months of age, have been demonstrated to be safe and effective (90 against entero virus A71 hand foot and mouth disease and 80 against enterovirus A71 serious disease) in phase 3 clinical trials. Three inactivated entero virus A71 vaccines have been licensed and approved for prevention of severe hand foot and mouth disease in China and are being studied in other Asian countries. Other vaccine strategies for enterovirus A71, including VP1 capsid proteinbased subunit, DNA, and vector vac cines; combined peptide vaccines; live attenuated vaccines; virus like particles; breast milk enriched with VP1 capsid protein or lactoferrin; and interferon expressing recombinant viral vectors, are also under investigation. Circulation of multiple enterovirus A71 types, antigenic drift, viral recombination, and potential immunologic cross reactivity with brain tissue may pose challenges to development of enterovirus A71 vaccines. Vaccine candidates against EV D68, including virus like particle vaccines and inactivated whole virus vaccines, are in develop ment, but have not progressed beyond animal studies. Most enterovi rus vaccines do not provide cross protection against other serotypes; however, the potential to create multivalent enterovirus vaccines tar geting several common strains with severe manifestations is under investigation. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com |
7,723 | by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 298 u Parvoviruses 1987 The parvoviruses are small, single stranded DNA viruses. They are common infectious agents of a wide variety of animal species, includ ing mammals, birds, and insects. Parvoviruses as a group include a number of important animal pathogens. There are five different types of parvoviruses known to infect humans: the dependoviruses, also called adeno associated viruses (AAVs), parvovirus B19 (B19V), human bocaviruses (HBoVs), parvovirus 4 (PARV4), and human bufa virus (HBuV). B19V and HBoV are the only two parvoviruses proven to be pathogenic in humans. B19V is the most well studied and clini cally important of the human parvoviruses and the cause of erythema infectiosum or fifth disease. Human bocavirus is an emerging human pathogen. ETIOLOGY The five human parvoviruses are distinct enough from each other to represent five different genera within the Parvoviridae family. B19V is a member of the genus Erythroparvovirus, is composed of an icosahedral protein capsid without an envelope, and contains a single stranded DNA genome of approximately 5.5 kb. It is relatively heat and solvent resistant. It is antigenically distinct from other mammalian parvovi ruses and has only one known serotype, with three distinct genotypes described. The relatively short genome in parvoviruses does not encode a DNA polymerase, so all parvoviruses require either host cell factors present in late S phase or coinfection with another virus to replicate their DNA. B19V can be propagated effectively in vitro only in CD36 erythroid progenitor cells derived from human bone marrow, umbili cal cord blood, or peripheral blood. HBoV is a member of the genus Bocaparvovirus. HBoV was first isolated from nasopharyngeal specimens from children with respira tory tract infection in 2005. It was identified using random polymerase chain reaction (PCR) amplification and sequencing methods specifi cally designed to detect previously unknown viral sequences. Analysis of the gene sequences showed similarities to both bovine and canine parvoviruses, and thus the virus was named human bocavirus. Later, three other HBoVs were identified in stool samples and designated as HBoV types 2, 3, and 4, with the initial respiratory isolate called HBoV1. The HBoV capsid structure and genome size are similar to those of B19V, but the genomic organization and replication are dif ferent (though not fully characterized to date). HBoVs cannot be propagated in conventional cell culture but have been grown in a pseu dostratified human airway epithelial cell culture system. The AAVs are members of the genus Dependoparvovirus and were the first parvoviruses to be found in humans. They were originally identified as contaminants in laboratory preparations of adenovirus, resulting in the designation adeno associated viruses. They were later isolated directly from human tissue samples, and now several AAV sero types are known to commonly infect humans. AAVs have a unique life cycle that can take one of two paths: (1) a lytic infection with replication of viral DNA and production of |
7,724 | new virus, or (2) viral integration into the host cell DNA. In the presence of a helper virus, usually an adeno virus or a herpesvirus, AAV can replicate its DNA, produce capsids, and release new virions by cell lysis. In the absence of a helper virus infec tion, the AAV genome becomes integrated into the host cell DNA. This feature has drawn interest in AAVs as potential vectors for gene therapy. Although human infection with AAVs is common, there is only one pos sible disease association (idiopathic hepatitis) (see Chapter 406). PARV4 was initially identified in 2005 from the blood of an adult patient with acute viral syndrome, who was also an intravenous drug user co infected with hepatitis C. Subsequently, this virus has been found in blood donors and donated plasma pools in many different coun tries. It appears to be present in approximately 3 of blood donors in the United States and 4 of plasma pools. There is currently no known disease association or clinical symptomology associated with infection. Likewise, BuV is a parvovirus that was first identified in 2012 in the feces from children 5 years of age with acute diarrhea but has an unclear role as a pathogen. PARV4 has been assigned to the genus Tetraparvovirus, and BuV is a member of the genus Protoparvovirus. The full epidemiol ogy and clinical relevance of these viruses await further study. EPIDEMIOLOGY Parvovirus B19 Infections with B19V are common and occur worldwide. Clinically apparent infections, such as the rash illness of erythema infectiosum and transient aplastic crisis, are most prevalent in school age children (70 of cases occur in patients between 5 and 15 years of age). Seasonal peaks occur in the late winter and spring, with sporadic infections throughout the year. Seroprevalence increases with age, with 4060 of adults having evidence of prior infection. Transmission of B19V is by the respiratory route, presumably via large droplet spread from nasopharyngeal viral shedding. The trans mission rate is 1530 among susceptible household contacts, and mothers are more commonly infected than fathers. In outbreaks of ery thema infectiosum in elementary schools, the secondary attack rates range from 1060. Nosocomial outbreaks also occur, with secondary attack rates of 30 among susceptible healthcare workers. Although respiratory spread is the primary mode of transmission, B19V is also transmissible in blood and blood products, as documented among children with hemophilia receiving pooled donor clotting fac tor. Given the resistance of the virus to solvents, fomite transmission could be important in childcare centers and other group settings, but this mode of transmission has not been definitively established. Human Bocaviruses The majority of published studies have used molecular methods to detect HBoV DNA in respiratory secretions, fecal samples, blood, and other tissues. HBoV DNA (HBoV1) can be found commonly in respiratory secretions from children hospitalized with acute lower respiratory tract infections (LRTIs). It is more prevalent in children younger than 2 years of age and seems to be associated with wheezing respiratory illness. However, it can be |
7,725 | isolated from respiratory secretions from asymp tomatic children and can often be found as a coinfection with other common respiratory pathogens of children this age, including respira tory syncytial virus, human metapneumovirus, and rhinoviruses. This has caused some confusion as to the pathogenic role of HBoV in acute LRTI, including whether it can persist in secretions long after a subclini cal infection or requires a helper virus. A limited number of seroepide miologic studies have been performed, and these suggest that infection is common in children younger than 5 years of age. The most recent studies provide evidence that the virus is in fact pathogenic, especially in chil dren younger than 2 years with wheezing and LRTI, because HBoV1 is more likely to be the only virus isolated in these patients and more likely to have an acute antibody response when coupled with specific antibody testing. When quantitative PCR is used, the virus is found to be much higher in titer in these symptomatic cases. HBoV DNA (HBoV2, HBoV3, and HBoV4) has also been found in fecal samples in studies from various countries, but its role as a cause of viral gastroenteritis is still undetermined. PATHOGENESIS Parvovirus B19 The primary target of B19V infection is the erythroid cell line, specifi cally erythroid precursors near the pronormoblast stage. Viral infec tion produces cell lysis, leading to a progressive depletion of erythroid precursors and a transient arrest of erythropoiesis. The virus has no apparent effect on the myeloid cell line. The tropism for erythroid cells is related to the erythrocyte P blood group antigen, which is the pri mary cell receptor for the virus and is also found on endothelial cells, placental cells, and fetal myocardial cells. Thrombocytopenia and Chapter 298 Parvoviruses William C. Koch Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1988 Part XV u Infectious Diseases neutropenia are often observed clinically, but the pathogenesis of these abnormalities is not completely understood. Experimental infection of normal volunteers with B19V revealed a biphasic illness. From 7 11 days after inoculation, subjects had viremia and nasopharyngeal viral shedding with fever, malaise, and rhinor rhea. Reticulocyte counts dropped to undetectable levels but resulted in only a mild, clinically insignificant fall in serum hemoglobin. With the appearance of specific antibodies, symptoms resolved and serum hemoglobin returned to normal. Several subjects experienced a rash associated with arthralgia 17 18 days after inoculation. Some manifes tations of B19 infection, such as transient aplastic crisis, appear to be a direct result of viral infection, whereas others, including the exan them and arthritis, appear to be postinfectious phenomena related to the immune response. Skin biopsy of patients with erythema infectiosum reveals edema in the epidermis and a perivascular mononuclear infil trate compatible with an immune mediated process. Individuals with chronic hemolytic anemia and increased red blood cell (RBC) turnover are very sensitive |
7,726 | to minor perturbations in erythropoiesis. Infection with B19V leads to a transient arrest in RBC production and a precipitous fall in serum hemoglobin, often requir ing transfusion. The reticulocyte count drops to undetectable levels, reflecting the lysis of infected erythroid precursors. Humoral immu nity is crucial in controlling infection. Specific immunoglobulin (Ig) M appears within 1 2 days of infection and is followed by anti B19 IgG, which leads to control of the infection, restoration of reticulocytosis, and a rise in serum hemoglobin. Individuals with impaired humoral immunity are at increased risk for more serious or persistent infection with B19V, which usually manifests as chronic RBC aplasia, although neutropenia, thrombocy topenia, and marrow failure are also described. Children undergoing chemotherapy for leukemia or other forms of cancer, transplant recipi ents, and patients with congenital or acquired immunodeficiency states (including AIDS) are at risk for chronic B19V infections. Infections in the fetus and neonate are somewhat analogous to infections in immunocompromised persons. B19V is associated with nonimmune fetal hydrops and stillbirth in women experiencing a primary infection but does not appear to be teratogenic. Like most mammalian parvoviruses, B19V can cross the placenta and cause fetal infection during primary maternal infection. Parvovirus cytopathic effects are seen primarily in erythroblasts of the bone marrow and sites of extramedullary hematopoiesis in the liver and spleen. Fetal infection can presumably occur as early as 6 weeks of gestation, when erythroblasts are first found in the fetal liver; after the fourth month of gestation, hematopoiesis switches to the bone marrow. In some cases, fetal infection leads to profound fetal anemia and subsequent high output cardiac failure (see Chapter 138). Fetal hydrops ensues and is often associated with fetal death. There may also be a direct effect of the virus on myocardial tissue that contributes to the cardiac failure. However, most infections during pregnancy result in normal deliveries at term. Some of the asymptomatic infants from these deliveries have been reported to have chronic postnatal infection with B19V that is of unknown significance. Human Bocaviruses Mechanisms of HBoV replication and pathogenesis are poorly charac terized to date. Growth of HBoV1 in tissue culture is difficult, though the virus has been cultured in primary respiratory epithelial cells as noted above. The primary site of viral replication appears to be the respiratory tract, because the virus has been detected most frequently and in highest copy numbers here. HBoV1 has also been found occa sionally in the serum, suggesting the potential for systemic spread. HBoV1 has also been detected in stool, but copy numbers are very low. In contrast, HBoV types 2 4 are found predominantly in the stool, but host cell types are not known. CLINICAL MANIFESTATIONS Parvovirus B19 Many infections are clinically inapparent (Table 298.1). Infected children characteristically demonstrate the rash illness of erythema infectiosum. Adults, especially women, frequently experience acute polyarthropathy with or without a rash. Erythema Infectiosum (Fifth Disease) The most common manifestation of B19V is erythema infectiosum, also known as fifth disease, which is |
7,727 | a benign, self limited exanthema tous illness of childhood. The incubation period for erythema infectiosum is 4 28 days (aver age: 16 17 days). The prodromal phase is mild and consists of low grade fever in 1530 of cases, headache, and symptoms of mild upper respiratory tract infection. The hallmark of erythema infectiosum is the characteristic rash, which occurs in three stages that are not always distinguishable. The initial stage is an erythematous facial flushing, often described as a slapped cheek appearance (Fig. 298.1). The rash spreads rapidly or concurrently to the trunk and proximal extremities as a diffuse macular erythema in the second stage. Central clearing of macular lesions occurs promptly, giving the rash a lacy, reticulated appearance (Fig. 298.2). The rash tends to be more prominent on extensor surfaces, sparing the palms and soles. Affected children are afebrile and do not appear ill. Some have petechiae. Older children and adults often complain of mild pruritus. The rash resolves spon taneously without desquamation but tends to wax and wane over 1 3 weeks. It can recur with exposure to sunlight, heat, exercise, and stress. TABLE 298.1 Clinical Associations with Parvovirus B19 Infection Asymptomatic infection Exanthematous disorders Erythema infectiosum (fifth disease) Papular purpuric gloves and socks syndrome Asymmetric periflexural exanthem Bathing trunk exanthem Petechial exanthems Other disorders Arthritis Transient aplastic crises Chronic anemia Refractory anemia after solid organ or stem cell transplantation Hemophagocytic lymphohistiocytosis Myelodysplastic syndrome Fetal hydrops Vasculitis Neurologic disease, including arterial ischemic stroke, encephalopathy, encephalitis Rheumatologic disease Liver failure Myocarditis From Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology, 6th ed. Philadelphia: Elsevier; 2022: Box 16.2, p. 452. Fig. 298.1 Erythema infectiosum. Erythema of the bilateral cheeks, which has been likened to a slapped cheek appearance. (From Paller AS, Macini AJ. Hurwitz Clinical Pediatric Dermatology, 3rd ed. Philadel phia: WB Saunders; 2006:431.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 298 u Parvoviruses 1989 Lymphadenopathy and atypical papular, purpuric and vesicular rashes are also described. Arthropathy Arthritis and arthralgia may occur in isolation or with other symp toms. Joint symptoms are much more common among adults and older adolescents with B19V infection. Females are affected more frequently than males. In one large outbreak of fifth disease, 60 of adults and 80 of adult women reported joint symptoms. Joint symptoms range from diffuse polyarthralgia with morning stiffness to frank arthritis. The joints most often affected are the hands, wrists, knees, and ankles, but practically any joint may be affected. The joint symptoms are self limited and, in the majority of patients, resolve within 2 4 weeks. Some patients may have a prolonged course of many months, suggesting rheumatoid arthritis. Transient rheumatoid factor positivity is reported in some of these patients but with no joint destruction. Transient Aplastic Crisis The transient arrest of erythropoiesis and absolute reticulocytopenia induced by B19V infection leads to |
7,728 | a sudden fall in serum hemoglobin in individuals with chronic hemolytic conditions. This B19V induced RBC aplasia or transient aplastic crisis occurs in patients with all types of chronic hemolysis andor rapid RBC turnover, including sickle cell disease, thalassemia, hereditary spherocytosis, and pyruvate kinase deficiency, among others. In contrast to children with erythema infec tiosum only, patients with aplastic crisis are ill at presentation with fever, malaise, and lethargy and have signs and symptoms of profound anemia, including pallor, tachycardia, and tachypnea. Rash is rarely present. The incubation period for transient aplastic crisis is shorter than that for erythema infectiosum because the crisis occurs coinci dent with the viremia. Children with sickle cell hemoglobinopathies may also have a concurrent vasoocclusive pain crisis, further confusing the clinical presentation. Immunocompromised Persons Individuals with impaired humoral immunity are at risk for chronic B19V infection. Chronic anemia is the most common manifesta tion, sometimes accompanied by neutropenia, thrombocytopenia, or complete marrow suppression. Chronic infections occur in per sons receiving cancer chemotherapy or immunosuppressive therapy for transplantation and persons with congenital immunodeficien cies, AIDS, and functional defects in IgG production who are thereby unable to generate neutralizing antibodies. Fetal Infection Primary maternal infection is associated with nonimmune fetal hydrops and intrauterine fetal demise, with the risk for fetal loss when infection occurs in pregnancy estimated at 25. The mechanism of fetal disease appears to be a viral induced RBC aplasia at a time when the fetal erythroid fraction is rapidly expanding, leading to profound anemia, high output cardiac failure, and fetal hydrops. Viral DNA has been detected in infected abortuses. The second trimester seems to be the most sensitive period, but fetal losses are reported at every stage of gestation. If maternal B19V infection is suspected, fetal ultrasonogra phy and measurement of the peak systolic flow velocity of the middle cerebral artery are sensitive, noninvasive procedures to diagnose fetal anemia and hydrops. Most infants infected in utero are born normal at term, including some who have had ultrasonographic evidence of hydrops. A small subset of infants infected in utero may acquire a chronic or persistent postnatal infection with B19V that is of unknown significance. Congenital anemia associated with intrauterine B19V infection has been reported in a few cases, sometimes following intra uterine hydrops. This process may mimic other forms of congenital hypoplastic anemia (e.g., Diamond Blackfan syndrome). Fetal infec tion with B19V has been associated with bone lesions but has not been associated with other birth defects. B19V is only one of many causes of hydrops fetalis (see Chapter 140). Myocarditis B19V infection has been associated with myocarditis in fetuses, infants, children, and a limited number of adults. Diagnosis has often been based on serologic findings suggestive of a concurrent B19V infection, but in many cases B19V DNA has been demonstrated in cardiac tissue. B19 related myocarditis is plausible because fetal myocardial cells are known to express P antigen, the cell receptor for the virus. In the few cases in which histology is reported, a |
7,729 | predominantly lymphocytic infiltrate is described. Outcomes have varied from complete recovery to chronic cardiomyopathy to fatal cardiac arrest. Although B19 associated myo carditis seems to be a rare occurrence, there appears to be enough evi dence to consider B19V as a potential cause of lymphocytic myocarditis, especially in infants and immunocompromised persons. Other Cutaneous Manifestations A variety of atypical skin eruptions have been reported with B19V infec tion. Most of these are petechial or purpuric, often with evidence of vasculitis on biopsy. Among these rashes, the papular purpuric gloves and socks syndrome (PPGSS) is well established in the dermatologic literature as distinctly associated with B19V infection (Figs. 298.3 and 298.4). PPGSS is characterized by fever, pruritus, and painful edema and erythema localized to the distal extremities in a distinct gloves and socks distribution, followed by acral petechiae and oral lesions. The syndrome is self limited and resolves within a few weeks. Although PPGSS was ini tially described in young adults, a number of reports of the disease in Fig. 298.2 Erythema infectiosum. Reticulate erythema on the upper arm of a patient with erythema infectiosum. (From Paller AS, Macini AJ. Hurwitz Clinical Pediatric Dermatology, 3rd ed. Philadelphia: WB Saunders; 2006:431.) Fig. 298.3 Papular purpuric gloves and socks syndrome. Petechial purpura of the palms in a patient with parvovirus B19 infection. (From Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology, 6th ed. Philadelphia: Elsevier; 2022: Fig. 16.18, p. 453.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1990 Part XV u Infectious Diseases children have since been published. In those cases linked to B19V infec tion, the eruption is accompanied by serologic evidence of acute infec tion. Generalized petechial rash has also been reported. Human Bocaviruses Many studies have reported an association between respiratory tract infection and HBoV1 infection as detected by PCR of respiratory secre tions, primarily nasopharyngeal secretions. Clinical manifestations in these studies have ranged from mild upper respiratory symptoms to pneumonia. However, the role of HBoV1 as a pathogen has been chal lenged by the detection of the virus in asymptomatic children and by the frequent detection of other respiratory viruses in the same samples. Nonetheless, studies that have included some combination of quantita tive PCR, serum PCR, and serology have been more convincing about HBoV1 as a human pathogen. The use of a quantitative PCR method also seems to differentiate between HBoV1 infection (and wheezing) and prolonged viral shedding, because patients with higher viral titers were more likely to be symptomatic, to be viremic, and to have HBoV1 isolated without other viruses. HBoV type 2 DNA has been found in the stool of 325 of chil dren with gastroenteritis, but often with another enteric virus. DNA of HBoV types 2, 3, and 4 has also been found in the stool of healthy, asymptomatic individuals. At present, there are few data linking HBoV2, |
7,730 | HBoV3, or HBoV4 to gastroenteritis or any clinical illness. Further studies are required to determine if any of the HBoVs are asso ciated with some cases of childhood gastroenteritis. DIAGNOSIS Parvovirus B19 Infection The diagnosis of erythema infectiosum is usually based on clinical pre sentation of the typical rash and rarely requires virologic confirmation. Similarly, the diagnosis of a typical transient aplastic crisis in a child with sickle cell disease is generally made on clinical grounds without specific virologic testing. Serologic tests for the diagnosis of B19V infection are available. B19 specific IgM develops within 2 3 days after infection and persists up to 6 months (Fig. 298.5). Anti B19 IgG serves as a marker of current or past infection. Seroconversion of anti B19 IgG antibodies in paired sera can also be used to confirm recent infection. Serologic diagnosis is unreliable in immunocompromised persons; diagnosis in these patients requires methods to detect viral DNA. Because the virus cannot be isolated by standard cell culture, methods to detect viral particles or viral DNA, such as PCR are necessary to establish the diagnosis. Viral DNA may be detectable for 1 month after infec tion in immunocompetent patients but longer in immune compromised patients. Some reports suggest that prolonged detection of viral DNA (months) may represent DNA but not the complete virus. Prenatal diag nosis of B19V induced fetal hydrops can be accomplished by detection of viral DNA in fetal blood or amniotic fluid by these methods. Human Bocavirus Infections HBoV1 infections cannot be differentiated from other viral respiratory infections on clinical grounds. HBoV DNA can be readily detected by PCR methods and is now included in several commercially available multiplex respiratory virus PCR assays. Quantitative PCR is useful to differentiate acute infection from persistent viral shedding, because higher viral copy numbers (104 HBoV1 genomesmL) correlate with acute illness, but this test is not widely available. Likewise, serologic methods to detect specific IgM and IgG antibodies have been devel oped, but these too are not routinely available and there are problems with cross reactivity among antibodies to the various HBoV types. The most reliable method to diagnose HBoV1 infection would include detection of viral DNA in serum by PCR and in respiratory tract sam ples by quantitative PCR, with concurrent detection of IgM or a diag nostic IgG response in paired samples. Fig. 298.4 Papular purpuric gloves and socks syndrome. Erythema and petechiae of the plantar feet were accompanied by pruritus and sore throat in this young girl with parvovirus B19 infection. (From Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology, 6th ed. Phila delphia: Elsevier; 2022: Fig. 16.19, p. 454.) Nonspecific febrile illness Aplastic crisis 0 7 14 Days 21 28 Virus excretion Erythema infectiosum IgM antibody Viremia Reticulocytes Fig. 298.5 Selected virologic, immunologic, hematologic, and clinical events in parvovirus B19 virus infection. (From Schulte DJ. Human parvovi rus B19. In Kaplan SL, Harrison GJ, Steinbach WJ, Cherry JD, Hotez PJ, eds. Feigin and Cherrys Textbook of Pediatric Infectious Diseases, 8th ed. |
7,731 | Philadelphia: Elsevier, 2019. Fig 152.1.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 299 u Herpes Simplex Virus 1991 DIFFERENTIAL DIAGNOSIS Parvovirus B19 The rash of erythema infectiosum must be differentiated from roseola, rubella, measles, enteroviral infections, and drug reactions. Rash and arthritis in older children should prompt consideration of juvenile idiopathic arthritis, systemic lupus erythematosus, serum sickness, and other connective tissue disorders. Human Bocavirus Respiratory illness and wheezing caused by HBoV1 cannot be dif ferentiated clinically from other common viral respiratory infections, especially respiratory syncytial virus, human metapneumovirus, rhino viruses, enterovirus D68, and parainfluenza viruses. HBoV1 infection in young children seems to most closely resemble that of respiratory syncytial virus and human metapneumovirus, because the clinical symptoms and age ranges will overlap. TREATMENT Parvovirus B19 There is no specific antiviral therapy approved for B19V infection. The acyclic nucleoside phosphonates cidofovir and brincidofovir have been shown to inhibit B19V replication in vitro, but no clini cal studies have been performed and thus antiviral therapy cannot be recommended. Commercial lots of intravenous immunoglobulin (IVIG) have been used with some success to treat B19V related epi sodes of anemia and bone marrow failure in immunocompromised children. Specific antibody may facilitate clearance of the virus but is not always necessary, because cessation of cytotoxic chemother apy with subsequent restoration of immune function often suffices. In patients whose immune function is not likely to recover, such as patients with AIDS, administration of IVIG may give only a tempo rary remission, and periodic reinfusions may be required. In patients with AIDS, clearance of B19V infection has been reported after ini tiation of highly active antiretroviral therapy (HAART) without the use of IVIG. No controlled studies have been published regarding dosing of IVIG for B19V induced RBC aplasia. Multiple case reports and limited clinical series have reported successful treatment of severe anemia secondary to chronic B19V infection using several differ ent IVIG dosing regimens. Initial reports recommended a starting dose of 400 mgkgday for up to 5 days. Other reports have used higher doses ranging from 12 gkg split into one to three infu sions. The dose and duration of IVIG may be adjusted based on the response to therapy. The optimal schedule of IVIG treatment is not known. B19V infected fetuses with anemia and hydrops have been managed successfully with intrauterine RBC transfusions, but this procedure has significant attendant risks. Once fetal hydrops is diagnosed, regardless of the suspected cause, the mother should be referred to a fetal therapy center for further evaluation because of the high risk for serious com plications (see Chapter 140). Human Bocavirus There is no specific antiviral therapy available. Appropriate support ive treatment for viral LRTI and pneumonia is recommended, as directed by clinical severity. For children with wheezing illness spe cifically caused by HBoV1 infection, there are no data examining their response |
7,732 | to bronchodilator therapy. COMPLICATIONS Parvovirus B19 Erythema infectiosum is often accompanied by arthralgias or arthritis in adolescents and adults that may persist after resolution of the rash (see Table 298.1). B19V may rarely cause thrombocytopenic purpura. Neurologic conditions, including aseptic meningitis, encephalitis, and peripheral neuropathy, have been reported in both immunocompro mised and healthy individuals in association with B19V infection. The incidence of stroke may be increased in children with sickle cell disease following B19V induced transient aplastic crisis. B19V is also a cause of infection associated hemophagocytic lymphohistiocytosis, usually in immunocompromised persons. Human Bocavirus There are no studies reporting on complications of HBoV1 infec tion. Complications of wheezing and viral pneumonia would be pos sible, including hypoxemia and secondary bacterial infection, among others. PREVENTION Parvovirus B19 Children with erythema infectiosum are not likely to be infectious at presentation because the rash and arthropathy represent immune mediated, postinfectious phenomena. Isolation and exclusion from school or childcare are unnecessary and ineffective after diagnosis. Children with B19V induced RBC aplasia, including the transient aplastic crisis, are infectious upon presentation and demonstrate a more intense viremia. Most of these children require transfusions and supportive care until their hematologic status stabilizes. They should be isolated in the hospital to prevent spread to susceptible patients and staff. Isolation should continue for at least 1 week and until fever has resolved. Pregnant caregivers should not be assigned to these patients. Exclusion of pregnant women from workplaces where children with erythema infectiosum may be present (e.g., primary and secondary schools) is not recommended as a general policy because it is unlikely to reduce their risk. There are no data to support the use of IVIG for postexposure prophylaxis in pregnant caregivers or immunocompro mised children. No vaccine is currently available, though this is a topic of ongoing research. Human Bocavirus There are no studies that have addressed the prevention of transmis sion of this infection. In the hospital setting, standard precautions should be observed to limit spread of the virus. Because HBoV1 causes respiratory infection and can be detected in respiratory secretions sometimes in very high titer, measures to limit contact with respiratory secretions should be considered, including contact and droplet isola tion for severely symptomatic young children. No vaccine is available, and no other preventive measures have been reported. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. The two closely related herpes simplex viruses (HSVs), HSV type 1 (HSV 1) and HSV type 2 (HSV 2), cause a variety of illnesses, depend ing on the anatomic site where the infection is initiated, the immune state of the host, and whether the symptoms reflect primary or recur rent infection. Common infections involve the skin, eye, oral cavity, and genital tract. Infections tend to be mild and self limiting, except in the immunocompromised patient and newborn infants, in whom they may be severe and life threatening. Primary infection occurs in individuals who have not been infected previously with either HSV 1 or HSV 2. Because these individuals are HSV |
7,733 | seronegative and have no preexisting immunity to HSV, primary infections can be severe. Nonprimary first infection occurs in indi viduals previously infected with one type of HSV (e.g., HSV 1) who Chapter 299 Herpes Simplex Virus Lawrence R. Stanberry and Philip Zachariah Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1992 Part XV u Infectious Diseases have become infected for the first time with the other type of HSV (HSV 2). Because immunity to one HSV type provides some cross protection against disease caused by the other HSV type, nonprimary first infections tend to be less severe than true primary infections. Dur ing primary and nonprimary initial infections, HSV establishes latent infection in regional sensory ganglion neurons. Virus is maintained in this latent state for the life of the host but periodically can reactivate and cause recurrent infection. Symptomatic recurrent infections tend to be less severe and of shorter duration than first infections. Asymp tomatic recurrent infections are extremely common and cause no physical distress, although patients with these infections are contagious and can transmit the virus to susceptible individuals. Reinfection with a new strain of either HSV 1 or HSV 2 at a previously infected ana tomic site (e.g., the genital tract) can occur but is relatively uncommon, suggesting that host immunity, perhaps site specific local immunity, resulting from the initial infection affords protection against exog enous reinfection. ETIOLOGY HSVs contain a double stranded DNA genome of approximately 152 kb that encodes at least 84 proteins. The DNA is contained within an icosadeltahedral capsid, which is surrounded by an outer envelope composed of a lipid bilayer containing at least 12 viral glycoproteins. These glycoproteins are the major targets for humoral immunity, whereas other nonstructural proteins are important targets for cellular immunity. Two encoded proteins, viral DNA polymerase and thymi dine kinase, are targets for antiviral drugs. HSV 1 and HSV 2 have a similar genetic composition with extensive DNA and protein homol ogy. One important difference in the two viruses is their glycoprotein G proteins, which have been exploited to develop a new generation of commercially available, accurate, type specific serologic tests that can be used to discriminate whether a patient has been infected with HSV 1 or HSV 2 or both. EPIDEMIOLOGY HSV infections are ubiquitous, and there are no seasonal variations in risk for infection. The only natural host is humans, and the mode of transmission is direct contact between mucocutaneous surfaces. There are no documented incidental transmissions from inanimate objects such as toilet seats. All infected individuals harbor latent infection and experience recurrent infections, which may be symptomatic or may go unrec ognized and thus are periodically contagious. This information helps explain the widespread prevalence of HSV. HSV 1 and HSV 2 are equally capable of causing initial infec tion at any anatomic site but differ in their capacity to |
7,734 | cause recur rent infections. HSV 1 has a greater propensity to cause recurrent oral infections, whereas HSV 2 has a greater proclivity to cause recurrent genital infections. For this reason, HSV 1 infection typically results from contact with contaminated oral secretions, whereas HSV 2 infection most commonly results from anogenital contact. HSV seroprevalence rates are highest in developing countries and among lower socioeconomic groups, although high rates of HSV 1 and HSV 2 infections are found in developed nations and among persons of the highest socioeconomic strata. Incident HSV 1 infec tions are more common during childhood and adolescence but are also found throughout later life. Data on HSV 1 and HSV 2 antibody prevalence from the National Health and Nutrition Examination Sur vey (NHANES) among persons age 14 49 years showed the prevalence of HSV 1 and HSV 2 to be 47.8 and 11.9, respectively. Prevalence of both HSV 1 and HSV 2 increased linearly with age and was higher among females than males. Modifiable factors that predict HSV 2 seropositivity include less education, poverty, cocaine use, and a greater lifetime number of sex ual partners. Studies show that only approximately 1020 of HSV 2 seropositive subjects report a history of genital herpes, emphasizing the asymptomatic nature of most HSV infections. A 3 year longitudinal study of Midwestern adolescent females 12 15 years of age found that 44 were seropositive for HSV 1 and 7 for HSV 2 at enrollment. At the end of the study, 49 were sero positive for HSV 1 and 14 for HSV 2. The attack rates, based on the number of cases per 100 person years, were 3.2 for HSV 1 infec tion among all females and 4.4 for HSV 2 infection among females who reported being sexually experienced. Findings of this study indicate that sexually active young women have a high attack rate for genital herpes and suggest that genital herpes should be consid ered in the differential diagnosis of any young woman who reports recurrent genitourinary complaints. In this study, participants with preexisting HSV 1 antibodies had a significantly lower attack rate for HSV 2 infection, and those who became infected were less likely to have symptomatic disease than females who were HSV seronega tive when they entered the study. Prior HSV 1 infection appears to afford adolescent females some protection against becoming infected with HSV 2; in adolescent females infected with HSV 2, the preexisting HSV 1 immunity appears to protect against devel opment of symptomatic genital herpes. Neonatal herpes is an uncommon but potentially fatal infection of the fetus or more likely the newborn. It is not a reportable disease in most states, and therefore there are no solid epidemiologic data regard ing its frequency in the general population. The overall U.S. incidence of neonatal HSV was estimated to be 9.6 per 100,000 births in 2006, which is higher than reported for the reportable perinatally acquired sexually transmitted infections such as congenital syphilis and gono coccal ophthalmia neonatorum. More than |
7,735 | 90 of the cases are the result of maternal child transmission. The risk for transmission is greatest during a primary or nonprimary first infection (3050) and much lower when the exposure is during a recurrent infection (2). HSV viral suppression therapy in mothers does not consistently elimi nate the possibility of neonatal infection. Infants born to mothers dually infected with HIV and HSV 2 are also at higher risk for acquir ing HIV than infants born to HIV positive mothers who are not HSV 2 infected. It is estimated that approximately 25 of pregnant women are HSV 2 infected and that approximately 2 of pregnant women acquire HSV 2 infection during pregnancy. HSV is a leading cause of sporadic, fatal encephalitis in children and adults. In the United States the annual hospitalization rate for HSV encephalitis has been calculated to be 10.3 2.2 casesmillion in neo nates, 2.4 0.3 casesmillion in children, and 6.4 0.4 casesmillion in adults. PATHOGENESIS In the immunocompetent host the pathogenesis of HSV infection involves viral replication in skin and mucous membranes followed by replication and spread in neural tissue. Viral infection typically begins at a cutaneous portal of entry such as the oral cavity, genital mucosa, ocular conjunctiva, or breaks in keratinized epithelia. The virus enters the cell through attachment and fusion, a multistep process mediated by interaction of viral envelope glycoproteins (e.g., gB and gH gL) with host surface receptors (e.g., Nectin 1). Virus replicates locally, result ing in the death of the cell, and sometimes produces clinically apparent inflammatory responses that facilitate the development of character istic herpetic vesicles and ulcers. Virus also enters nerve endings and spreads beyond the portal of entry to sensory ganglia by intraneuronal transport. Virus replicates in some sensory neurons, and the progeny virions are sent via intraneuronal transport mechanisms back to the periphery, where they are released from nerve endings and replicate fur ther in skin or mucosal surfaces. It is virus moving through this neural arc that is primarily responsible for the development of characteristic herpetic lesions, although most HSV infections do not reach a thresh old necessary to cause clinically recognizable disease. Although many sensory neurons become productively infected during the initial infec tion, some infected neurons do not initially support viral replication. It is in these neurons that the virus establishes a latent infection, a condi tion in which the viral genome persists within the neuronal nucleus in a largely metabolically inactive state. Intermittently throughout the Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 299 u Herpes Simplex Virus 1993 life of the host, undefined changes can occur in latently infected neu rons that trigger the virus to begin to replicate. This replication occurs despite the hosts having established a variety of humoral and cellular immune responses that successfully controlled the initial infection. With reactivation of the |
7,736 | latent neuron, progeny virions are produced and transported within nerve fibers back to cutaneous sites somewhere in the vicinity of the initial infection, where further replication occurs and causes recurrent infections. Recurrent infections may be symp tomatic (with typical or atypical herpetic lesions) or asymptomatic. In either case, virus is shed at the site where cutaneous replication occurs and can be transmitted to susceptible individuals who come in contact with the site or with contaminated secretions. Latency and reactivation are the mechanisms by which the virus is successfully maintained in the human population. Viremia, or hematogenous spread of the virus, does not appear to play an important role in HSV infections in the immunocompetent host but can occur in neonates, individuals with eczema, and severely malnourished children. It is also seen in patients with depressed or defective cell mediated immunity, as occurs with HIV infection, malignancy, or immunosuppressive therapies. Viremia can result in dissemination of the virus to visceral organs, including the liver and adrenals. Hematogenous dissemination of virus to the central nervous system appears to only occur in neonates. The pathogenesis of HSV infection in newborns is complicated by their relative immunologic immaturity. The source of virus in neona tal infections is typically but not exclusively the mother. Transmis sion generally occurs during delivery, although it is well documented to rarely occur with cesarean delivery with intact fetal membranes. The most common portals of entry are the conjunctiva, mucosal epithelium of the nose and mouth, and breaks or abrasions in the skin that occur with scalp electrode use or forceps delivery. With prompt antiviral therapy, virus replication may be restricted to the site of inoculation (the skin, eye, or mouth). However, virus may also extend from the nose to the respiratory tract to cause pneumonia, move via intraneuronal transport to the central nervous system to cause encephalitis, or spread by hematogenous dissemination to vis ceral organs and the brain. Factors that may influence neonatal HSV infection include the virus type, portal of entry, inoculum of virus to which the infant is exposed, gestational age of the infant, and pres ence of maternally derived antibodies specific to the virus causing infection. Latent infection is established during neonatal infection, and survivors may experience recurrent cutaneous and neural infec tions. Persistent central nervous system infection may affect the neu rodevelopment of the infant. CLINICAL MANIFESTATIONS The hallmarks of common HSV infections are skin vesicles and shallow ulcers. Classic infections manifest as small, 2 to 4 mm vesicles that may be surrounded by an erythematous base. These may persist for a few days before evolving into shallow, minimally erythematous ulcers. The vesicular phase tends to persist longer when keratinized epithelia is involved and is generally brief and sometimes just fleeting when moist mucous membranes are the site of infection. Because HSV infections are common, and their natural history is influenced by many factors, including portal of entry, immune status of the host, and whether it is an initial or recurrent infection, the typical |
7,737 | manifestations are seldom classic. Most infections are asymptomatic or unrecognized, and nonclassic presentations, such as small skin fissures and small erythematous nonvesicular lesions, are common. Acute Oropharyngeal Infections Herpes gingivostomatitis most often affects children 6 months to 5 years of age but is seen across the age spectrum. It is an extremely pain ful condition with sudden onset, pain in the mouth, drooling, refusal to eat or drink, and fever of up to 40.040.6C (104105.1F). The gums become markedly swollen, and vesicles may develop throughout the oral cavity, including the gums, lips, tongue, palate, tonsils, pharynx, and perioral skin (Fig. 299.1). The vesicles may be more extensively distributed than typically seen with enteroviral herpangina. During the initial phase of the illness there may be tonsillar exudates suggestive of bacterial pharyngitis. The vesicles are generally present only a few days before progressing to form shallow indurated ulcers that may be covered with a yellow gray membrane. Tender submandibular, sub maxillary, and cervical lymphadenopathy is common. The breath may be foul as a result of overgrowth of anaerobic oral bacteria. Untreated, the illness resolves in 7 14 days, although the lymphadenopathy may persist for several weeks. In older children, adolescents, and college students, the initial HSV oral infection may manifest as pharyngitis and tonsillitis rather than gingivostomatitis. The vesicular phase is often over by the time the patient presents to a healthcare provider, and signs and symptoms may be indistinguishable from those of streptococcal pharyngitis, consist ing of fever, malaise, headache, sore throat, and white plaques on the tonsils. The course of illness is typically longer than for untreated strep tococcal pharyngitis. Herpes Labialis Fever blisters (cold sores) are the most common manifestation of recurrent HSV 1 infections. The most common site of herpes labialis is the vermilion border of the lip, although lesions sometimes occur on the nose, chin, cheek, or oral mucosa. Older patients report experienc ing burning, tingling, itching, or pain 3 6 hours (rarely as long as 24 48 hours) before the development of the herpes lesion. The lesion gener ally begins as a small grouping of erythematous papules that progress over a few hours to create a small, thin walled vesicle. The vesicles may form shallow ulcers or become pustular. The short lived ulcer dries and develops a crusted scab. Complete healing without scarring occurs with reepithelialization of the ulcerated skin, usually within 6 10 days. Some patients experience local lymphadenopathy but no constitutional symptoms. Cutaneous Infections In the healthy child or adolescent, cutaneous HSV infections are gener ally the result of skin trauma with macroabrasions or microabrasions and exposure to infectious secretions. This situation most often occurs in play or contact sports such as wrestling (herpes gladiatorum) and rugby (scrum pox). An initial cutaneous infection establishes a latent infection that can subsequently result in recurrent infections at or near the site of the initial infection. Pain, burning, itching, or tingling often precedes the herpetic eruption by a few hours to a few days. Like herpes labialis, |
7,738 | lesions begin as grouped, erythematous papules that progress to vesicles, pustules, ulcers, and crusts and then heal without scar ring in 6 10 days. Although herpes labialis typically results in a single lesion, a cutaneous HSV infection results in multiple discrete lesions Fig. 299.1 Clustered perioral vesicles and erosions in an infant with primary herpetic gingivostomatitis. (From Schachner LA, Hansen RC, eds. Pediatric Dermatology, 3rd ed. Philadelphia: Mosby; 1988:1078.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1994 Part XV u Infectious Diseases and involves a larger surface area. Regional lymphadenopathy may occur, but systemic symptoms are uncommon. Recurrences are some times associated with local edema and lymphangitis or local neuralgia. Herpes whitlow is a term generally applied to HSV infection of fin gers or toes, although strictly speaking it refers to HSV infection of the paronychia. Among children, this condition is most commonly seen in infants and toddlers who suck the thumb or fingers and who are experiencing either a symptomatic or a subclinical oral HSV 1 infec tion (Fig. 299.2). An HSV 2 herpes whitlow occasionally develops in an adolescent as a result of exposure to infectious genital secretions. The onset of the infection is heralded by itching, pain, and erythema 2 7 days after exposure. The cuticle becomes erythematous and ten der and may appear to contain pus, although if it is incised, little fluid is present. Incising the lesion is discouraged, because this maneuver typically prolongs recovery and increases the risk for secondary bacte rial infection. Lesions and associated pain typically persist for about 10 days, followed by rapid improvement and complete recovery in 18 20 days. Regional lymphadenopathy is common, and lymphangitis and neuralgia may occur. Unlike other recurrent herpes infections, recur rent herpetic whitlows are often as painful as the primary infection but are generally shorter in duration. Cutaneous HSV infections can be severe or life threatening in patients with disorders of the skin such as eczema (eczema herpeti cum), pemphigus, burns, and Darier disease and following laser skin resurfacing. The lesions are frequently ulcerative and nonspecific in appearance, although typical vesicles may be seen in adjacent normal skin (Fig. 299.3). If untreated, these lesions can progress to dissemi nated infection and death. Recurrent infections are common but gen erally less severe than the initial infection. Genital Herpes Genital HSV infection is common in sexually experienced adolescents and young adults, but up to 90 of infected individuals are unaware they are infected. Infection may result from genital genital transmis sion (usually HSV 2) or oral genital transmission (usually HSV 1). Symptomatic and asymptomatic individuals periodically shed virus from anogenital sites and hence can transmit the infection to sexual partners or, in the case of pregnant women, to their newborns. Clas sic primary genital herpes may be preceded by a short period of local burning and tenderness before vesicles |
7,739 | develop on genital mucosal surfaces or keratinized skin and sometimes around the anus or on the buttocks and thighs. Vesicles on mucosal surfaces are short lived and rupture to produce shallow, tender ulcers covered with a yellowish gray exudate and surrounded by an erythematous border. Vesicles on kera tinized epithelium persist for a few days before progressing to the pus tular stage and then crusting. Patients may experience urethritis and dysuria severe enough to cause urinary retention and bilateral, tender inguinal and pelvic lymphadenopathy. Women may experience a watery vaginal discharge, and men may have a clear mucoid urethral discharge. Significant local pain and systemic symptoms such as fever, headache, and myalgia are common. Aseptic meningitis develops in an estimated 15 of cases. The course of classic primary genital herpes from onset to complete healing is 2 3 weeks. Most patients with symptomatic primary genital herpes experience at least one recurrent infection in the following year. Recurrent geni tal herpes is usually less severe and of shorter duration than the pri mary infection. Some patients experience a sensory prodrome with pain, burning, and tingling at the site where vesicles subsequently develop. Asymptomatic recurrent anogenital HSV infections are common, and all HSV 2seropositive individuals appear to periodi cally shed virus from anogenital sites. Most sexual transmissions and maternal neonatal transmissions of virus result from asymptomatic shedding episodes. Genital infections caused by HSV 1 and HSV 2 are indistinguish able, but HSV 1 causes significantly fewer subsequent episodes of recurrent infection; hence, knowing which virus is causing the infec tion has important prognostic value. Genital HSV infection increases the risk for acquiring HIV infection. Rarely, genital HSV infections are identified in young children and preadolescents. Although genital disease in children should raise concerns about possible sexual abuse, there are documented cases of autoinoculation, in which a child has inadvertently trans mitted virus from contaminated oral secretions to his or her own genitalia. Ocular Infections HSV ocular infections may involve the conjunctiva, cornea, or retina and may be primary or recurrent. Conjunctivitis or keratoconjunc tivitis is usually unilateral and is often associated with blepharitis and tender preauricular lymphadenopathy. The conjunctiva appears edematous but there is rarely purulent discharge. Vesicular lesions may be seen on the lid margins and periorbital skin. Patients typically Fig. 299.2 Herpes simplex infection of finger (whitlow). (From Schach ner LA, Hansen RC, eds. Pediatric Dermatology, 3rd ed. Philadelphia: Mosby; 1988:1079.) Fig. 299.3 Widespread cutaneous herpes infection in a child with un derlying eczema (eczema herpeticum). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 299 u Herpes Simplex Virus 1995 have fever. Untreated infection generally resolves in 2 3 weeks. Obvi ous corneal involvement is rare, but when it occurs it can produce ulcers that are described as appearing dendritic or geographic. Exten sion to the stroma is uncommon although more likely to |
7,740 | occur in patients inadvertently treated with corticosteroids. When it occurs, it may be associated with corneal edema, scarring, and corneal per foration. Recurrent infections tend to involve the underlying stroma and can cause progressive corneal scarring and injury that can lead to blindness. Retinal infections are rare and are more likely among infants with neonatal herpes and immunocompromised persons with disseminated HSV infections. Central Nervous System Infections HSV encephalitis is the leading cause of sporadic, nonepidemic encephalitis in children and adults in the United States. It is an acute necrotizing infection generally involving the frontal andor tempo ral cortex and the limbic system and, beyond the neonatal period, is almost always caused by HSV 1. The infection may manifest as nonspecific findings, including fever, headache, nuchal rigidity, nau sea, vomiting, generalized seizures, and alteration of consciousness. Injury to the frontal or temporal cortex or limbic system may pro duce findings more indicative of HSV encephalitis, including anos mia, memory loss, peculiar behavior, expressive aphasia and other changes in speech, hallucinations, and focal seizures. The untreated infection progresses to coma and death in 75 of cases. Examination of the cerebrospinal fluid (CSF) typically shows a moderate number of mononuclear cells and polymorphonuclear leukocytes, a mildly elevated protein concentration, a normal or slightly decreased glu cose concentration, and often a moderate number of erythrocytes. HSV has also been associated with autoimmune (NMDA receptor) encephalitis (see Chapter 638.4). Genetic factors that increase the susceptibility to HSV encephalitis include pathogenic variants in toll like receptor 3 (TLR3) dependent interferon immunity, DBR1, RNA5SP141, TRAF3, and other genes involved in TLR3 sensing or downstream signaling. HSV is also a cause of aseptic meningitis and is the most common cause of recurrent aseptic meningitis (Mollaret meningitis). Infections in Immunocompromised Persons Severe, life threatening HSV infections can occur in patients with compromised immune functions, including neonates, the severely malnourished, those with primary or secondary immunodeficiency diseases (including AIDS), and those receiving some immunosup pressive regimens, particularly for cancer and organ transplantation. Mucocutaneous infections, including mucositis and esophagitis, are most common, although their presentations may be atypical and can result in lesions that slowly enlarge, ulcerate, become necrotic, and extend to deeper tissues. Other HSV infections include tra cheobronchitis, pneumonitis, and anogenital infections. Dissemi nated infection can result in a sepsis like presentation, with liver and adrenal involvement, disseminated intravascular coagulopathy, and shock. Perinatal Infections HSV infection may be acquired in utero, during the birth process, or during the neonatal period. Intrauterine (prenatal) and postpartum (cutaneous lesions in caretakers) infections are well described but occur infrequently. Postpartum transmission may be from the mother or another adult with a nongenital (typically HSV 1) infection such as herpes labialis. Most cases of neonatal herpes result from maternal infection and transmission, usually during passage through an infected birth canal of a mother with asymptomatic genital herpes. Transmis sion is well documented in infants delivered by cesarean section. Fewer than 30 of mothers of an infant with neonatal herpes have a history of |
7,741 | genital herpes. The risk for infection is higher in infants born to moth ers with primary genital infection (30) than with recurrent genital infection (2). Use of scalp electrodes may also increase risk. There also have been rare cases of neonatal herpes associated with Jewish ritual circumcisions, but only with ritual oral contact with the circum cision site. Neonatal HSV infection is thought to never be asymptomatic. Its clinical presentation reflects timing of infection, portal of entry, and extent of spread. Infants with the rare onset of intrauterine infection typically have skin vesicles or scarring; eye findings, including chorio retinitis and keratoconjunctivitis; and microcephaly or hydranenceph aly that are present at delivery. Few infants survive without therapy, and those who do gener ally have severe sequelae. Infants infected during delivery or the postpartum period present with one of the following three pat terns of disease: (1) disease localized to the skin, eyes, or mouth; (2) encephalitis with or without skin, eye, and mouth disease; and (3) disseminated infection involving multiple organs, including the brain, lungs, liver, heart, adrenals, and skin (Fig. 299.4). Most pres ent in the first 28 days of life. Approximately 20 present between 5 and 9 weeks of age. Infants with skin, eye, and mouth disease generally present at 5 11 days of life and typically demonstrate a few clustered small vesicles, particularly on the presenting part or at sites of trauma such as sites of scalp electrode placement. If untreated, skin, eye, and mouth disease in infants may progress to encephalitis or dis seminated disease. Infants with encephalitis typically present at 8 17 days of life with clinical findings suggestive of bacterial meningitis, including irrita bility, lethargy, poor feeding, poor tone, and seizures. Fever or hypo thermia may occur but is not universal; skin vesicles occur in only approximately 60 of cases (Fig. 299.5). If untreated, 50 of infants with HSV encephalitis die and most survivors have severe neurologic sequelae. Infants with disseminated HSV infections generally become ill at 5 11 days of life. Their clinical picture is similar to that of infants with bacterial sepsis, consisting of hyperthermia or hypothermia, irritability, poor feeding, and vomiting. They may also exhibit respi ratory distress, cyanosis, apneic spells, jaundice, purpuric rash, and evidence of central nervous system infection; seizures are common. Skin vesicles are seen in approximately 75 of cases. If untreated, the infection causes shock and disseminated intravascular coagula tion; approximately 90 of these infants die, and most survivors have severe neurologic sequelae. Infants with neonatal herpes whose mothers received antiherpes antiviral drugs in the weeks before delivery may present later than their untreated counterparts; whether the natural history of the infection in these infants is different is an unanswered question. 07d N u m b er o f su b je ct s 0 2 4 6 8 10 12 14 814d 1521d Disseminated CNS SEM 2228d 28d Fig. 299.4 Herpes simplex virus (HSV). Age at presentation by HSV disease type. SEM, skin, eye, mouth. (From |
7,742 | Curfman AL, Glissmeyer EW, Ahmad FA, et al. Initial presentation of neonatal herpes simplex virus infection. J Pediatr. 2016;172:121126, p. 124.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1996 Part XV u Infectious Diseases DIAGNOSIS The clinical diagnosis of HSV infections, particularly life threatening infections and genital herpes, should be confirmed by laboratory test, preferably isolation of virus or detection of viral DNA by polymerase chain reaction (PCR). Histologic findings or imaging studies may sup port the diagnosis but should not substitute for virus specific tests. HSV immunoglobulin M tests are notoriously unreliable, and the dem onstration of a fourfold or greater rise in HSV specific immunoglobu lin G titers between acute and convalescent serum samples is useful only in retrospect. The highest yield for virus cultures comes from rupturing a sus pected herpetic vesicle and vigorously rubbing the base of the lesion to collect fluid and cells. Culturing dried, crusted lesions is gener ally of low yield. Although not as sensitive as viral culture, direct detection of HSV antigens in clinical specimens can be done rap idly and has very good specificity. The use of DNA amplification methods such as PCR for detection of HSV DNA is highly sensi tive and specific and in some instances can be performed rapidly. It is the test of choice in examining CSF in cases of suspected HSV encephalitis. Evaluation of the neonate with suspected HSV infection should include cultures andor PCR of suspicious lesions as well nasophar ynx, mouth, conjunctivae, rectum, umbilicus, and scalp electrode site (if applicable), and PCR of both CSF and blood. In neonates testing for elevation of liver enzymes may provide indirect evidence of HSV dissemination to visceral organs. Efforts to develop clinical scoring systems for invasive HSV in infants have identified younger age, pre maturity, seizure at home, ill appearance, abnormal triage temperature (fever or hypothermia), vesicular rash, thrombocytopenia, and CSF fluid pleocytosis as predictors. Culture or antigen detection should be used in evaluating lesions associated with suspected acute genital herpes. HSV 2 type specific antibody tests are useful for evaluating sexually experienced adoles cents or young adults who have a history of unexplained recurrent nonspecific urogenital signs and symptoms, but these tests are less use ful for general screening in populations in which HSV 2 infections are of low prevalence. Because most HSV diagnostic tests take at least a few days to com plete, treatment should not be withheld but rather initiated promptly so as to ensure the maximum therapeutic benefit. LABORATORY FINDINGS Most self limited HSV infections cause few changes in routine labo ratory parameters. Mucocutaneous infections may cause a moderate polymorphonuclear leukocytosis. In HSV meningoencephalitis there can be an increase in mononuclear cells and protein in CSF, the glu cose content may be normal or reduced, and red blood cells may be present. The electroencephalogram and MRI |
7,743 | of the brain may show temporal lobe abnormalities in HSV encephalitis beyond the neonatal period. Encephalitis in the neonatal period tends to be more global and not limited to the temporal lobe (Fig. 299.6). Disseminated infection may cause elevated liver enzymes, thrombocytopenia, and abnormal coagulation. TREATMENT AND PREVENTION See Chapter 292 for more information about principles of antiviral therapy. Three antiviral drugs are available in the United States for the man agement of HSV infections, namely acyclovir, valacyclovir, and famci clovir. All three are available in oral form, but only acyclovir is available in a suspension form. Acyclovir has the poorest bioavailability and hence requires more frequent dosing. Valacyclovir, a prodrug of acy clovir, and famciclovir, a prodrug of penciclovir, both have very good oral bioavailability and are dosed once or twice daily. Acyclovir and penciclovir are also available in a topical form, but these preparations provide limited or no benefit to patients with recurrent mucocutane ous HSV infections. Only acyclovir has an intravenous formulation. Early initiation of therapy results in the maximal therapeutic benefit. All three drugs have exceptional safety profiles and are safe to use in pediatric patients. Doses should be modified in patients with renal impairment. Resistance to acyclovir and penciclovir is rare in immunocompe tent persons but does occur in immunocompromised persons and is usually mediated by mutations within the thymidine kinase and DNA polymerase genes. Virus isolates from immunocompromised persons whose HSV infection is not responding or is worsening with acyclovir therapy should be tested for drug sensitivities. Foscarnet and cidofovir have been used in the treatment of HSV infections caused by acyclovir resistant mutants. Topical trifluridine and topical ganciclovir are used in the treatment of herpes keratitis. Patients with genital herpes also require counseling to address psychosocial issues, including possible stigma, and to help them understand the natural history and management of this chronic infection. Acute Mucocutaneous Infections For gingivostomatitis, limited evidence suggests that oral acyclovir (15 mgkgdose 5 times a day PO for 7 days; maximum: 1 gday) started within 72 hours of onset reduces the severity and duration of the illness. Pain associated with swallowing may limit oral intake of infants and children, putting them at risk for dehydration. Intake should be encouraged through the use of cold beverages, ice cream, and yogurt. For herpes labialis, oral treatment is superior to topical antiviral therapy. For treatment of a recurrence in adolescents, oral valacyclo vir (2,000 mg bid PO for 1 day), acyclovir ( 400 mg 5 times daily PO for 5 days), or famciclovir (1,500 mg once daily PO for 1 day) short ens the duration of the episode. Long term daily use of oral acyclovir (400 mg bid PO) or valacyclovir (500 mg once daily PO) has been used to prevent recurrences in individuals with frequent or severe recurrences. Anecdotal reports suggest that treatment of adolescents with herpes gladiatorum with valacyclovir (500 mg bid PO for 7 10 days) at the Fig. 299.5 Vesicular pustular lesions on the face of a |
7,744 | neonate with herpes simplex virus infection. (From Kohl S. Neonatal herpes simplex virus infection. Clin Perinatol. 1997;24:129150.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 299 u Herpes Simplex Virus 1997 first signs of the outbreak can shorten the course of the recurrence with accompanying guidance on the importance of good hydration. For patients with a history of recurrent herpes gladiatorum, chronic daily prophylaxis with valacyclovir (500 1,000 mgday) has been reported to prevent recurrences. There are no clinical trials assessing the benefit of antiviral treatment for herpetic whitlow. High dose oral acyclovir (1,600 2,000 mgday divided in two or three doses PO for 10 days) started at the first signs of illness has been reported to abort some recurrences and reduce the duration of others in adults. Children with mild cases of eczema herpeticum can be treated with oral acyclovir (1020 mgkg three times daily) or valacyclovir (20 mgkg per day in three divided doses) for 721 days. However, seri ous infections should be treated with intravenous acyclovir. Oral facial HSV infections can reactivate after cosmetic facial laser resurfacing, causing extensive disease and scarring. Treatment of adults beginning the day before the procedure with either valacyclovir (500 mg twice daily PO for 10 14 days) or famciclovir (250 500 mg bid PO for 10 days) has been reported to be effective in preventing the infections. HSV infections in burn patients can be severe or life threatening and have been treated with intravenous acyclovir (10 20 mgkgday divided every 8 hours). Antiviral drugs are not effective in the treatment of HSV associated erythema multiforme, but their daily use as for herpes labialis prophy laxis prevents reoccurrences of erythema multiforme. Genital Herpes Pediatric patients, usually adolescents or young adults, with suspected first episode genital herpes should be treated with antiviral therapy. Treatment of the initial infection reduces the severity and duration of the illness but has no effect on the frequency of subsequent recurrent infections. Treatment options for adolescents include acyclovir (400 mg tid PO for 7 10 days), famciclovir (250 mg tid PO for 7 10 days), or valacyclovir (1,000 mg bid PO for 7 10 days). The twice daily valacyclo vir option avoids treatment during school hours. For smaller children, acyclovir suspension can be used at a dose of 10 20 mgkgdose 4 times daily, not to exceed the adult dose. The first episode of genital herpes can be extremely painful, and use of analgesics is generally indicated. Intravenous acyclovir is indicated for those with severe or complicated primary infections that may require hospitalization. All patients with genital herpes should be offered counseling to help them deal with psy chosocial issues and understand the chronic nature of the illness. There are three strategic options regarding the management of recurrent infections. The choice should be guided by several factors, including the frequency and |
7,745 | severity of the recurrent infections, the psychologic impact of the illness on the patient, and concerns regarding transmission to a susceptible sexual partner. Option 1 is no therapy; option 2 is episodic therapy; and option 3 is long term suppressive therapy. For episodic therapy, treatment should be ini tiated at the first signs of an outbreak. Recommended choices for episodic therapy in adolescents include famciclovir (1,000 mg bid PO for 1 day), acyclovir (800 mg tid PO for 2 days), or valacyclovir (500 mg bid PO for 3 days.) Long term suppressive therapy offers the advantage that it prevents most outbreaks, improves patient quality of life in terms of the psychosocial impact of genital her pes, and, with daily valacyclovir therapy, also reduces (but does not eliminate) the risk for sexual transmission to a susceptible sexual partner. Options for long term suppressive therapy are acyclovir (400 mg bid PO), famciclovir (250 mg bid PO), and valacyclovir (500 or 1,000 mg qd PO). Ocular Infections HSV ocular infections can result in blindness. Management should involve consultation with an ophthalmologist. Fig. 299.6 Involvement of corti cospinal tract and thalamus in a 2 wk old infant. A, Axial T1 weighted MRI demonstrating subtle loss of T1 hyperintensity corresponding to myelination in the posterior limb of the right internal capsule (white arrow). T1 hyperintensity in the left posterior limb of the internal cap sule is maintained (black arrow). B, T2 weighted image showing find ings similar to those seen on T1 weighted imaging. C, Axial T1 and (D) T2 weighted images through the vertex demonstrating subtle indis tinct margins of the cortex around the right central sulcus (white arrow) compared to the normal appear ance on the left side (black arrow). E and F, Diffusion weighted im ages with more extensive diffusion restriction in the posterior limb of the right internal capsule and lateral thalamus (arrows), and in the right precentral and postcentral gyrus (arrows). (From Bajaj M, Mody S, Natarajan G. Clinical and neuroim aging findings in neonatal herpes simplex virus infection. J Pediatr. 2014;165:404407. Fig. 1.) A B C D E F Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1998 Part XV u Infectious Diseases Central Nervous System Infections Patients older than neonates who have herpes encephalitis should be promptly treated with intravenous acyclovir (10 mgkg every 8 hours given as a 1 hour infusion for 21 days). Treatment for increased intra cranial pressure, management of seizures, and respiratory compromise may be required. Infections in Immunocompromised Persons Severe mucocutaneous and disseminated HSV infections in immuno compromised patients should be treated with intravenous acyclovir (30 mgkg per day, in three divided doses for 7 14 days) until there is evidence of resolution of the infection. Oral antiviral therapy with acyclovir, famciclovir, or valacyclovir has been used for treatment of less severe HSV infections and for suppression |
7,746 | of recurrences during periods of significant immunosuppression. Drug resistance does occur occasionally in immunocompromised patients, and in individuals whose HSV infection does not respond to antiviral drug therapy, viral isolates should be tested to determine sensitivity. Acyclovir resistant viruses are often also resistant to famciclovir but may be sensitive to foscarnet or cidofovir. Perinatal Infections All infants with proven or suspected neonatal HSV infection should be treated immediately with high dose intravenous acyclovir (60 mgkgday divided every 8 hours). Treatment may be discontinued in infants shown by laboratory testing not to be infected. Infants with HSV disease limited to skin, eyes, and mouth should be treated for 14 days, whereas those with disseminated or central nervous system disease should receive a minimum of 21 days of therapy. Patients receiving high dose therapy should be monitored for neutropenia. Suppressive oral acyclovir therapy for 6 months after completion of the intravenous therapy has been shown to improve the neurodevelop ment of infants with central nervous system infection and to prevent cutaneous recurrences in infants regardless of disease pattern. Infants surviving neonatal HSV disease of any classification should receive 300 mgm2 per dose 3 times daily for 6 months. The absolute neutrophil count should be measured at weeks 2 and 4 after initiation of treatment and then monthly. PROGNOSIS Most HSV infections are self limiting, last from a few days (for recurrent infections) to 2 3 weeks (for primary infections) and heal without scarring. Recurrent oral facial herpes in a patient who has undergone dermabrasion or laser resurfacing can be severe and lead to scarring. Because genital herpes is a sexually transmitted infec tion, it can be stigmatizing, and its psychologic consequences may be much greater than its physiologic effects. Some HSV infections can be severe and may have grave consequences without prompt antiviral therapy. Life threatening conditions include neonatal her pes, herpes encephalitis, and HSV infections in immunocompro mised patients, burn patients, and severely malnourished infants and children. Recurrent ocular herpes can lead to corneal scarring and blindness. PREVENTION Transmission of infection occurs through exposure to virus either as the result of skin to skin contact or from contact with contami nated secretions. Good handwashing and, when appropriate, the use of gloves provide healthcare workers with excellent protection against HSV infection in the workplace. Healthcare workers with active oral facial herpes or herpetic whitlow should take precautions, particularly when caring for high risk patients such as newborns, immunocompromised individuals, and patients with chronic skin conditions. Patients and parents should be advised about good hygienic practices, including handwashing and avoiding contact with lesions and secretions, during active herpes outbreaks. Schools and daycare centers should clean shared toys and athletic equipment such as wrestling mats at least daily after use. Athletes with active herpes infections who participate in contact sports such as wrestling and rugby should be excluded from practice or games until the lesions are completely healed. Genital herpes can be prevented by avoiding genital genital and oral genital contact. The risk for |
7,747 | acquiring genital herpes can be reduced but not eliminated through the correct and consistent use of condoms. Male circumcision is associated with a reduced risk of acquiring genital HSV infection. The risk for trans mitting genital HSV 2 infection to a susceptible sexual partner can be reduced but not eliminated by the daily use of oral valacyclovir by the infected partner. For pregnant women with active genital herpes at the time of delivery, the risk for mother to child transmission can be reduced but not eliminated by delivering the baby via a cesarean section. The risk for recurrent genital herpes, and therefore the need for cesarean delivery, can be reduced but not eliminated in pregnant women with a history of genital herpes by the daily use of oral acyclovir, valacyclo vir, or famciclovir during the last 4 weeks of gestation, which is rec ommended by the American College of Obstetrics and Gynecology. There are documented cases of neonatal herpes occurring in infants delivered by cesarean section, as well as in infants born to mothers who have been appropriately treated with antiherpes antiviral drugs for the last month of gestation. Therefore a history of cesarean deliv ery or antiviral treatment at term does not rule out consideration of neonatal herpes. Asymptomatic infants delivered vaginally to women with first episode genital herpes are at very high risk for acquiring HSV infec tion. The nasopharynx, mouth, conjunctivae, rectum, umbilicus, and scalp electrode site (if applicable) should be cultured (with PCR sur face testing if available) at approximately 24 hours after birth for all infants born to mothers with primary genital herpes. Some also rec ommend HSV PCR on blood and CSF. Some authorities recommend that these infants receive anticipatory acyclovir therapy for at least 10 days, and others treat such infants if signs develop or if there is evidence of HSV infection. Infants delivered to women with a history of recurrent genital herpes are at low risk for development of neona tal herpes. In this setting, while surface cultures and PCRs are done, empirical acyclovir is not started. Parents should be educated about the signs and symptoms of neonatal HSV infection and should be instructed to seek care without delay at the first suggestion of infec tion. When the situation is in doubt, infants should be evaluated and tested with surface culture (and PCR) for neonatal herpes as well as with PCR on blood and CSF; intravenous acyclovir is begun until culture and PCR results are negative or until another explanation can be found for the signs and symptoms. Recurrent genital HSV infections can be prevented by the daily use of oral acyclovir, valacyclovir, or famciclovir, and these drugs have been used to prevent recurrences of oral facial (labialis) and cutaneous (gladiatorum) herpes. Oral and intravenous acyclovir also have been used to prevent recurrent HSV infections in immunocompromised patients. Use of sun blockers is reported to be effective in preventing recurrent oral facial herpes in patients with a history of sun induced recurrent |
7,748 | disease. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 300 u VaricellaZoster Virus 1999 Varicella zoster virus (VZV) causes primary, latent, and reactivation infections. The primary infection manifests as varicella (chickenpox) and results in establishment of a lifelong latent infection of sensory ganglionic neurons. Reactivation of the latent infection causes herpes zoster (shingles). Although often a mild illness of childhood, varicella can cause substantial morbidity and mortality in otherwise healthy children. Morbidity and mortality are higher in immunocompetent infants, adolescents, and adults, as well as in immunocompromised persons. Varicella predisposes to severe group A streptococcus and staphylococcus infections. Primary clinical disease can be prevented by immunization with live attenuated varicella vaccine. A clinically modified disease can occur among vaccinated persons (breakthrough varicella), usually with milder presentation. Varicella and herpes zoster can be treated with antiviral drugs. Vaccines are also available to pre vent herpes zoster in older adults. ETIOLOGY VZV is a neurotropic human herpesvirus with similarities to herpes simplex virus. VZV enveloped viruses contain double stranded DNA genomes that encode 71 proteins, including proteins that are targets of cellular and humoral immunity. EPIDEMIOLOGY Before the introduction of the varicella vaccine in 1995, varicella was an almost universal communicable infection of childhood in the United States. Annual varicella epidemics occurred in winter and spring, and there were about 4 million cases of varicella, 11,000 13,500 hospitalizations, and 100 150 deaths every year in the United States. Most children were infected by 10 years of age, with fewer than 5 of adults remaining susceptible. This pattern of infection at younger ages remains characteristic in all countries in temperate climates. By contrast, in tropical areas, children acquire varicella at older ages and a higher proportion of young adults remain susceptible, leading to a higher proportion of cases occurring among adults. Varicella is a more serious disease in young infants, adults, and immunocompromised per sons, in whom there are higher rates of complications and deaths than in healthy children. Primary varicella is highly transmissible. Within households, transmission of VZV to susceptible individuals occurs at a rate of 6586; more casual contact, such as occurs in a school class room, is associated with lower attack rates among susceptible children. Persons with varicella may be contagious 24 48 hours before the rash is evident and until vesicles are crusted, usually 4 7 days after onset of rash, consistent with evidence that VZV is spread by aerosolization of virus in cutaneous lesions; spread from oropharyngeal secretions may occur but to a much lesser extent. Susceptible persons may also acquire varicella after close, direct contact with adults or children who have herpes zoster, again via aerosolization of virus in skin lesions. Since implementation of the varicella vaccination program in 1995, there have been substantial declines in varicella morbidity and mortality in the United |
7,749 | States. By 2006, before implementation of the two dose program, one dose vaccination coverage had reached 90 and varicella incidence had declined 90 since 1995 in sites where active surveillance was being conducted; varicella related hospitalizations had declined 84 from prevaccine years. Varicella related deaths decreased by 88 from 19901994 to 20052007; in persons younger than 20 years of age there was a 97 decline in deaths. Declines in morbidity and mortality were seen in all age groups, including infants younger than 12 months of age who were not eligible for vaccination, indicating protection from exposure by indirect vaccination effects. The continued occurrence of breakthrough infections and of outbreaks in settings with high one dose varicella vaccine coverage, together with the evidence that one dose is only 82 effective against all varicella, prompted adoption in 2007 of a routine two dose childhood varicella vaccination program with catch up vaccination of all individuals without evidence of immunity. Further declines in morbidity and mortality occurred during the twodose pro gram so that by 2019, declines reached more than 97 for incidence and 90 for hospitalizations and deaths. The greatest decline occurred in persons younger than 20 years of age, born during the varicella vac cination program, with 99, 97, and 99 reduction in incidence, hospitalizations, and deaths, respectively. Additionally, the twodose program led to a reduction in the number, size, and duration of varicella outbreaks. Although the agespecific incidence has declined in all age groups, the median age at infection has increased, with cases occurring predominantly in children in ages 710 years rather than in the preschool years. This change in varicella epidemiology highlights the importance of offering vaccine to every susceptible child, adolescent, and adult. Herpes zoster is caused by the reactivation of latent VZV. It is not common in childhood and shows no seasonal variation in incidence. Zoster is not caused by exposure to a patient with varicella; in fact, expo sures to varicella boost the cell mediated immune response to VZV in individuals with prior infection, decreasing the likelihood of reactivation of latent virus. The lifetime risk for herpes zoster for individuals with a history of varicella is at least 30, with 75 of cases occurring after 45 years of age. Herpes zoster is unusual in healthy children younger than 10 years of age, with the exception of those infected with VZV in utero or in the first year of life, who have an increased risk for develop ment of zoster in the first few years of life. Herpes zoster in otherwise healthy children tends to be milder than herpes zoster in adults, is less frequently associated with acute pain, and is generally not associated with postherpetic neuralgia. In children receiving immunosuppressive therapy for malignancy or other diseases and in those who have HIV infection, herpes zoster occurs more frequently, occasionally multiple times, and may be severe. The attenuated VZV in the varicella vaccine can establish latent infection and reactivate as herpes zoster. However, the risk for development of |
7,750 | subsequent herpes zoster is much lower after vaccination than after natural VZV infection among both healthy and immunocompromised children. Although the Oka vaccine type VZV is attenuated, in children the severity of zoster caused by the Oka strain seems to be similar to or slightly milder than that caused by the natural or wild type VZV. Vaccinated children who do develop zoster may have disease resulting from either vaccine or wild type VZV, due to break through varicella or subclinical infection of some vaccinees with wild type VZV occurring at some point after immunization. PATHOGENESIS Primary infection (varicella) results from inoculation of the virus onto the mucosa of the upper respiratory tract and tonsillar lymphoid tissue. During the early part of the 10 to 21 day incubation period, virus repli cates in the local lymphoid tissue and spreads to T lymphocytes, causing a viremia that delivers the virus to skin where innate immunity controls VZV replication for several days. After innate immunity is overcome in skin, widespread cutaneous lesions develop as the incubation period ends. Adaptive host immune responses, especially cellular immunity, limit viral replication and lead to recovery from infection. In the immu nocompromised child, the failure of adaptive immunity, especially cel lular immune responses, results in continued viral replication that may lead to prolonged andor disseminated infection with resultant compli cations of infection in the lungs, liver, brain, and other organs. Latent infection develops during the incubation period or the dis ease itself. VZV is transported in a retrograde manner through sensory axons to the dorsal root ganglia in the spinal cord and to cranial nerve ganglia. Latency may also develop from viremia, infecting spinal and cranial nerve ganglia as well as autonomic ganglia that do not project to Chapter 300 Varicella Zoster Virus Shivang S. Shah, Mona Marin, Philip S. LaRussa, and Anne A. Gershon The findings and conclusions in this report are those of the authors and do not necessar ily represent the official position of the Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2000 Part XV u Infectious Diseases the skin, including the enteric nervous system of the intestine. Latency of VZV occurs only in ganglionic neurons. Subsequent reactivation of latent VZV causes herpes zoster, usually manifested by a vesicular rash that is unilateral and dermatomal in distribution. Reactivation of VZV may also occur without a rash; examples are unilateral dermato mal pain without rash (zoster sine herpete), aseptic meningitis, and gastrointestinal illness (enteric zoster). During herpes zoster, necrotic changes may be produced in the neurons and surrounding satellite cells in associated ganglia. The skin lesions of varicella and herpes zoster have identical histopathology, and infectious VZV is present in both. Varicella elicits humoral and cell mediated immunity that is highly protective against symptomatic reinfection. |
7,751 | Suppression of cell mediated immunity to VZV correlates with an increased risk for VZV reactivation as herpes zoster. CLINICAL MANIFESTATIONS Varicella is an acute febrile rash illness that was common in children in the United States before the universal childhood vaccination pro gram. It has variable severity but is usually self limited. It may be associated with severe complications, including bacterial superinfec tion, especially with staphylococci and group A streptococci, pneu monia, encephalitis, bleeding disorders, congenital infection, and life threatening perinatal infection. Herpes zoster is not common in children and typically causes localized cutaneous symptoms, but may disseminate in immunocompromised patients. Varicella in Unvaccinated Individuals The illness usually begins 14 16 days after exposure, although the incubation period can range from 10 21 days. Subclinical varicella is rare; almost all exposed, susceptible persons experience a rash, albeit so mild in some cases that it may go unnoticed. Prodromal symptoms may be present, particularly in older children and adults. Fever, mal aise, anorexia, headache, and occasionally mild abdominal pain may occur 24 48 hours before the rash appears. Temperature elevation is usually 37.838.9C (100102F) but may be as high as 41.1C (106F); fever and other systemic symptoms usually resolve within 2 4 days after the onset of the rash. Varicella lesions often appear first on the scalp, face, or trunk. The initial exanthem consists of intensely pruritic erythematous macules that evolve through the papular stage to form clear, fluid filled vesicles. Clouding and umbilication of the lesions begin in 24 48 hours. While the initial lesions are crusting, new crops form on the trunk and then the extremities; the simultaneous presence of lesions in various stages of evolution is characteristic of varicella (Fig. 300.1). The distribution of the rash is predominantly central or centripetal, with the greatest concentration on the trunk and proximally on the extremities. Ulcer ative lesions involving the mucosa of the oropharynx and vagina are also common; many children have vesicular lesions on the eyelids and conjunctivae, but corneal involvement and serious ocular disease are rare. The average number of varicella lesions is about 300, but healthy children may have fewer than 10 to more than 1,500 lesions. In cases resulting from secondary household spread and in older children, more lesions usually occur, and new crops of lesions may continue to develop for more than 7 days. The exanthem may be much more exten sive in children with skin disorders, such as eczema or recent sunburn. Hypopigmentation or hyperpigmentation of lesion sites persists for days to weeks in some children, but severe scarring is unusual unless the lesions were secondarily infected. The differential diagnosis of varicella includes vesicular rashes caused by other infectious agents, such as herpes simplex virus, entero virus, monkey pox (mpox), rickettsial pox, and Staphylococcus aureus; drug reactions; disseminated herpes zoster; contact dermatitis; and insect bites (especially for breakthrough varicella). Severe varicella was the most common illness confused with smallpox before the eradica tion of smallpox. Varicelliform Rashes in Vaccinated Individuals Varicelliform rashes that occur |
7,752 | after vaccination could be a result of wild type VZV, vaccine strain VZV, or other causes (e.g., insect bites, coxsackievirus). During days 0 42 after vaccination, the likelihood of rash from wild type or vaccine strain VZV varies depending on the stage of a countrys vaccination program. In the early stages of a vac cination program, rash within 1 2 weeks is still most commonly caused by wild type VZV, reflecting exposure to varicella before vaccination could provide protection. Rash occurring 14 42 days after vaccination is a result of either wild type or vaccine strains, reflecting exposure and infection before protection from vaccination or an adverse event of vaccination (vaccine associated rash), respectively. As wild type vari cella continues to decline as a consequence of the vaccination program, wild type VZV circulation will also decline and rashes in the inter val 0 42 days after vaccination will be less commonly caused by wild type VZV, as is the case in the United States. Spread of vaccine type VZV from a vaccinee with skin lesions has occurred but is rare. The resulting illness in contacts is commonly mild with only a few vesicu lar lesions. Clinical reversion of the vaccine virus to virulence has not been described. Breakthrough varicella is disease caused by wild type virus in a vaccinated person, occurring after 42 days past vaccination. One dose of varicella vaccine is 98 effective in preventing moderate and severe varicella and is 82 effective in preventing all disease after exposure to wild type VZV. This means that after close exposure to VZV, as may occur in a household or an outbreak setting in a school or daycare cen ter, about 1 of every 5 children who received one dose of vaccine may experience breakthrough varicella. Exposure to VZV may also result in asymptomatic infection in the previously immunized child. The rash in breakthrough disease is frequently atypical and predominantly maculopapular, and vesicles are seen less commonly. The illness is most commonly mild with fewer than 50 lesions, shorter duration of rash, fewer complications, and little or no fever. However, approximately 2530 of breakthrough cases in vaccinees who received one dose are not mild, with clinical features more similar to those of wild type infection. Breakthrough cases are overall less contagious than wild type infections within household settings, but contagiousness varies proportionally with the number of lesions; typical breakthrough cases (50 lesions) are about one third as contagious as disease in unvac cinated cases, whereas breakthrough cases with 50 lesions are as con tagious as wild type cases. Consequently, children with breakthrough disease should be considered potentially infectious and excluded from school until lesions have crusted or, if there are no vesicles present, until no new lesions are occurring. Transmission has been documented to occur from breakthrough cases in household, childcare, and school settings. Two doses of varicella vaccine provide better protection than a one dose schedule. One clinical trial estimated the two dose vac cine efficacy for preventing all disease |
7,753 | at 98; the estimate is 92 in conditions of everyday clinical practice. Institution of two doses rou tinely in the United States substantially reduced the school outbreaks that were occurring among children who had received only one dose. A B Fig. 300.1 A, Varicella lesions in unvaccinated persons display the characteristic cropping distribution, or manifest themselves in clus ters; the simultaneous presence of lesions in various stages of evolution is characteristic. B, Breakthrough varicella lesions are predominantly maculopapular, and vesicles are less common; the illness is most com monly mild with 50 lesions. (Courtesy Centers for Disease Control and Prevention and Dr. John Noble, Jr.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 300 u Varicella Zoster Virus 2001 Breakthrough cases have been reported among two dose vaccinees; however, recipients of two doses of varicella vaccine are less likely to have breakthrough disease than those who received one dose. Addi tionally, data suggest that breakthrough varicella may be further atten uated among two dose vaccine recipients. Neonatal Varicella Mortality is particularly high in neonates born to susceptible moth ers who contract varicella around the time of delivery. Infants whose mothers demonstrate varicella in the period from 5 days before deliv ery to 2 days afterward are at high risk for severe varicella. These infants acquire the infection transplacentally as a result of maternal viremia, which may occur up to 48 hours before onset of maternal rash. The infants rash usually occurs toward the end of the first week to the early part of the second week of life (although it may be as soon as 2 days). Because the mother has not yet developed a significant antibody response, the infant receives a large dose of virus without the moderating effect of maternal anti VZV antibody. If the mother demonstrates varicella more than 5 days before delivery, she still may pass virus to the soon to be born child, but infection is attenuated because of transmission of maternal VZV specific antibody across the placenta. This moderating effect of maternal antibody is present if delivery occurs after about 30 weeks of gestation, when maternal immunoglobulin (Ig) G (IgG) is able to cross the placenta in signifi cant amounts. The recommendations for use of human varicella zoster immunoglobulin (VZIG) differ based on when the infant is exposed to varicella. Newborns whose mothers develop varicella during the period of 5 days before to 2 days after delivery should receive VZIG as soon as possible after birth. Although neonatal varicella may occur in about half of these infants despite administration of VZIG, it is milder than in the absence of VZIG administration. All premature infants born 28 weeks of gestation to a mother with active varicella at delivery (even if the maternal rash has been present for 1 week) should receive VZIG. If VZIG is not available, intravenous |
7,754 | immu noglobulin (IVIG) may provide some protection, although varicella specific antibody titers may vary from lot to lot. Because perinatally acquired varicella may be life threatening, the infant should usually be treated with acyclovir (1015 mgkg every 8 hours IV) when lesions develop. Neonatal varicella can also follow a postpartum exposure of an infant delivered to a mother who was susceptible to VZV, although the frequency of complications declines rapidly in the weeks after birth. Recommendations for VZIG administration for these infants are presented in the postexposure prophylaxis section. Neonates with community acquired varicella who experience severe varicella, espe cially those who have a complication such as pneumonia, hepatitis, or encephalitis, should also receive treatment with intravenous acy clovir (10 mgkg every 8 hours). Infants with neonatal varicella who receive prompt antiviral therapy have an excellent prognosis. Congenital Varicella Syndrome In utero transmission of VZV can occur; however, because most adults in temperate climates are immune, pregnancy complicated by varicella is unusual in these settings. When pregnant women do contract vari cella early in pregnancy, experts estimate that as many as 25 of the fetuses may become infected. Fortunately, clinically apparent disease in the infant is uncommon: the congenital varicella syndrome occurs in approximately 0.4 of infants born to women who have varicella during pregnancy before 13 weeks of gestation and in approximately 2 of infants born to women with varicella between 13 and 20 weeks of gestation. Rarely, cases of congenital varicella syndrome have been reported in infants of women infected after 20 weeks of pregnancy, the latest occurring at 28 weeks of gestation. Before availability of varicella vaccine in the United States, 44 cases of congenital varicella syndrome were estimated to occur each year. The congenital varicella syndrome is characterized by cicatricial skin scarring in a zoster like distribu tion; limb hypoplasia; and abnormalities of the neurologic system (e.g., microcephaly, cortical atrophy, seizures, and intellectual disability), eye (e.g., chorioretinitis, microphthalmia, and cataracts), renal system (e.g., hydroureter and hydronephrosis), and autonomic nervous system (e.g., neurogenic bladder, swallowing dysfunction, and aspiration pneumonia). Low birthweight is common among infants with con genital varicella syndrome. Most of the manifestations can be attrib uted to virus induced injury to the nervous system, although there is no obvious explanation why certain regions of the body are preferen tially infected during fetal VZV infection. The characteristic cutaneous lesion has been called a cicatrix, a zigzag scarring, in a dermatomal distribution, often associated with atrophy of the affected limb (Fig. 300.2). Many infants with severe manifestations of congenital varicella syndrome (atrophy and scarring of a limb) have significant neurologic deficiencies. Alternatively, there may be neither skin nor limb abnor malities, but the infant may show cataracts or even extensive aplasia of the entire brain. There are rare case reports of fetal abnormalities after the develop ment of herpes zoster in the mother; whether these cases truly repre sent the congenital varicella syndrome is unclear. If it does occur, the congenital syndrome acquired as a result of |
7,755 | maternal herpes zoster is exceedingly rare. Maternal herpes zoster was associated with typical congenital varicella syndrome in one case, but the mother had dissemi nated herpes zoster (at 12 weeks of gestation). The diagnosis of VZV fetopathy is based mainly on the history of gestational varicella combined with the presence of characteristic abnormalities in the newborn infant. Virus cannot be cultured from the affected newborn, but viral DNA may be detected in tissue samples by polymerase chain reaction (PCR). Because many infants with con genital varicella syndrome develop zoster before a year of age, it may be possible to isolate VZV from that rash. Alternatively, use of PCR to identify VZV DNA in vesicular fluid or scabs from zoster lesions in such an infant may be diagnostic. VZV specific IgM antibody is detect able in the cord blood sample in some infants, although the IgM titer drops quickly in the postpartum period and can be nonspecifically pos itive. Chorionic villus sampling and fetal blood collection for the detec tion of viral DNA, virus, or antibody have been used in an attempt to diagnose fetal infection and embryopathy. The usefulness of these tests for patient management and counseling has not been defined. Because these tests may not distinguish between infection and disease, their utility may primarily be that of reassurance when the result is negative. Ultrasound may be useful to try to identify limb atrophy, which is com mon in congenital varicella syndrome. A persistently positive VZV IgG antibody titer at 12 18 months of age is a reliable indicator of prenatal Fig. 300.2 Newborn with congenital varicella syndrome. The infant had severe malformations of both lower extremities and cicatricial scar ring over his left abdomen. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2002 Part XV u Infectious Diseases infection in the asymptomatic child, as is the development of zoster in the first year of life without evidence of postnatal infection. VZIG has often been administered to the susceptible mother exposed to varicella to modify maternal disease severity; it is uncer tain whether this step modifies infection in the fetus, although some evidence suggests that it may be beneficial for the fetus too. Similarly, acyclovir treatment may be given to the mother with severe varicella. A prospective registry of acyclovir use in the first trimester demon strated that the occurrence of birth defects approximates that found in the general population. Acyclovir is a class B drug for pregnancy and should be considered when the benefit to the mother outweighs the potential risk to the fetus. The efficacy of acyclovir treatment of the pregnant woman in preventing or modifying the severity of congenital varicella is not known, but its use should be considered to protect the mother from severe disease. Because the damage caused by fetal VZV infection does not progress in the postpartum period, |
7,756 | antiviral treat ment of infants with congenital VZV syndrome is not indicated. COMPLICATIONS The complications of VZV infection (varicella or zoster) occur more com monly in immunocompromised patients. In the otherwise healthy child, asymptomatic transient varicella hepatitis is relatively common. Mild thrombocytopenia occurs in 12 of children with varicella and may be associated with petechiae. Purpura, hemorrhagic vesicles, hematu ria, and gastrointestinal bleeding are rare complications that may have serious consequences. Other complications of varicella, some of them rare, include acute cerebellar ataxia, encephalitis, pneumonia, nephri tis, nephrotic syndrome, hemolytic uremic syndrome, arthritis, myo carditis, pericarditis, pancreatitis, orchitis, and acute retinal necrosis. A reduction in the number and rates of varicella related complications is seen in vaccinated populations. Reports of serious varicella related complications in vaccinated persons (breakthrough) are rare (menin gitis, pneumonia, acute transverse myelitis, encephalitis one fatal case in an apparently immunocompetent child, and sepsis). Severe break through varicella can occur among healthy persons, but cases appear to be more common among immunocompromised persons who are usually not recommended to receive varicella vaccine. Declines in varicella related hospitalizations and deaths in the United States since implementation of the varicella vaccination pro gram provide supporting evidence that varicella vaccine reduces severe complications from varicella. Approximately 105 deaths (with varicella listed as the underlying cause of death) occurred in the United States annually before the introduction of the varicella vaccine; during 2017 2019 the annual average number of varicella deaths was 18. In both the pre and postvaccine eras, the majority of deaths (80) have been among persons without high risk preexisting conditions. Bacterial Infections Secondary bacterial infections of the skin, usually caused by group A streptococcus or S. aureus, may occur in children with varicella. These range from impetigo to cellulitis, lymphadenitis, and subcutaneous abscesses. An early manifestation of secondary bacterial infection is erythema of the base of a new vesicle. Recrudescence of fever 3 4 days after the initial exanthem may also herald a secondary bacterial infec tion. Varicella is a well described risk factor for serious invasive infec tions caused by group A streptococcus, which can have a fatal outcome. The more invasive infections, such as varicella gangrenosa, bacterial sepsis, pneumonia, arthritis, osteomyelitis, cellulitis, and necrotizing fasciitis, account for much of the morbidity and mortality of varicella in otherwise healthy children. Bacterial toxinmediated diseases (e.g., toxic shock syndrome) also may complicate varicella. A substantial decline in varicella related invasive bacterial infections is associated with the use of the varicella vaccine. Encephalitis and Cerebellar Ataxia Encephalitis (1 per 50,000 cases of varicella in unvaccinated chil dren) and acute cerebellar ataxia (1 per 4,000 cases of varicella in unvaccinated children) are well described neurologic complications of varicella; morbidity from central nervous system complications is highest among patients younger than 5 years and older than 20 years. Nuchal rigidity, altered consciousness, and seizures character ize meningoencephalitis. Patients with cerebellar ataxia have a gradual onset of gait disturbance, nystagmus, and slurred speech. Neurologic symptoms usually begin 2 6 days after the |
7,757 | onset of the rash but may occur during the incubation period or after resolution of the rash. Clinical recovery is typically rapid, occurring within 24 72 hours, and is usually complete. Although severe hemorrhagic encephalitis, analo gous to that caused by herpes simplex virus, is very rare in children with varicella, the consequences are similar to those of herpes simplex virus encephalitis. Reye syndrome (hepatic dysfunction with hypogly cemia and encephalopathy) associated with varicella and other viral illnesses such as influenza is rare now that salicylates are no longer used as antipyretics in these situations (see Chapter 405). Pneumonia Varicella pneumonia (viral, due to VZV) is a severe complication that accounts for most of the increased morbidity and mortality from varicella in adults and other high risk populations, but viral pneumonia may also complicate varicella in young children. Respiratory symptoms, which may include cough, dyspnea, cyanosis, pleuritic chest pain, and hemoptysis, usually begin within 1 6 days after the onset of the rash. Smoking has been described as a risk factor for severe pneumonia complicating varicella. The frequency of varicella pneumonia may be greater in the parturient. Progressive Varicella Progressive varicella, with visceral organ involvement, coagulopathy, severe hemorrhage, and continued vesicular lesion development after 7 days, is a severe complication of primary VZV infection. Severe abdominal pain, which may reflect involvement of mesenteric lymph nodes or the liver, or the appearance of hemorrhagic vesicles in other wise healthy adolescents and adults, immunocompromised children, pregnant women, and newborns, may herald severe, and potentially fatal, disease. Although rare in healthy children, the risk for progres sive varicella is highest in children with congenital cellular immune deficiency disorders and those with malignancy, particularly if chemo therapy, and especially corticosteroids, had been given during the incu bation period and the absolute lymphocyte count is 500 cellsL. The mortality rate for children who acquired varicella while undergoing treatment for malignancy and who were not treated with antiviral ther apy approached 7; varicella related deaths usually occurred within 3 days after the diagnosis of varicella pneumonia. Children who acquire varicella after organ transplantation are also at risk for progressive VZV infection. Children undergoing long term, low dose systemic or inhaled corticosteroid therapy are not considered to be at higher risk for severe varicella, but progressive varicella does occur in patients receiving high dose corticosteroids. There are case reports in patients receiving inhaled corticosteroids as well as in asthmatic patients receiv ing multiple short courses of systemic corticosteroid therapy. Unusual clinical findings of varicella, including lesions that develop a hyper keratotic appearance and continued new lesion formation for weeks or months, have been described in children with untreated, late stage HIV infection. Immunization of HIV infected children who have a CD4 T lymphocyte percent 15, as well as children with leukemia and solid organ tumors who are in remission and whose chemotherapy can be interrupted for 2 weeks around the time of immunization or has been terminated, have reduced frequency of severe disease. Moreover, since the advent |
7,758 | of the universal immunization program in the United States, many children who would become immunocompromised later in life because of disease or treatment are protected before the immu nosuppression occurs; also, as a result of reductions in varicella inci dence, immunocompromised children are less likely to be exposed to varicella. Herpes Zoster Herpes zoster manifests as vesicular lesions clustered within one or, less commonly, two adjacent dermatomes (Fig. 300.3). In the elderly, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 300 u Varicella Zoster Virus 2003 herpes zoster typically begins with burning pain or itching followed by clusters of skin lesions in a dermatomal pattern. Almost half of the elderly with herpes zoster experience complications; the most fre quent complication is postherpetic neuralgia, a painful condition that affects the nerves despite resolution of the skin lesions. Approximately 4 of patients suffer a second episode of herpes zoster; three or more episodes are rare. Unlike herpes zoster in adults, zoster in children is infrequently associated with localized pain, hyperesthesia, pruritus, low grade fever, or complications. In children, the rash is mild, with new lesions appearing for a few days (Fig. 300.4); symptoms of acute neuritis are minimal; and complete resolution usually occurs within 1 2 weeks. Unlike in adults, postherpetic neuralgia is unusual in chil dren. An increased risk for herpes zoster early in childhood has been described in children who acquire infection with VZV in utero or in the first year of life. Immunocompromised children may have more severe herpes zos ter, similar to the situation in adults, including postherpetic neuralgia. Immunocompromised patients may also experience disseminated cutaneous disease that mimics varicella, with or without initial derma tomal rash, as well as visceral dissemination with pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulopathy. Severely immunocompromised children, particularly those with advanced HIV infection, may have unusual, chronic, or relapsing cutaneous disease, retinitis, or central nervous system disease without rash. The finding of a lower risk for herpes zoster among vaccinated children with leu kemia than in those who have had varicella suggested that the vaccine virus reactivates less commonly than wild type VZV. A study of HIV infected vaccinated children found no cases of zoster 4.4 years after immunization, which was significantly different from the rate in chil dren who had experienced varicella. Studies to date indicate that the risk for herpes zoster in healthy children who have received one or more doses of vaccine is 78 lower than in children who had wild type varicella, with two dose vaccination providing 50 greater protection than one dose. Many more years of follow up are needed to determine whether this lower risk is maintained among older persons who are at greatest risk for herpes zoster. DIAGNOSIS Varicella and herpes zoster are usually diagnosed primarily by their clinical appearance. Laboratory evaluation has not been considered necessary for |
7,759 | diagnosis or management. However, as varicella dis ease has declined to low levels, laboratory confirmation has become increasingly necessary. The atypical nature of breakthrough varicella, with a higher proportion of papular rather than vesicular rashes, poses both clinical and laboratory diagnostic challenges. Rapid laboratory diagnosis of VZV is often important in high risk patients and can be important for infection control, especially for breakthrough cases that have mild or atypical presentations. Con firmation of VZV infections can be accomplished by many referral hospital laboratories and all state health laboratories. VZV can be identified quickly by either PCR amplification testing (vesicular fluid, crusts) or direct fluorescence assay of cells from cutaneous lesions (vesicular fluid). In the absence of vesicles or scabs, scrapings of mac ulopapular lesions can be collected for PCR or direct fluorescence assay testing. Infectious virus may be recovered by means of tissue culture methods; such methods require specific expertise, and virus may take days to weeks to grow. Of available tests, PCR is the most sensitive and also allows for differentiation of wild type and vaccine strains. Direct fluorescence assay is specific and less sensitive than PCR but when available allows for rapid diagnosis. Although multi nucleated giant cells can be detected with nonspecific stains (Tzanck smear), they have poor sensitivity and do not differentiate VZV from herpes simplex virus infections. Strain identification (genotyping) can distinguish wild type VZV from the vaccine strain in a vac cinated child; however, genotyping is available only at specialized reference laboratories. Laboratory tests of lesions cannot be used to distinguish between varicella and disseminated herpes zoster. VZV IgG antibodies can be detected by several methods, and a fourfold or greater rise in IgG antibodies is confirmatory of acute infection (although this requires a 2 to 3 week delay to collect a convalescent specimen). In vaccinated persons, commercially available tests are not sufficiently sensitive to always detect antibodies following immu nization, and a fourfold rise in IgG antibodies may not occur. Test ing for VZV IgM antibodies is not useful for routine confirmation or ruling out of varicella because commercially available methods are unreliable and the kinetics of the IgM response have not been well defined. IgM is inconsistently detected, even among patients with PCR confirmed disease. Furthermore, IgM detection does not con firm a primary infection because specific IgM antibodies are tran siently produced on each exposure to VZV, whether through primary infection, reinfection, or reactivation from latency, even subclinical. Serologic tests are not useful for the initial diagnosis of herpes zoster, but a significant rise in IgG titer in convalescent titer in the pres ence of an atypical zoster rash is confirmatory. As with any laboratory test, a negative varicella test should be considered in the context of the clinical presentation. Clinicians should use clinical judgment to decide on the best course of therapy. VZV IgG antibody can be useful to determine the immune status of individuals whose clinical history of varicella is unknown or equivocal. However, caution must be taken |
7,760 | in interpreting tests for immunity to VZV, especially in immunocom promised patients after a close exposure to VZV. Due to the possibil ity of falsepositive results, it is preferable to rely on clinical rather than laboratory information, and if in doubt, assume the individual is susceptible to varicella and proceed accordingly. Fig. 300.3 Herpes zoster involving the lumbar dermatome. (From Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infec tious Diseases, 6th ed. Philadelphia: Elsevier; 2005:1783.) Fig. 300.4 Many groups of blisters occurring over the arm in a child with herpes zoster. (From Weston WL, Lane AT, Morelli J. Color Text book of Pediatric Dermatology, 3rd ed. St. Louis: Mosby; 2002: Fig. 8 28.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2004 Part XV u Infectious Diseases TREATMENT Antiviral treatment with acyclovir or valacyclovir modifies the course of both varicella and herpes zoster. Antiviral drug resistance is rare for VZV but has occurred, primarily in children with HIV infection and other immunocompromising conditions in which frequent relapse of VZV infections has resulted in multiple courses of antiviral therapy. Foscarnet and cidofovir may be useful for the treatment of acyclovir resistant VZV infections, but consultation of an infectious diseases specialist is recommended. Varicella Given the safety profile of acyclovir and valacyclovir, and their dem onstrated efficacy in the treatment of varicella, treatment of all chil dren, adolescents, and adults with varicella is acceptable. Oral therapy with acyclovir (20 mgkgdose; maximum: 800 mgdose) given as four dosesday for 5 days can be used to treat uncomplicated varicella. Therapy is particularly important for individuals at increased risk for moderate to severe varicella: individuals older than 12 years of age; individuals older than 12 months of age with chronic cutaneous or pulmonary disorders; individuals receiving short term, intermittent, or aerosolized corticosteroid therapy; individuals receiving long term salicylate therapy; and possibly secondary cases among household contacts. To be most effective, treatment should be initiated as early as possible, preferably within 24 hours of the onset of the exanthem. There is less clinical benefit if treatment is initiated more than 72 hours after onset of the exanthem. Acyclovir therapy does not interfere with the induction of VZV immunity. Acyclovir has been successfully used to treat varicella in pregnant women. Valacyclovir or famciclovir may be given to older children who can swallow tablets. These drugs are highly active against VZV by the same mechanism as acyclovir and are better absorbed by the oral route than acyclovir. Valacyclovir (20 mg kgdose; maximum: 1,000 mgdose, administered 3 times daily for 5 days) is licensed for treatment of varicella in children 2 to 18 years of age, and both valacyclovir and famciclovir are approved for treatment of herpes zoster in adults. Patients receiving these antivirals should be well hydrated, and for prolonged use, renal function and white blood cell counts |
7,761 | (especially neutrophils) should be monitored frequently. Common adverse symptoms during valacyclovir treatment are neu rologic (headache, agitation, dizziness) and gastrointestinal (nausea, abdominal pain). Intravenous therapy is indicated for severe disease and for vari cella in immunocompromised patients (even if begun more than 72 hours after onset of rash). Any patient who has signs of disseminated VZV, including pneumonia, severe hepatitis, thrombocytopenia, or encephalitis, should receive immediate treatment. Intravenous acyclovir therapy (10 mgkg or 500 mgm2 every 8 hours) initiated within 72 hours of development of initial symptoms decreases the likelihood of progressive varicella and visceral dissemination in high risk patients. Treatment is continued for 7 10 days or until no new lesions have appeared for 48 hours. Delaying antiviral treatment in high risk individuals until it is obvious that prolonged new lesion formation is occurring is not recommended because visceral dissemi nation occurs during the same period. Acyclovir resistant VZV has been identified primarily in children infected with HIV. These children may be treated with intravenous foscarnet (120 mgkgday divided every 8 hours). The dose should be modified in the presence of renal insufficiency. Resistance to foscar net has been reported with prolonged use. Cidofovir is also useful in this situation. Because of the increased toxicity profile of foscarnet and cidofovir, these two drugs should be initiated in collaboration with an infectious diseases specialist. Herpes Zoster Antiviral drugs are effective for treatment of herpes zoster. In healthy adults, acyclovir (800 mg 5 times a day PO for 5 7 days), famciclovir (500 mg tid PO for 7 days), and valacyclovir (1,000 mg tid PO for 7 days) reduce the duration of the illness but do not prevent development of postherpetic neuralgia. In otherwise healthy children, herpes zos ter is a less severe disease, and postherpetic neuralgia usually does not occur. Therefore treatment of uncomplicated herpes zoster in the child with an antiviral agent may not always be necessary, although some experts would treat with oral acyclovir (20 mgkgdose; maximum: 800 mgdose) to shorten the duration of the illness. It is important to start antiviral therapy as soon as possible. Delay beyond 72 hours from onset of rash limits its effectiveness. In contrast, herpes zoster in immunocompromised children can be severe, and disseminated disease may be life threatening. Patients at high risk for disseminated disease should receive intravenous acyclovir (500 mgm2 or 10 mgkg every 8 hours). Oral acyclovir, famciclovir, and valacyclovir are options for immunocompromised patients with uncomplicated herpes zoster, who are considered at low risk for vis ceral dissemination. Neuritis with herpes zoster should be managed with appropriate analgesics. Use of corticosteroids in the treatment of herpes zoster in children is not recommended. PROGNOSIS Primary varicella in unvaccinated persons has a mortality rate of 2 3 per 100,000 cases, with the lowest case fatality rates among children 1 9 years of age (1 deaths100,000 cases). Compared with these age groups, infants have a 4 times greater risk of dying and adults have a 25 times greater risk of dying. |
7,762 | The most common complications among people who died from varicella were pneumonia, central ner vous system complications, secondary infections, and hemorrhagic conditions. The mortality rate of untreated primary infection was 7 in immunocompromised children in the 1960s. In the era of antiviral therapy and improved supportive care, the prognosis has improved with treatment administered early in the course of illness, but deaths have continued to occur. Herpes zoster among healthy children has an excellent prognosis and is usually self limited. Severe presentation with complications and sometimes fatalities can occur in immuno compromised children. PREVENTION VZV transmission is difficult to prevent, especially from persons with varicella, because a person with varicella may be contagious for 24 48 hours before the rash is apparent. Herpes zoster is less infectious than varicella; nonetheless, transmission has been reported even in the absence of direct contact with the patient. Infection control practices, including caring for patients with varicella in isolation rooms with filtered air systems, are essential. All healthcare workers should have evidence of varicella immunity (Table 300.1). Unvaccinated healthcare workers without other evidence of immunity who have had a close exposure to VZV should be furloughed for days 8 21 after exposure because they are potentially infectious during this period. Routine test ing for VZV antibodies after vaccination is not useful for identifying individuals who are immune to varicella because the tests are insensi tive for this purpose. Vaccine Varicella is a vaccine preventable disease. Varicella vaccine contains live, attenuated VZV (Oka strain) and is indicated for subcutane ous or intramuscular administration. In the United States, varicella vaccine is recommended for routine administration as a two dose regimen to healthy children at ages 12 15 months and 4 6 years. Administration of the second dose earlier than 4 6 years of age is acceptable, but it must be at least 3 months after the first dose. Catch up vaccination with the second dose is recommended for children and adolescents who received only one dose. Vaccination with two doses is recommended for all persons without evidence of immunity. The minimum interval between the two doses is 3 months for persons 12 years of age or younger and 4 weeks for older children, adoles cents, and adults. Administration of varicella vaccine within 4 weeks of measles mumps rubella (MMR) vaccination is associated with a Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 300 u Varicella Zoster Virus 2005 higher risk for breakthrough disease; therefore it is recommended that the varicella and MMR vaccines either be administered simulta neously at different sites or be given at least 4 weeks apart. Varicella vaccine can be administered as a monovalent vaccine (for all healthy persons 12 months of age) or as the quadrivalent measles mumps rubella varicella (MMRV) vaccine (for children age 12 months through 12 years only). Varicella vaccine is contraindicated |
7,763 | for persons who have a history of anaphylactic reaction to any component of the vaccine; pregnant women; persons with cell mediated immune deficiencies, including those with leukemia, lymphoma, and other malignant neoplasms affecting the bone marrow or lymphatic systems; persons receiving immunosuppressive therapy; and persons who have a family his tory of congenital or hereditary immunodeficiency in first degree relatives unless the immune competence of the potential vaccine recipient is demonstrated. Children with isolated humoral immuno deficiencies may receive varicella vaccine. The monovalent varicella vaccine has been studied in clinical trial settings in children with acute lymphocytic leukemia and certain solid tumors who were in remission, but this practice is not recommended except in a research setting. Varicella vaccine can be administered to patients with leuke mia, lymphoma, or other malignancies whose disease is in remission, who have restored immunocompetence, and whose chemotherapy has been terminated for at least 3 months. The vaccine should be considered for HIV infected children with a CD4 T lymphocyte count 200 cellsmm3 or percentage 15. These children should receive two doses of the monovalent vaccine, 3 months apart. Specific guidelines for immunizing these children should be reviewed before vaccination. Data indicate that varicella vaccine is highly effective in preventing herpes zoster among children infected with HIV. MMRV should not be administered as a substitute for the component vaccines in HIV infected children. A recombinant subunit (non live) adjuvanted vaccine is available in the United States for use for prevention of herpes zoster and its related complications among individuals 50 years and older and among those 19 years and older who are or will be immunodeficient or immuno suppressed because of disease or therapy. The zoster vaccine is not indicated for primary prevention of varicella, or for the treatment of zoster or postherpetic neuralgia. Vaccine Associated Adverse Events Varicella vaccine is safe and well tolerated. The incidence of injec tion site complaints observed 3 days after vaccination was slightly higher after dose 2 (25) than after dose 1 (22). A mild vaccine associated varicelliform rash was reported in approximately 15 of healthy vaccinees, consisting of 6 10 papular vesicular, erythem atous lesions with peak occurrence 8 21 days after vaccination. Seri ous adverse reactions confirmed to be caused by the vaccine strain are rare and include pneumonia, hepatitis, meningitis, recurrent herpes zoster, severe rash, and seven deaths (all deaths occurred in persons with immunocompromising conditions). Transmission of vaccine virus to susceptible contacts is a very rare event from healthy vaccine recipients (13 instances from 11 immunocompe tent varicella vaccine recipients, all in the presence of a rash in the vaccinee, 6 varicella like and 5 herpes zoster). MMRV vaccine is associated with a greater risk for febrile seizures 5 12 days after the first dose among children 12 23 months of age compared with simultaneous MMR and varicella vaccines (one extra febrile seizure for every 2,500 children vaccinated). Postexposure Prophylaxis Vaccine given to healthy children within 3 and up to 5 days after exposure (as |
7,764 | soon as possible is preferred) is effective in preventing or modifying varicella. Varicella vaccine is recommended for postexpo sure use and for outbreak control. Oral acyclovir administered late in the incubation period may modify subsequent varicella in the healthy child; however, its use in this manner is not recommended until it can be further evaluated. High titer anti VZV immune globulin as postexposure prophy laxis is recommended for immunocompromised children, pregnant women, and newborns exposed to varicella. Since 2012 the product licensed for use in the United States is VariZIG. VariZIG is com mercially available from a broad network of specialty distributors in the United States (list available at https:www.varizig.com). The recommended dose is 1 vial (125 units) for each 10 kg increment of body weight (maximum: 625 units), except for infants weighing 2 kg who should receive 0.5 vial. VariZIG should be given intra muscularly as soon as possible but may be efficacious up to 10 days after exposure. Newborns whose mothers have varicella 5 days before to 2 days after delivery should receive VariZIG (0.5 vial for those weighing 2 kg and 1 vial for those weighing 2 kg). VariZIG is also indicated for pregnant women and immunocompromised persons without evidence of varicella immunity; hospitalized premature infants born at 28 weeks of gestation (or weight 1,000 g) who were exposed to varicella, regardless of maternal varicella immunity; and hospitalized premature infants born at 28 weeks of gestation who were exposed to varicella and whose mothers have no evidence of varicella immunity. Patients given VariZIG should be monitored closely and treated with acyclovir if necessary once lesions develop. Close contact between a susceptible high risk patient and a patient with herpes zoster is also an indication for VariZIG prophylaxis. Pas sive antibody administration or treatment does not reduce the risk for herpes zoster or alter the clinical course of varicella or herpes zoster when given after the onset of symptoms. Although licensed pooled IVIG preparations contain anti VZV antibodies, the titer varies from lot to lot. In situations in which admin istration of VariZIG is not possible, IVIG can be administered (400 mg kg administered once within 10 days of exposure). Immunocompro mised patients who have received high dose IVIG (400 mgkg) for other indications within 3 weeks before VZV exposure can be expected to have serum antibodies to VZV. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 300.1 Evidence of Immunity to Varicella Evidence of immunity to varicella consists of any of the following: Documentation of age appropriate vaccination with a varicella vaccine: Preschool age children (i.e., age 12 mo): one dose School age children, adolescents, and adults: two doses Laboratory evidence of immunity or laboratory confirmation of disease Birth in the United States before 1980 Diagnosis or verification of a history of varicella disease by a healthcare provider Diagnosis or verification of a history of herpes zoster by a healthcare provider For children who received their first dose at younger than age 13 years and for whom |
7,765 | the interval between the two doses was 28 or more days, the second dose is considered valid. Commercial assays can be used to assess disease induced immunity, but they lack sensitivity to always detect vaccine induced immunity (i.e., they might yield false negative results). For healthcare personnel, pregnant women, and immunocompromised persons, birth before 1980 should not be considered evidence of immunity. Verification of history or diagnosis of typical disease can be provided by any healthcare provider (e.g., school or occupational clinic nurse, nurse practitioner, physician assistant, or physician). For persons reporting a history of, or reporting with, atypical or mild cases, assessment by a physician or hisher designee is recommended, and one of the following should be sought: (1) an epidemiologic link to a typical varicella case or to a laboratory confirmed case or (2) evidence of laboratory confirmation if it was performed at the time of acute disease. When such documentation is lacking, persons should not be considered as having a valid history of disease, because other diseases might mimic mild atypical varicella. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2006 Part XV u Infectious Diseases Infectious mononucleosis is the best known clinical syndrome caused by Epstein Barr virus (EBV). It is characterized by systemic somatic complaints consisting primarily of fatigue, malaise, fever, sore throat, and generalized lymphadenopathy. Originally described as glandular fever, it derives its name from the mononuclear lymphocytosis with atypical appearing lymphocytes that accompany the illness. ETIOLOGY EBV is a double stranded DNA virus that is a member of the gamma herpesviruses and causes 90 of cases of infectious mononucleosis. Two distinct types of EBV, type 1 and type 2 (also called type A and type B), have been characterized and have 7085 sequence homol ogy. EBV 1 is more prevalent worldwide, although EBV 2 is more com mon in Africa than in the United States and Europe. Both types lead to persistent, lifelong, latent infection. Dual infections with both types have been documented among immunocompromised persons. EBV 1 induces in vitro growth transformation of B lymphocytes more effi ciently than does EBV 2, but no type specific disease manifestations or clinical differences have been identified. As many as 510 of infectious mononucleosislike illnesses are caused by other types of primary infections, particularly cytomegalovi rus but also pathogens such as Toxoplasma gondii, adenovirus, hepatitis viruses, and HIV. In the majority of EBV negative cases of infectious mononucleosis, the exact cause remains unknown. EPIDEMIOLOGY EBV infects more than 95 of the worlds population. It is transmit ted primarily via oral secretions. Among children, transmission may occur by exchange of saliva from child to child, such as occurs between children in out of home childcare. EBV is shed in oral secretions con sistently for more than 6 months after acute infection and then inter mittently for life. As many as |
7,766 | 2030 of healthy EBV infected persons shed virus at any particular time. EBV is also found in male and female genital secretions, and some studies suggest the possibility of spread through sexual contact. Nonintimate contact, environmental sources, and fomites do not contribute to transmission of EBV. Infection with EBV in developing countries and among socioeco nomically disadvantaged populations in developed countries usually occurs during infancy and early childhood. In central Africa, almost all children are infected by 3 years of age. Among more affluent popu lations in industrialized countries, half of the population is infected by 6 8 years of age, with approximately 30 of infections occurring during adolescence and young adulthood. In the United States, sero prevalence increases with age, from approximately 54 for children 6 8 years to 83 for patients 18 19 years. Seroprevalence at each age is substantially higher for Mexican Americans and non Hispanic Blacks than for non Hispanic Whites. Large differences are seen by family income, with highest seroprevalence in children of families with lowest income. The epidemiology of the disease manifestations of infectious mono nucleosis is related to the age of acquisition of EBV infection. Primary infection with EBV during childhood is usually asymptomatic or mild and indistinguishable from other childhood infections. Primary EBV infection in adolescents and adults manifests in 3050 of cases as the classic triad of fatigue, pharyngitis, and generalized lymphadenop athy, which constitute the major clinical manifestations of infectious mononucleosis. This syndrome may be seen at all ages but is rarely apparent in children younger than 4 years of age, when most EBV infec tions are asymptomatic, or in adults older than 40 years of age, when most individuals have already been infected by EBV. The true incidence of the syndrome of infectious mononucleosis is unknown but is esti mated to occur in 20 70 per 100,000 person years. In young adults, the incidence increases to approximately 100 per 100,000 person years. The prevalence of serologic evidence of past EBV infection increases with age; almost all adults in the United States are seropositive. EBV infection has been implicated in other diseases, including both nonmalignant and malignant disorders such as lymphoproliferative diseases and lymphomas (Table 301.1). In addition, various mono genic immune susceptibility defects predispose to EBV associated hemophagocytic lymphohistiocytosis, lymphoproliferative disorders, or lymphoma (Fig. 301.1; see also Chapter 174.3). PATHOGENESIS After transmission by saliva to the oral cavity, EBV infects both oral epithelial cells and tonsillar B lymphocytes, although it is unclear which cells are the primary initial targets. Ongoing viral replication leads to viremia and dissemination of infected B lymphocytes into peripheral blood and the lymphoreticular system, including the liver and spleen. Clinical manifestations of infectious mononucleosis, which are due to the host immune response to EBV infection, occur after a 6 week incubation period following acute infection. The atypical lymphocytes that are frequently detected in patients with infectious mononucleosis are primarily CD8 T lymphocytes. Polyclonal CD8 T lymphocyte acti vation occurs early during the incubation period following |
7,767 | infection, whereas expansion of EBV specific CD8 T lymphocytes is detected closer to the time of symptom onset. Natural killer (NK) cells also Chapter 301 Epstein Barr Virus Terri L. Stillwell and Jason B. Weinberg Table 301.1 Diseases Caused by Epstein Barr Virus Infection INFECTED CELL TYPE NONMALIGNANT DISEASES MALIGNANT DISEASES B lymphocytes B lymphoproliferations (B LPD) Posttransplant B LPD Hemophagocytic lymphohistiocytosis (HLH) Hodgkin lymphoma (HL) Diffuse large B cell lymphoma (DLBCL) Burkitt lymphoma (BL) TNK lymphocytes Systemic TNK cell type chronic active EBV (CAEBV) Cutaneous CAEBV Hydroa vacciniformelike lymphoproliferation (HVL) Severe mosquito bite allergy (SMBA) HLH Systemic EBV T cell lymphoma of childhood (STLC) Extranodal NKT cell lymphoma (ENKTL) Aggressive NK cell leukemia (ANKL) Smooth muscle cells Smooth muscle tumorleiomyoma (SMT) Epithelial cells Hairy leukoplakia Nasopharyngeal carcinoma (NPC) Gastric carcinoma Hairy leukoplakia is a benign epithelialmucosal disease caused by uncontrolled lytic infection that occurs in immunocompromised patients. It is characterized by white patches with hairy appearance on the tongue. From Fournier B, Latour S. Immunity to EBV as revealed by immunodeficiencies. Curr Opin Immunol. 2021;72:107115. Table 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 301 u Epstein Barr Virus 2007 expand in frequency and number following infection, particularly a CD56dim CD16 NK cell subset that is more effective than other NK cell subsets at recognizing infected cells. The host immune response is effective in rapidly reducing the EBV viral load, although persistent shedding of high levels of virus can be detected in the oropharynx for up to 6 months. Intermittent shedding from the oropharynx occurs for many years following primary infection. EBV, like the other herpesviruses, establishes lifelong latent infection after the primary infection. Latent virus persists primarily in memory B lymphocytes. The EBV genome persists as an episome in the nucleus of an infected cell and replicates with cell division. Viral integration into the cell genome is not typical. Only a few viral proteins, including the EBV determined nuclear antigens (EBNAs), are produced during latency. These proteins are important in maintaining the viral episome during the latent state. Reactivation and new viral replication occur at a low rate in populations of latently infected cells and is responsible for intermittent viral shedding in oropharyngeal secretions of infected individuals. Reactivation is unlikely to be accompanied by distinctive clinical symptoms. CLINICAL MANIFESTATIONS The incubation period of infectious mononucleosis in adolescents is 30 50 days. In children, it may be shorter. The majority of cases of primary EBV infection in infants and young children are clinically silent. In older patients, the onset of illness is usually insidious and vague. Patients may complain of malaise, fatigue, acute or prolonged (1 week) fever, head ache, sore throat, nausea, abdominal pain, and myalgia. This prodromal period may last 1 2 weeks. The complaints of sore throat and fever grad ually increase until patients seek medical care. Splenic |
7,768 | enlargement may be rapid enough to cause left upper quadrant abdominal discomfort and tenderness, which may be the presenting complaint. The classic physical examination findings are generalized lymph adenopathy (90 of cases), splenomegaly (50 of cases), and hepa tomegaly (10 of cases). Lymphadenopathy occurs most commonly in the anterior and posterior cervical nodes and the submandibular nodes and less commonly in the axillary and inguinal lymph nodes. Epitrochlear lymphadenopathy is particularly suggestive of infectious mononucleosis. Although liver enzymes are usually elevated, symp tomatic hepatitis or jaundice is uncommon. Splenomegaly to 2 3 cm below the costal margin is typical (1565 of cases); massive enlarge ment is uncommon. The sore throat is often accompanied by moderate to severe phar yngitis with marked tonsillar enlargement, occasionally with exudates (Fig. 301.2). Palatal petechiae at the junction of the hard and soft pal ate are frequently seen. The pharyngitis is similar to that caused by streptococcal infection. Other clinical findings may include rashes and edema of the eyelids. Rashes are usually maculopapular and have been reported in 315 of patients. Patients with infectious mono nucleosis who are treated with ampicillin or amoxicillin may experi ence an ampicillin rash, which may also occur with other lactam antibiotics (Fig. 301.3). This morbilliform, vasculitic rash is probably immune mediated and resolves without specific treatment. EBV can also be associated with Gianotti Crosti syndrome, a symmetric rash on the cheeks with multiple erythematous papules, which may coalesce into plaques and persist for 15 50 days. The rash has the appearance of atopic dermatitis and may also appear on the extremities and buttocks. DIAGNOSIS A presumptive diagnosis of infectious mononucleosis may be made by the presence of classic clinical symptoms with atypical lymphocytosis in the peripheral blood. The diagnosis is usually confirmed by serologic testing, either for heterophile antibody or specific EBV antibodies. Differential Diagnosis EBV is the most common cause of infectious mononucleosis. Infec tious mononucleosislike illnesses may also be caused by primary infection with other pathogens, such as cytomegalovirus, T. gon dii, adenovirus, and HIV. Streptococcal pharyngitis may cause sore throat and cervical lymphadenopathy indistinguishable from that of Hemophagocytic lymphohistiocytosis Bcell lymphoproliferative disordersLymphoma TNKcell cytotoxicity defects Tcell activationexpansion defects XIAP UNC13D STX11, STXBP2 RAB27 LYST PERF1 ITK, MAGT1, CTPS1, RASGRP1, DEF6, CD70, TNFSF9 CD27 (20 HLH) TNFRSF9 (20 HLH) SH2D1A (30 lymphoma) Fig. 301.1 Classification of gene defects predisposing to Epstein Barr virus (EBV) driven hemophagocytic lymphohistiocytosis (HLH) or B cell lymphoproliferative disorders. Red circle, Gene defects associ ated with impaired cell cytotoxicity causing HLH. Green circle, Gene defects associated with impaired T cell activationexpansion causing B cell lymphoproliferative disorder (B LPD)lymphoma. Gene defects with a highly selective predisposition to EBV are in bold. In parentheses is the percentage of patients having developed HLH or B lymphoma for defects associated with both HLH and B LPDlymphoma. (From Fourni er B, Latour S. Immunity to EBV as revealed by immunodeficiencies. Curr Opin Immunol. 2021;72:107115. Fig.1.) Fig. 301.2 Tonsillitis with membrane formation in infectious mononu cleosis. (Courtesy Alex J. |
7,769 | Steigman, MD.) Fig. 301.3 Amoxicillin induced rash in Epstein Barr virus infection. Morbilliform maculopapular rash on the leg, which appeared shortly after starting amoxicillin. The rash is typical of that seen in the context of Epstein Barr virus infection in patients treated with amoxicillin or am picillin. (From Norman SD, Murray IA, Shetty D, et al. Jaundice, abdomi nal pain, and fever in a young woman. Lancet. 2017;390:17131714. Fig. A.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2008 Part XV u Infectious Diseases infectious mononucleosis, but it is not typically associated with hepato splenomegaly. Approximately 5 of cases of EBV associated infectious mononucleosis have throat cultures positive for group A Streptococcus, representing pharyngeal streptococcal carriage. Failure of a patient with presumed streptococcal pharyngitis to improve within 48 72 hours should evoke suspicion of infectious mononucleosis. Hemato logic malignancies should also be considered in a patient with an infec tious mononucleosislike illness, particularly when lymphadenopathy and hepatosplenomegaly are appreciated and the results of an initial laboratory evaluation are not consistent with an infectious etiology. Laboratory Diagnosis The majority of patients (90) have a leukocytosis of 10,000 20,000 cellsL, of which at least two thirds are lymphocytes; atypical lym phocytes usually account for 2040 of the total number. The atypical cells are mature T lymphocytes that have been antigenically activated. Compared with regular lymphocytes microscopically, atypical lym phocytes are larger overall, with larger, eccentrically placed indented and folded nuclei with a lower nuclear to cytoplasm ratio. Although atypical lymphocytosis may be seen with many other infections associ ated with lymphocytosis, the highest degree of atypical lymphocytes is classically seen with EBV infection. Mild thrombocytopenia to 50,000 200,000 plateletsL occurs in more than 50 of patients but only rarely is associated with purpura. Mild elevation of hepatic trans aminases occurs in approximately 75 of uncomplicated cases, but it is usually asymptomatic and without jaundice. Detection of Heterophile Antibodies Heterophile antibodies are cross reactive immunoglobulin (Ig) M antibodies that agglutinate mammalian erythrocytes but are not EBV specific. Heterophile antibody tests, such as the monospot test, are positive in 90 of cases of EBV associated infectious mononucleosis in adolescents and adults during the second week of illness, but in only up to 50 of cases in children younger than 4 years of age. Test results can remain positive for up to 12 months. The false positive rate is low, generally 10. A positive heterophile antibody test in a patient with classic clinical manifestations of mononucleosis strongly supports that diagnosis. However, because of the nonspecific nature of heterophile antibody testing, EBV specific antibody testing should be performed when a precise diagnosis is necessary. Detection of Epstein Barr VirusSpecific Antibodies If the heterophile test result is negative and an EBV infection is sus pected, EBV specific antibody testing is indicated. Measurement of antibodies to EBV proteins, including viral capsid antigen |
7,770 | (VCA), Epstein Barr nuclear antigen (EBNA), and early antigen (EA), are used most frequently (Fig. 301.4 and Table 301.2). The acute phase of infec tious mononucleosis is characterized by rapid IgM and IgG antibody responses to VCA in all cases and an IgG response to EA in most cases. The IgM response to VCA is transient but can be detected for at least 4 weeks and occasionally up to 3 months; in rare cases, anti VCA IgM can persist even longer. The IgG response to VCA usually peaks late in the acute phase, declines slightly over the next several weeks to months, and then persists at a relatively stable level for life. Anti EA IgG antibodies are usually detectable for several months but may persist or be detected intermittently at low levels for many years. Antibodies to the diffuse staining component of EA (EA D) are found transiently in 80 of patients during the acute phase of infec tious mononucleosis. Antibodies to the cytoplasmic restricted com ponent of EA (EA R) emerge transiently in the convalescence from infectious mononucleosis. High levels of antibodies to EA D or EA R may be found also in immunocompromised patients with persistent EBV infections and active EBV replication. Anti EBNA IgG antibodies are the last to develop in infectious mononucleosis and gradually appear 3 4 months after the onset of illness and remain at low levels for life. Absence of anti EBNA when other antibodies are present implies recent infection, whereas the pres ence of anti EBNA implies infection occurring more than 3 4 months previously. The wide range of individual antibody responses and the various laboratory methods used can occasionally make interpretation of an antibody profile difficult. The detection of IgM antibody to VCA is generally sufficient to confirm the diagnosis of acute EBV infection, although false positive results can still occasionally occur. Detection of Viral DNA EBV DNA can be detected and viral genome copy number quantified in whole blood, peripheral blood mononuclear cells (PBMCs), and plasma using real time polymerase chain reaction. EBV DNA can be detected in PBMCs and plasma of patients with infectious mononu cleosis for a brief period after the onset of symptoms and in PBMCs for an extended period. However, detection of EBV DNA is usually not necessary to diagnose infectious mononucleosis in immunocompetent patients with typical manifestations of disease. In contrast, serial mea surements of EBV genome copy number are often used following solid organ or hematopoietic stem cell transplantation as surveillance for posttransplant lymphoproliferative disease (PTLD). Very high or con sistently increasing EBV genome copy number suggests an increased risk for PTLD, although definitive diagnosis is typically based on tissue biopsy. The frequency and duration of monitoring EBV genome copy number is determined by the time after transplant and risk factors such as the type of transplant and the degree of immunosuppression. Serial measurement of EBV genome copy number can be useful in monitor ing response to therapy for PTLD. Measurement of EBV genome copy |
7,771 | number can also be used for screening and to determine prognosis for some EBV associated malignancies, such as nasopharyngeal carci noma and Hodgkin lymphoma. COMPLICATIONS Severe complications are unusual in patients with infectious mononu cleosis. Splenic rupture, either spontaneous or following mild trauma, may occur in approximately 0.1 of cases but is rarely fatal. Airway obstruction due to swelling of oropharyngeal lymphoid tissue occurs in 5 of cases. A variety of neurologic conditions have been associated with EBV infectious mononucleosis. Headache is a common symptom, but symptomatic meningitis or encephalitis is uncommon. More severe neurologic manifestations, such as seizures and ataxia, may occur in 15 of cases. Perceptual distortions of sizes, shapes, and spatial rela tionships, known as the Alice in Wonderland syndrome (metamor phopsia), may be a presenting symptom. Some reports suggest an association between infectious mononucleosis and the possible devel opment of multiple sclerosis. Hematologic abnormalities such as mild hemolytic anemia, thrombocytopenia, and neutropenia are relatively common, but aplastic anemia, severe thrombocytopenia, and severe neutropenia are rare. Other rare complications include myocarditis, interstitial pneumonia, pancreatitis, parotitis, and orchitis. Patients with dysregulated immune responses to primary infection, such as individuals with primary or secondary hemophagocytic lym phohistiocytosis (HLH), can develop severe, life threatening com plications with primary EBV infection (see Fig. 301.1). Patients with other primary immunodeficiencies that result in failure to control EBV infection andor abnormal inflammatory responses to infection are at risk for severe manifestations of EBV infection, often with fulminant infectious mononucleosis, chronic viremia, dysgammaglobulinemia, and lymphoproliferation. Immunodeficiencies most commonly linked to severe EBV infection tend to be those affecting aspects of NK cell, T lymphocyte, and NKT lymphocyte function. Examples include X linked lymphoproliferative (XLP) syndrome, which is caused by variants in genes encoding the signaling lymphocytic activation mole cule (SLAM) associated protein (SAP) or X linked inhibitor of apopto sis (XIAP); X linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN), caused by mutations in MAGT1, which encodes a magnesium transporter protein; and deficiencies in interleukin 2inducible T cell kinase (ITK), CD27, or CD70 (see Fig. 301.1; Chapter 174.3). ONCOGENESIS Infection with EBV, the first human virus to be associated with malig nancy, accounts for up to 2 of cancers worldwide (see Table 301.1). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 301 u Epstein Barr Virus 2009 Manipulation of infected cells by EBV can lead to transformation and oncogenesis. EBV is associated with lymphoid malignancies, such as Burkitt lymphoma, Hodgkin lymphoma, aggressive NK cell leukemia, T and NK cell lymphoproliferative disorder, and epithelial cell malig nancies such as nasopharyngeal carcinoma and gastric carcinoma. Endemic Burkitt lymphoma is the most common childhood cancer in equatorial East Africa and Papua New Guinea. These regions are holoendemic for Plasmodium falciparum malaria and have a high rate of EBV infection early in life. Constant exposure to malaria is thought |
7,772 | to act as a B lymphocyte mitogen that contributes to the polyclonal B lymphocyte proliferation with EBV infection, impairs T lymphocyte surveillance of EBV infected B lymphocytes, and increases the risk for developing Burkitt lymphoma. Approximately 98 of cases of endemic Burkitt lymphoma contain the EBV genome compared with only 20 of nonendemic (sporadic) Burkitt lymphoma cases in other areas of the world. The incidence of Hodgkin lymphoma peaks in childhood in devel oping countries and in young adulthood in developed countries. Infec tion with EBV increases the risk for Hodgkin lymphoma by a factor of 2 4, with the risk of developing Hodgkin lymphoma peaking at 2.4 years following infectious mononucleosis. EBV is associated with more than half of cases of mixed cellularity Hodgkin lymphoma and approximately one quarter of cases of the nodular sclerosing subtype, but it is rarely associated with lymphocyte predominant Hodgkin lymphoma. Immunohistochemical studies have localized EBV to the Reed Sternberg cells and their variants, the pathognomonic malignant cells of Hodgkin lymphoma. Numerous congenital and acquired immunodeficiency syn dromes are associated with an increased incidence of EBV associated B lymphocyte lymphoma, especially central nervous system lymphoma and leiomyosarcoma (see Fig. 301.1). Congenital immunodeficiencies predisposing to EBV associated lymphoproliferation include XLP syn drome, common variable immunodeficiency, ataxia telangiectasia, Wiskott Aldrich syndrome, and Chdiak Higashi syndrome. Indi viduals with acquired immunodeficiencies resulting from anticancer chemotherapy, immunosuppression after solid organ or hematopoietic cell transplantation, or HIV infection have a significantly increased risk for EBV associated lymphoproliferation. The lymphomas may be focal or diffuse and are usually histologically polyclonal but may become monoclonal. EBV associated PTLD can occur following solid organ transplantation and, less commonly, allogeneic hematopoietic cell transplantation. The most important risk factors for PTLD are the degree of T lymphocyte immunosuppression and recipient EBV serostatus. TREATMENT There is no specific treatment for infectious mononucleosis. The main stays of management are rest, adequate fluid and nutrition intake, and symptomatic treatment to manage fever, throat discomfort, and malaise. Bed rest is necessary only when the patient has debilitating fatigue. As soon as there is definite symptomatic improvement, the patient should be encouraged to resume normal activities. Because blunt abdominal trauma may predispose patients to splenic rupture, it is customary and prudent to advise against participation in contact sports and strenuous athletic activities during the first 2 3 weeks of ill ness or while splenomegaly is present. Antiviral therapy is not recommended. Although nucleoside analogs such as acyclovir and ganciclovir inhibit viral replication in vitro and decrease the duration of oropharyngeal viral shedding in patients with infectious mononucleosis, they have not been shown to provide con sistent clinical benefit for patients with infectious mononucleosis or EBV associated malignancies. Short courses of corticosteroids may be helpful for selected complications of infectious mononucleosis, such as airway obstruction, but there are insufficient data to support the use of corticosteroids to control typical symptoms in patients with infec tious mononucleosis. Adoptive immunotherapy involving the infusion of EBV specific cytotoxic T lymphocytes has shown some |
7,773 | promise in early trials for transplant recipients with PTLD and for other patients with EBV associated malignancies. PROGNOSIS The prognosis for complete recovery is excellent. The major symptoms typically last 2 4 weeks, followed by gradual recovery within 2 months of symptom onset. Cervical lymphadenopathy and fatigue may resolve more slowly. Prolonged and debilitating fatigue and malaise may wax and wane for several weeks to 6 months and are common complaints even in otherwise unremarkable cases. Occasional persistence of fatigue for a few years after infectious mononucleosis is well recog nized. There is no convincing evidence linking EBV infection or EBV reactivation to chronic fatigue syndrome. PREVENTION Vaccination against EBV would be an appealing strategy to prevent acute disease (infectious mononucleosis) and complications such as EBV associated malignancies. Early clinical trials using strategies targeting the EBV gp350 envelope glycoprotein demonstrated some protection against symptomatic infectious mononucleosis, although vaccination did not prevent EBV infection. No EBV vaccine is cur rently approved for clinical use. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. VCAIgG EBNAIgG EAIgG A nt ib od y tit er 0 2 4 2 4 6 1 2 3 Weeks Months Years Time after onset of symptoms VCAIgM In fe ct io us m on on uc le os is Fig. 301.4 Kinetics of antibody responses to Epstein Barr virus (EBV) antigens in infectious mononucleosis. EA, Early antigen; EBNA, EBV determined nuclear antigens; IgG, immunoglobulin G; IgM, immuno globulin M; VCA, viral capsid antigen. Table 301.2 Correlation of Clinical Status and Antibody Responses to Epstein Barr Virus Infection CLINICAL STATUS VCA IgM VCA IgG EA IgG EBNA IgG Susceptible Acute primary infection Recent primary infection Past infection EA, Early antigen (typically the diffuse staining component, or EA D); EBNA, EBV determined nuclear antigens; EBV, Epstein Barr virus; IgG, immunoglobulin G; IgM, immunoglobulin M; VCA, viral capsid antigen. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2010 Part XV u Infectious Diseases Human cytomegalovirus (CMV) is ubiquitous in the population, with serologic evidence of infection in 50 of adults in the United States and 96 in many populations in South America, Africa, and Asia. Individuals who become infected remain persistently infected for life and shed infectious virus intermittently from mucosal surfaces, thus serving as a source of infectious virus for transmission within popu lations. Although CMV infection rarely causes symptoms in immu nocompetent individuals, it is an important cause of morbidity and sometimes death in immunocompromised hosts. CMV remains a well recognized cause of disease in the newborn infant following intrauter ine infection (congenital CMV) and in allograft recipients undergoing posttransplantation immunosuppression. CMV emerged as the most common opportunistic infection in HIVAIDS patients before the advent of effective antiretroviral therapy. Invasive CMV infections can also be observed in patients treated with immunosuppressive biologics such as antitumor necrosis factor (TNF) antibodies. In each of these clinical |
7,774 | settings that share some degree of immunosuppression, the association of disease with CMV infection has been linked to high lev els of virus replication and end organ disease, usually associated with virus dissemination. In contrast, there is likely another group of disease states associated with chronic effects of persistent CMV infection that reflects the robust inflammatory response induced by this virus during persistent infection. Such associations have been proposed to include coronary artery disease, transplant vasculopathy and cardiac allograft loss, renal tubular sclerosis and renal allograft loss, exacerbations of inflammatory bowel disease, and possibly even some cancers such as glioblastoma. Whether definitive evidence will eventually directly link CMV to these disease states is uncertain. THE VIRUS AND ITS HOST INTERACTIONS CMV is the largest of the human herpesviruses, with an estimated size of 190 nm. The 230 kb double stranded DNA genome is about 50 larger than the herpes simplex virus genome and encodes over 200 open read ing frames, which conservatively estimated includes 100 unique virion proteins and an unknown number of nonstructural proteins. Viral DNA replication takes place in the nucleus of the infected cell followed by virus assembly in both the nucleus and cytoplasm. The structure of the virus is typical of herpesviruses and includes a complex envelope com posed of host cellderived membrane studded with virion glycoproteins, a less well structured area between the envelope and the capsid called the tegument layer, and an icosahedral capsid that contains the virion DNA. The tegument layer is highly immunogenic and induces strong adaptive immune responses, including CMV specific CD8 cytotoxic T lymphocytes that are thought to play a pivotal role in controlling CMV replication in the infected host. Likewise, the protein components of the viral envelope are also immunogenic and induce antibody responses that have been correlated with virus neutralization, antibody dependent cel lular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and other potential protective effector functions. In vivo, CMV appears to replicate in nearly all tissue and cell types, whereas in vitro productive virus replication (production of infectious progeny) occurs in primary fibroblasts and cells derived from epithelial tissue. Human CMV is species specific and productively infects only cells of human origin. Each strain of CMV that is isolated from epidemiologically unre lated individuals is genetically unique, a finding that suggests an extraor dinarily large and undefined number of genetically unique viruses exist in the human population. Furthermore, studies using next generation sequencing technologies have provided evidence that CMV can exist as genetically diverse populations of viruses within an individual. This finding has argued that during replication, CMV DNA synthesis is error prone, resulting in sequence error rates in its genome that are much higher than previous studies would predict andor a high likelihood of recombination events between viral genomes if permissive cells are infected with genetically diverse populations of viruses. Thus repeated exposures to CMV over time could result in an individual acquiring a library of CMVs as reinfection of previously infected individuals with new strains |
7,775 | of CMV also appears commonplace. These observations have led many investigators to argue that CMV must express an arma mentarium of immune evasion functions that allow it to persist even in the presence of robust host immunity. This relationship between host and virus is best illustrated by the finding that over years a persistently infected individual can maintain a stable virus load in sites of persis tence, unwavering antiviral antibody responses, and, in some individu als, up to 15 of total peripheral blood CD8 cytotoxic T lymphocyte activity can be directed at CMV antigens derived from a diverse number of virus encoded proteins. These observations have resulted in a central paradigm of CMV biology in which, following infection, a detente is established between virus replication and host innate and adaptive anti viral immunity. Thus CMV can efficiently persist in an infected host for a lifetime while inducing chronic immune activation. This latter charac teristic of the biology of CMV infection has supported a linkage between CMV and chronic inflammation, a link that could provide a common mechanism for many of the chronic diseases that have been associated with this ubiquitous virus. EPIDEMIOLOGY CMV infections can be acquired through several settings: (1) commu nity exposure, (2) nosocomial transmission, and (3) intrauterine infec tion leading to congenital infection. Community acquisition of CMV occurs throughout life and is linked by exposure to CMV shed from mucosal surfaces such as saliva, genital secretions, and urine. Peaks in exposure to infectious virus occur during childhood and in adolescents and young adults, presum ably secondary to initiation of sexual activity in the latter age group. In addition, differences in age specific and overall rates of virus infec tion in the United States are observed in different racial, ethnic, and socioeconomic groups. Common routes of infection of the very young infant include perinatal exposure to infected genital secretions dur ing birth and ingestion of CMV containing breast milk. Breastfeed ing is the most common route of CMV infection in infancy. Ingestion of breast milk from seropositive women results in a rate of infection of about 60 in infants. Infection is most common during the first several months of breastfeeding, but the risk continues for the dura tion of breastfeeding. Infants infected through breast milk can shed large amounts of virus in the saliva and urine for prolonged periods measured in months to years, thus serving as a reservoir of virus for transmission to other infants, children, and adults. After this period of intense exposure to CMV during the first year of life, infection in the remainder of childhood and early teenage years depends on specific exposures such as enrollment in group childcare facilities andor expo sure to infected, similarly aged siblings. Up to 50 of young infants and children attending group care facilities can be excreting CMV, a source of virus that can result in infection of children enrolled in the facility and in some cases the adult workers within the facility. Further more, infants and children |
7,776 | who acquire CMV in a group care setting can then transmit virus to their parents and siblings, thus providing a mechanism for spread of CMV within the community. Throughout childhood and early adulthood, CMV is transmitted by exposure to saliva and urine. However, in adolescence and early adulthood there is a spike in infection presumably associated with sexual exposure. CMV is considered a sexually transmitted infection (STI); data have shown an increased rate of CMV infection in sexually active populations and high rates of virus transmission in CMV discordant couples. Nosocomial infections with CMV are well described and can be associated with exposure to blood products containing CMV or to an allograft following transplantation of an organ from a CMV infected donor. Before improvements in blood banking that limited the number of leukocytes in red cell transfusions and that more efficiently identified Chapter 302 Cytomegalovirus Suresh B. Boppana and William J. Britt Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 302 u Cytomegalovirus 2011 CMV infected donors, transmission of CMV by blood transfusion was not uncommon and was closely related to the volume of blood that was transfused. Transfusion acquired CMV infections often resulted in symptomatic illness, with laboratory findings including hepatitis and thrombocytopenia in children and adults. Severe and sometimes fatal infections can develop following exposure to CMV infected blood products in newborn infants who lack transplacentally transferred antibodies to CMV either as a result of being born to women without seroimmunity to CMV or secondary to extreme prematurity. Similarly, immunocompromised patients who receive CMV containing blood can also develop severe infection, regardless of their prior exposure to CMV. Methodologies that efficiently deplete contaminating leukocytes and the use of blood products from CMV seronegative donors have greatly decreased the incidence of transfusion associated CMV infec tions. CMV transmission through infected allografts is well described; infections arising from CMV transferred in an infected allograft are a major cause of morbidity in both the early and late period after trans plantation. Severe infections and graft loss following solid organ trans plantation (SOT) are more often associated with mismatches between the donor and recipient, such as that following transplantation of an organ from a donor with a history of CMV infection (donor, CMV positive) into a recipient who has not been exposed to CMV (recipi ent, CMV negative; DR mismatch). However, clinically significant CMV infections can occur even in moderate risk allograft recipients (DR). In contrast to the risk stratification for CMV infection and disease in SOT recipients, the highest risk of posttransplant CMV infection and disease occurs follows reactivation of CMV in hemato poietic stem cell transplant (HSCT) recipients with prior CMV infec tion (DR) presumably because the risk of transmission in the graft is considerably lower than reactivation of persistent infection in the previously infected recipient. Even with effective antiviral therapy to modify |
7,777 | CMV infections in the early posttransplant period during intense immunosuppression, CMV infection is linked to long term graft dysfunction and graft loss and in specific patient groups such as cardiac and lung transplant recipients, can represent a barrier to long term graft survival. Congenital CMV infection (present at birth) occurs following intrauterine transmission of CMV and infection of the fetus. Rates of congenital infection between 0.4 and 1.0 have been reported in the United States, with perhaps the best estimate being about 0.4 based on a large multicenter study of nearly 100,000 births. Rates as high as 2 in some areas in Asia and Africa have been described. CMV is thought to be transferred to the developing fetus following hema togenous spread of CMV to the placenta, infection of resident cells of the placenta followed by cell free transfer of virus to the fetal blood system. The rate of transmission to the fetus is about 30 in nonim mune women with primary infection during pregnancy; in utero infec tions also occur in previously immune women (nonprimary infection), albeit at a reduced rate that has been suggested to be 12. The rate of transmission of CMV is more frequent following primary maternal infection; the absolute number of congenitally infected infants born to women with nonprimary infections in most populations outnum ber those resulting from primary maternal infection by threefold to fourfold. This is particularly true in Africa, South America, and Asia, where maternal seroimmunity to CMV often exceeds 95. Interest ingly, many of these highly CMV seroimmune maternal populations also have the highest prevalence of congenital CMV infections and almost certainly account for overall burden of congenital CMV infec tions in most regions of the world. In fact, recent estimates based on the prevalence of congenital CMV infections in sub Saharan Africa, Asia, and South America suggest that 90 of all cases of congenital CMV infections followed nonprimary material infections. The source of nonprimary maternal infection remains less well defined. Reinfec tion by genetically distinct strains of CMV is frequent in previously infected women and viruses acquired by maternal reinfection can be transmitted to the developing fetus. The reinfection rates are 1520, with annualized rates as high as 25. Thus immunity to CMV is far from protective, although it can modify the risk of transmission to the developing fetus. In addition to the impact of maternal to fetal transmission, the type of maternal infection (primary versus nonprimary) has also been shown to be a major determinant in the outcome of the intrauterine infection. The existing paradigm is that maternal immunity can modify the severity of the intrauterine infection, thus maternal infections in women with preexisting CMV immunity (nonprimary maternal infec tions) that result in intrauterine transmission are less likely to result in a severe infection in the fetus. Nonetheless, severe CMV infections may occur in fetuses infected following a nonprimary maternal infection, suggesting that the characteristics of the fetal infection such as timing of infection during gestation could be as important |
7,778 | to the outcome of a fetal infection as the maternal immune status during pregnancy. Stud ies have documented a higher frequency of severe infections in fetuses that were infected in the first and early second trimester of gestation, findings that parallel similar risk stratifications for other intrauterine infections, including those caused by Zika virus, rubella virus, and Toxoplasma gondii. Mechanisms of Disease Associated with Cytomegalovirus Infections The mechanism(s) of disease associated with CMV infections remains either undefined or incompletely defined for many of the clinical syn dromes that follow CMV infection. Several reasons have contributed to the overall lack of understanding of the pathogenesis of CMV infec tions and include (1) the asymptomatic nature of infections in almost all immunocompetent individuals; (2) the complexity of the multiple disease processes in immunocompromised hosts that can confound the assignment of specific manifestations of CMV infection; (3) the species specific tropism of human CMV; and, perhaps most impor tantly, (4) limitations inherent in observational studies in humans. Although CMV replicates in a limited number of cell types in vitro, CMV inclusions, antigens, and nucleic acids can be demonstrated in almost all organ systems and most cell types in individuals with severe, disseminated infections. Thus CMV does not exhibit strict cellular or organ system tropism in vivo. Hematogenous dissemination has been argued to be associated primarily with cell associated virus, and sig nificant levels of plasma virus are usually detected only in severely immunocompromised hosts with high levels of total blood viral loads. Virus and viral DNA can be recovered from neutrophils, monocytes, and endothelial cells present in peripheral blood, thus providing evi dence for the significance of cell associated spread of this virus. High levels of virus replication can result in end organ disease secondary to direct virus mediated cellular damage. These manifestations of CMV infections are thought to result from uncontrolled virus replication, dissemination, and virus induced cytopathology secondary to defi cits in innate and adaptive immune responses to CMV. In some cases, clinical disease has also been observed in patients without significant levels of virus replication, a finding suggesting indirect mechanisms of disease such as immunopathologic responses to CMV. Such a mecha nism of disease was shown to be operative in patients with immune recovery vitritis, a pathologic T lymphocytemediated response to CMV in HIVAIDS patients with CMV retinitis that developed after successful active retroviral therapy and reconstitution of their CMV specific T lymphocyte responses. Likewise, the level of virus replication has not been closely correlated with several chronic diseases thought to be linked to CMV, an observation that is consistent with indirect mechanisms of disease such as immunopathologic responses to a per sistent infection. From early observations in allograft recipients with invasive CMV infections it was apparent that immunosuppressive therapies that resulted in altered T lymphocyte function predisposed these patients to severe infections. Definitive evidence consistent with the critical role of CMV specific T lymphocyte immunity in protection from dis ease in these patients was provided by a clinical study |
7,779 | in which in vitro expanded, CMV specific cytotoxic T lymphocytes limited invasive infection in hematopoietic cell transplant recipients. Invasive infec tions associated with end organ disease, such as retinitis and coli tis in HIVAIDS patients with very low CD4 T lymphocyte counts, also clearly demonstrated the importance of T lymphocyte response Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2012 Part XV u Infectious Diseases control of invasive CMV infections, as the risk for these manifestations of CMV infections could be predicted in models that were based on CD4 T lymphocyte counts in these patients. However, a role of anti CMV antibodies in limiting the early events of CMV infection was also shown in studies in SOT recipients. These early studies demonstrated the transfer of immune globulins containing high titers of anti CMV antibodies when used in a prophylaxis protocol could provide some degree of protection from CMV infections and end organ disease. This important finding was consistent with the proposed role of anti viral antibodies in limiting CMV dissemination and disease in animal models of invasive CMV infections. The importance of innate immune responses such as natural killer (NK) cells and T lymphocytes in limiting invasive infections have been well documented in animal models. Similarly, NK cells have been associated with both control of CMV reactivation and limiting the severity of CMV end organ dis ease in human HCST and SOT recipients. Effector molecules such as interferon appear to contribute to the control of local CMV infec tions in animal models, but evidence of a similar role in humans has not been demonstrated. Studies in immunocompromised human hosts have shown that the control of acute CMV infection depends on an effective adaptive immune response; however, even a vigorous T lymphocyte response is not sufficient to eliminate CMV from the infected host, because CMV persists for the lifetime of the host either as a low level chronic infection andor as a latent infection with limited transcription from multiple regions of its genome. The inability of the host to completely clear CMV remains incompletely understood, but the large array of immune evasion functions encoded by this virus likely contributes to the blunted innate and adaptive immune response. Examples of these functions include (1) inhibition of cell death functions of infected cells, including apoptosis, necroptosis, and pyroptosis, (2) inhibition of interferon regulated responses, (3) inhibition of NK cell activa tion, (4) downregulation of class I major histocompatibility complex (MHC) expression and inhibition of class II MHC function, and (5) mechanisms to limit antibody recognition of envelope proteins, including carbohydrate masking of antibody recognition sites and variation in amino acid sequences in virion envelope proteins tar geted by antiviral antibodies. Although each of these functions by itself could potentially have only limited effects on virus clearance, the redundancy of these viral immune evasion functions when act ing |
7,780 | in concert likely provide the virus a sufficient advantage to favor persistence. CLINICAL MANIFESTATIONS The clinical manifestations of CMV infection reflect two parameters of the infection that are often linked: (1) the level of virus replication and (2) the degree of end organ involvement. The manifestations of CMV infections that have been most well described in clinical stud ies are those that are present in acutely infected individuals without existing immunity to the virus. Such infections are termed acute or primary infections to distinguish these infections from persistent infections that are established after an acute infection. Similar clini cal findings can be observed in patients with significant underlying deficits in innate and adaptive immune responses, regardless if infec tion follows an acute infection or recurrencereactivation of persis tent infection and reflect loss of immune control of virus replication. In contrast, the clinical manifestations of persistent or chronic CMV infections are frequently overlaid on underlying disease syndromes such as cardiovascular disease, thus confounding the contribution of CMV to the primary disease process and clinical findings in these patients. Normal Host In the overwhelming majority of patients with acute CMV infections, there are no specific symptoms or clinical findings. In patients with symptomatic, acute CMV infection, clinical findings have been most commonly reported to resemble a mononucleosis like syndrome, with fatigue and occasionally cervical adenopathy. Up to 20 of heterophile antibody negative mononucleosis may be attributed to CMV. Labora tory findings can include mild elevation of hepatic transaminases and decreased platelet counts. Immunocompromised Host The clinical presentation of CMV infection in immunocompro mised hosts often reflects the magnitude of the immunodeficiency. Profoundly immunocompromised hosts such as HSCT recipients can present with disseminated infection and clinical manifestations of disease in multiple organ systems, including liver, lung, gastroin testinal tract, and, less frequently, the CNS. Organ threatening and life threatening disease is not infrequent in these patients. In less immunocompromised patients such as the case of most SOT recipi ents, CMV infection can present with fever, fatigue, hematologic abnormalities, including leukopenia and thrombocytopenia, and mild hepatocellular dysfunction, a collection of laboratory findings and symptoms described as the CMV syndrome (Table 302.1). In contrast to renal and liver SOT recipients, heart lung and lung trans plant recipients are at high risk for severe manifestations from CMV infection, presumably because the transplanted organ is a site of virus replication, disease, and virus induced life threatening organ dys function (see Table 302.1). Before the widespread use of antivirals for prophylaxis of allograft recipients, clinical disease usually developed between 30 and 60 days after transplantation. Prolonged antiviral prophylaxis has greatly reduced the frequency of CMV disease in the early posttransplant period in most SOT and HCST recipients; late manifestations of CMV infection often become apparent after discon tinuation of antiviral prophylaxis. These late manifestations are most worrisome in HSCT recipients, because they may signal deficits in graft function that in turn predispose these patients to invasive CMV infections. Long term graft function has been reported to be influ |
7,781 | enced by CMV infection. This has been most well studied in renal allograft recipients and is thought by many investigators to represent a significant cause of chronic graft dysfunction and eventual loss of the graft. Perhaps the most dramatic impact of CMV infection late in the posttransplant period can be seen in heart transplant recipients, in whom CMV is thought to play a major role in transplant vascular sclerosis, a vasculopathy of the coronary arteries in the allograft lead ing to loss of the transplanted heart allograft. Congenital Infection Congenital infection with CMV can present with clinically apparent (symptomatic) infection (Table 302.2) in about 10 of infected new borns, whereas 90 of infected infants will have no clinical manifes tations of infection in the newborn period (asymptomatic infection) and can be identified only by screening newborns for the presence Table 302.1 Findings in Cytomegalovirus Infections in Solid Organ Transplant Recipients CLINICAL FINDINGS LABORATORY FINDINGS CMV SYNDROME Fever, nonspecific findings, fatigue Leukopenia, thrombocytopenia, reactive lymphocytosis, hepatitis, CMV DNA in blood END ORGAN DISEASE Gastrointestinal disease, including esophagitis, colitis, and hepatitis Detection of CMV DNA in blood; detection of CMV in tissue biopsy; hepatitis, including elevated bilirubin Lung disease; hypoxemia Abnormalities in lung imaging CMV in bronchoalveolar lavage fluid Encephalitis CSF pleocytosis, elevated CSF protein Abnormalities in CNS imaging Allograft dysfunction Evidence of graft rejection Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 302 u Cytomegalovirus 2013 of CMV in saliva, urine, or, less commonly, blood. Severe multior gan disease is infrequent and occurs in approximately 30 of infants with symptomatic congenital CMV infections. The clinical findings in infants with symptomatic congenital CMV infections can include hepatosplenomegaly, petechial rashes, jaundice, and microcephaly. Intrauterine growth restriction is also a finding of symptomatic con genital CMV infection. Laboratory findings are consistent with the clinical findings and include direct hyperbilirubinemia, elevation of hepatic transaminases, thrombocytopenia, and abnormal findings on cranial ultrasonographycomputed tomographyMRI (Fig. 302.1). If cerebrospinal fluid is obtained, there can be evidence of encephali tis, with elevation of mononuclear cell number and, in some cases, elevation of protein. A small number of symptomatically infected infants (10) will have chorioretinitis. Because hearing loss is the most common long term sequela associated with congenital CMV infection, the failure of an infant to pass a newborn hearing screen ing exam should alert caregivers to the possibility of congenital CMV infection. Hearing loss in the older infant and young child should also alert the clinician to the possibility of congenital CMV infec tion, because about 50 of infants with hearing loss associated with congenital CMV infection will pass an initial hearing screening exam but will exhibit hearing loss in later infancy and early childhood. Importantly, hearing loss can be progressive in infants with congeni tal CMV infections and late onset hearing loss andor progression of hearing loss can only be identified |
7,782 | by follow up testing of hearing in congenitally infected infants (see later). Finally, the diagnosis of congenital CMV infection must be made within the first 2 3 weeks of life, and congenital CMV infection cannot be assumed to be the cause of hearing loss in older infants without evidence of CMV infection in the newborn period. An organized plan for follow up is an important component of the clinical management of infants with congenital CMV infection. Because permanent sequelae are limited to disorders of the central nervous system (CNS), long term follow up should include appro priate assessment of development and neuromuscular function in infected infants, with referral to specialized care if necessary. This is particularly important for infected infants who present with evidence of CNS damage such as microcephaly, seizures, or obvious motor defi cits. Overall, about 11 of infected infants will exhibit some degree of hearing loss; hearing loss in some infants will progress during infancy or less frequently, develop later in infancy. Thus comprehensive audi ologic testing and follow up are mandatory in these patients. Other sequelae such as vision loss are infrequent, but vision testing and com prehensive eye examinations should be included in the care plan of infants with congenital CMV infection. Perinatal Infection Perinatal infections can be acquired during birth or following ingestion of CMV containing breast milk. In almost all cases perinatal infections have not been associated with clinical manifestations of the infection and have not been associated with long term sequelae that have been described in infants with congenital CMV infections. In rare cases such as is seen in breast milk transmission of CMV to extremely premature infants or infants born to nonimmune women, perinatal infection can result in severe, disseminated infections associated with end organ dis ease and death. These more severe infections are thought to develop in infants that lack transplacentally acquired antiviral antibodies, either secondary to extreme prematurity or as the product of a mother lack ing anti CMV antibodies. DIAGNOSIS In the nonimmunocompromised individual, diagnosis of CMV infec tion has required evidence of a primary or acute infection. Serologic reactivity for CMV is lifelong following primary infection; therefore the presence of immunoglobulin (Ig) G antibody to CMV does not provide evidence of acute infection unless the absence of CMV specific IgG reactivity in a prior serum specimen can be demon strated, thus providing evidence of IgG seroconversion. In addition, IgM reactivity for CMV can be detected for prolonged periods after acute infection and cannot be used to reliably estimate the duration of a primary infection. Furthermore, recovery of virus from body fluids such as saliva or urine does not in itself permit diagnosis of Table 302.2 Findings in Infants with Symptomatic Congenital Cytomegalovirus Infection FINDINGS OF INFANTS CLINICAL FINDINGS Prematurity (37 wk) 24 Jaundice (direct bilirubin 2 mgdL) 42 Petechiae 54 Hepatosplenomegaly 19 Purpura 3 Microcephaly 35 IUGR 28 1 clinical finding 41 2 clinical findings 59 LABORATORY FINDINGS Elevated ALT (80 IUmL) 71 Thrombocytopenia (100,000 kmm3) 43 |
7,783 | Direct hyperbilirubinemia (2 mgdL) 54 Head CT abnormalities 42 Findings in 70 infants with symptomatic congenital CMV infection identified during newborn screening program for infants with congenital CMV infection at the University of Alabama Hospitals over an approximate 20 yr interval. CMV, Cytomegalovirus; IUGR, in utero growth restriction; ALT, alanine aminotransferase. Fig. 302.1 Cytomegalovirus (CMV). One day old with congenital CMV infection. Noncontrast CT of the head demonstrates multiple ar eas of confluent calcifications within the periventricular regions bilater ally (arrows), typical of the expected distribution of calcification second ary to CMV. Note the abnormal sulcal pattern of the right hemisphere, indicating associated polymicrogyria (arrowheads). (From Rothenberg Maddocks AB, Pollok AN. Infection and inflammation. In: Coley BD, ed. Caffeys Pediatric Diagnostic Imaging, 13th ed. Philadelphia: Elsevier; 2019: Fig. 34.31, p. 342.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2014 Part XV u Infectious Diseases CMV infection, because persistently infected individuals can inter mittently shed virus. In contrast, in the immunocompromised host, CMV can frequently be recovered from patients in the absence of evidence of invasive CMV infection. Thus assignment of CMV as a cause of disease in immunocompromised patients must be made carefully, and other potential causes of symptoms and clinical find ings in these patients must also be considered. Serologic assays are of limited value in the transplant recipient secondary to the impact of immunosuppression on antibody responses in the allograft recipient. Moreover, IgM antibodies can be produced following a nonprimary infection in these patients. Sequential viral load measurements by nucleic acid amplification testing (NAAT) such as polymerase chain reaction (PCR) in relevant body fluids such as blood and detection of CMV DNA in biopsy tissue can be of great value in establishing CMV as a cause of disease in allograft recipients because increasing viral loads can provide evidence of the lack of host control of CMV replication (Table 302.3). Detection of CMV in urine, saliva, blood, and tissue specimens obtained at biopsy can most reliably be accom plished by NAAT, and because findings can be quantified, treatment responses can be monitored. However, conventional culture of CMV using human dermal fibroblasts often combined with immunofluo rescence detection of CMV encoded immediate early antigens also remains standard in many institutions. Histopathologic studies of tissue specimens that permit detection of CMVinfected cells con taining characteristic nuclear inclusions (owlseye inclusions) are relatively insensitive but can aid in the diagnosis of an invasive CMV infection. The addition of immunohistochemistry for the detection of CMV encoded proteins andor in situ hybridization for the detection of CMV nucleic acids has greatly improved the sensitivity of histo logic detection of CMV in tissue andor biopsy specimens (see Table 302.3). In practice, in nonimmunocompromised patients the demonstra tion of CMV specific IgG seroconversion or the presence of CMV specific IgM antibodies is considered evidence of a recently acquired CMV infection. |
7,784 | However, in the case of pregnant women the timing of a primary infection often requires a more precise estimate of when the infection was acquired because CMV infections before conception carry significantly less risk to the developing fetus than infections acquired after conception. Furthermore, as noted in previous sections, maternal infections acquired in the first and early second trimester are more frequently associated with severe intrauterine infections and result in more significant long term sequelae in infants with congenital CMV infections. Because IgM anti CMV antibody reactivity can per sist for months depending on the sensitivity of the particular assay, the use of IgM detection to precisely time the acquisition of CMV is of lim ited value. However, when combined with IgG avidity assays in which CMV specific binding antibodies are eluted with increasing concen trations of chaotropic agents such as urea, IgG serology can provide a more accurate estimate of the duration of infection. Thus the IgG avidity assay has been used almost exclusively in the management of CMV infections during pregnancy to aid in identifying primary mater nal infections in women who present at the first prenatal visits with CMV specific IgM antibodies. The presence of CMV specific IgG anti bodies with high avidity argues for an infection that occurred in the distant past, whereas low avidity CMV specific IgG antibodies argues for a more proximal timing of infection. The presence of anti CMV IgG antibodies with intermediate avidity is considered uninterpretable (see Table 302.3). Congenital Infections The diagnosis of congenital CMV infections requires the recovery of replicating virus andor viral nucleic acids within the first 2 3 weeks of life. Sources of virus and viral nucleic acids include urine, saliva, and blood. Methods of detection include routine virus culture combined with immunofluorescence and NAAT. Although quantification of virus in various specimens can suggest the likelihood of long term sequelae such as hearing loss for a population of infected newborns, the predic tive value for the individual patient remains limited. A considerable amount of effort has been devoted to identifying screening assays that would be suitable for populations of newborn infants. Initial interest centered on dried blood spots, because these samples are routinely col lected as a component of newborn screening programs. Unfortunately, studies have indicated that the sensitivity of detection of congenitally infected infants using dried blood spots is too low to be considered Table 302.3 Laboratory Detection of Cytomegalovirus Infection ASSAY APPLICATION CHARACTERISTICS OF ASSAY TISSUE CULTURE Virus isolation Detection of virus in clinical material Requires prolonged culture periods; low sensitivity compared with molecular techniques; expensive HISTOPATHOLOGY Histopathology Identification of CMV infected cells (owls eye inclusions) Routine for most laboratories; low sensitivity is improved with IHC (see below) Viral antigen detection (immunohistochemistry) Sensitive and allows detection of CMV infected cells in variety of specimens Rapid and can be quantitative MOLECULAR METHODOLOGIES Nucleic acid amplification (NAAT), including quantitative PCR, transcription mediated amplification (TMA) Quantitation of CMV DNA and viral RNA Rapid, sensitive, and quantitative; can be applied |
7,785 | to variety of clinical specimens (blood, saliva, urine, biopsy specimens, etc.) DNARNA in situ hybridization Sensitive detection of CMV DNA or RNA transcripts in tissue specimens Technically more difficult than NAAT, long turnaround times, can identify specific cells infected with CMV SEROLOGIC TESTING CMV specific IgM serology Screening for recent infections Variability in duration of response and low levels of IgM antibodies decrease sensitivity and specificity CMV specific IgG serology Detection of infection with HCMV, useful for seroprevalence studies Rapid, specific, and quantitative; gold standard for CMV infection (acute and past) CMV specific IgG avidity Estimate of duration of HCMV infection Interpretation limited to high and low values of avidity; useful for timing of recent CMV infections in pregnancy; not useful in allograft recipients Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 302 u Cytomegalovirus 2015 useful for screening. In contrast, newborn screening using saliva has proven sensitive and specific and is used for newborn screening in many institutions. The identification of an infected infant by screen ing of saliva requires confirmation, preferably by assaying urine for the presence of CMV. TREATMENT Treatment of immunocompromised hosts with invasive CMV disease limits both the morbidity and the mortality in the patient with dis seminated CMV infections with end organ disease. This has been shown in allograft transplant recipients and patients with HIVAIDS. Similarly, antiviral prophylaxis can limit the development of clinically important CMV disease in allograft recipients and is the standard of care in most transplant centers, with the remaining centers using pre emptive treatment in which antivirals are given once a predetermined level of CMV viremia is detected during routine monitoring in the posttransplant period. Several agents are licensed for CMV infec tions, including ganciclovir, foscarnet, and cidofovir; all have appre ciable toxicity. Letermovir is another agent that has been licensed for use in adults; it is expected that indications for this agent will extend into pediatrics in the future. The antiviral agent, maribavir, has been licensed to treat refractory CMV infections in adult transplant recipi ents. In some transplant centers, high titer CMV immunoglobulins have been included as a component of prophylaxis, most commonly in heart and lung SOT recipients. Early on, when the treatment of CMV infections with antiviral agents was in its infancy, treatment with CMV immunoglobulins was shown to alter the natural history of CMV infection in renal and liver allograft recipients. However, the efficacy of antiviral agents when used as prophylaxis in the immedi ate posttransplant period has resulted in less frequent use of these biologics. Treatment of congenitally infected infants with ganciclovir has been studied in several clinical trials, and a significant number of infected infants with symptomatic congenital CMV infections have been treated off label with this agent. In addition, infants with severe perinatal CMV infection following breast milk ingestion with documented end organ disease have |
7,786 | been successfully treated with ganciclovir. Two studies have suggested that 6 weeks of intra venously administered ganciclovir or 6 months of valganciclovir, an oral preparation of ganciclovir, could limit hearing loss and possi bly improve developmental outcome of infected infants followed for approximately 2 years. In contrast to the apparent efficacy of val ganciclovir treatment in congenitally CMV infected infants in these studies with relatively short term follow up, another study reported that valganciclovir failed to provide evidence of efficacy in altering the long term outcomes of congenitally infected infants when fol lowed over a longer time. Currently, there are no recommendations for the treatment of infants with congenital CMV infection. PREVENTION Passive Immunoprophylaxis Passive transfer of anti CMV antibodies has been used to limit dis ease but not infection in allograft recipients. A similar approach has also been considered for prevention of intrauterine transmission of CMV; disease based on studies from limited observational data sug gests that antiviral antibodies could limit disease following CMV infections in the perinatal period. An uncontrolled trial of human immune globulin provided provocative evidence that passive trans fer of anti CMV antibodies to pregnant women undergoing primary CMV infection could limit intrauterine transmission and disease. A second study using the same immune globulin preparation failed to demonstrate that immune globulins provided protection from intrauterine transmission or disease. Another multicenter trial sponsored by the NIH was terminated secondary to the lack of any efficacy of the treatment. It remains to be determined if passively transferred anti CMV antibodies can modulate infection and dis ease following intrauterine exposure to CMV. Active Immunoprophylaxis Active immunization for the prevention of congenital CMV infec tion (and in transplant recipients) has been a goal of biomedical research for over 3 decades. A number of different vaccine platforms have been explored, including replicating attenuated CMV vaccines, protein based vaccines, heterologous virus vectored CMV vaccines, DNA vaccines, and mRNA based vaccines. In all cases, some level of immunity has been induced by each of these candidate vaccines. Larger scale trials have been carried out using replication compe tent, attenuated CMV vaccines and adjuvanted recombinant protein vaccines. Current approaches are directed toward development of an adequately attenuated replicating CMV strain that retains suffi cient immunogenicity to induce protective responses. In contrast to programs testing candidate attenuated CMV vaccines, considerable progress has been made in the testing of adjuvanted recombinant viral proteins. An adjuvanted recombinant glycoprotein B, a major protein component of the envelope and target of neutralizing anti bodies, has been shown to induce virus neutralizing antibodies and CD4 T lymphocyte proliferative responses. Moreover, this vaccine reduced virus acquisition by about 50 in a trial carried out in young women. Closer examination of this particular trial revealed that pro tection was very short lived and that the effectiveness of the vaccine was not convincingly demonstrated because of the small numbers of subjects in the trial, despite attaining minimal statistical significance. A follow up trial in adolescent women using the same vaccine prepa ration |
7,787 | failed to show any statistically significant difference between vaccine and placebo recipients. A major question that will face all vaccine programs is whether existing immunity in seropositive women can be augmented to a level to prevent damaging infection in their offspring. The maternal population with existing immunity to CMV before childbearing age is responsible for the vast major ity of congenitally infected infants in almost all regions of the world; thus merely recapitulating naturally acquired adaptive immunity to CMV with a vaccine may not be sufficient to prevent congenital CMV infection andor limit disease. Counseling Studies of the natural history of CMV have repeatedly demonstrated that transmission requires repeated close, often direct contact with infected material such as secretions from the oral or genitourinary tract. Although limited data suggest that CMV can be transmitted on fomites, infectivity can persist for hours on surfaces such as toys. Limiting exposure to such secretions and attention to hygiene such as handwashing can drastically limit acquisition of CMV. Coun seling has been shown to be very effective in the prevention of CMV infection in women of childbearing age. In fact, counseling programs have been shown to be more effective in limiting CMV infection during pregnancy than any vaccine that has been tested to date. Sexual transmission is an important route of infection, because CMV is considered to be an STI. Limiting sexual trans mission through education and counseling should be considered in sexually active individuals. The acquisition of CMV by hospital workers and other healthcare providers has been shown to be less than in age matched individuals in the general public. Importantly, these early studies in healthcare workers were carried out before universal precautions that are in place in most hospitals today. Thus patient education with an emphasis on describing the sources of infectious virus in communities and attention to general hygiene could dramatically reduce community acquired CMV, particularly in women of childbearing age. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2016 Part XV u Infectious Diseases Human herpesvirus 6 (HHV 6A and HHV 6B) and human herpesvi rus 7 (HHV 7) cause ubiquitous infection in infancy and early child hood. HHV 6B is responsible for the majority of cases of roseola infantum (exanthem subitum or sixth disease) and is associated with other diseases, including encephalitis, especially in immunocompro mised hosts. A small percentage of children with roseola have primary infection with HHV 7. ETIOLOGY HHV 6A, HHV 6B, and HHV 7 are the sole members of the Roseo lovirus genus in the Betaherpesvirinae subfamily of human herpesvi ruses. Human cytomegalovirus, the only other herpesvirus, shares limited sequence homology with HHV 6 and HHV 7. Morphologically all human herpesviruses are composed of an icosahedral nucleocapsid, protein dense tegument, and lipid envelope. Within the nucleocapsid, HHV 6 and HHV 7 both |
7,788 | contain large, linear, double stranded DNA genomes that encode more than 80 unique proteins. Initially, two strain groups of HHV 6 were recognized: HHV 6 vari ant A and HHV 6 variant B. Despite sharing highly conserved genomes with approximately 90 sequence identity, the two variants could be distinguished by restriction fragment length polymorphisms, reactiv ity with monoclonal antibodies, differential cell tropism, and epidemi ology. Because of these differences, the two were reclassified as separate species in the genus Roseolovirus by the International Committee on the Taxonomy of Viruses in 2012. HHV 6A detection is quite rare, and HHV 6B is the overwhelmingly predominant virus found in both immunocompetent and immunocompromised hosts. Previous reports of HHV 6A detection in children in Africa have not been substantiated in a large cohort using a more specific PCR target. EPIDEMIOLOGY Primary infection with HHV 6B is acquired rapidly by essentially all children after the loss of maternal antibodies in the first few months of infancy, with 95 of children being infected by 2 years of age. The peak age of primary HHV 6B infection is 6 9 months of life, with infections occurring sporadically and without seasonal predilection or contact with other ill individuals. Infection with HHV 7 is also widespread but occurs later in childhood and at a slower rate; only 50 of children have evidence of prior infection with HHV 7 by 3 years of age. Sero prevalence reaches 75 by 6 years of age. In a small study of children with primary HHV 7 infection, the mean age of the patients was 26 months, significantly older than that of children with primary HHV 6 infection. Preliminary data suggest that the majority of children acquire pri mary infection with HHV 6 from the saliva or respiratory droplets of asymptomatic adults or older children. However, congenital infection with HHV 6 occurs in 1 of newborns. Two mechanisms of vertical transmission of HHV 6 have been identified: transplacental infection and chromosomal integration. HHV 6 is unique among the human her pesviruses in that it is integrated at the telomere end of human chromo somes at a frequency of 0.22.2 of the population and is passed from parent to child via the germline. Chromosomal integration of HHV 7 has been suggested in only a single case report thus far. Chromosomal integration has been identified as the major mechanism by which HHV 6 is vertically transmitted, accounting for 86 of congenital infections, with one third resulting from HHV 6A, a percentage much higher than in primary infection in the United States. The clinical con sequences of chromosomal integration or transplacental infection with HHV 6 have yet to be determined. In one series of infants identified with HHV 6 congenital infection, no evidence of disease was present in the early neonatal period. However, reactivation of chromosomally integrated HHV 6 virus has been demonstrated following hematopoi etic stem cell transplantation (HSCT). Primary infection with HHV 7 is presumed to be spread by the saliva of asymptomatic individuals. |
7,789 | DNA of both HHV 6 and HHV 7 has been identified in the cervical secretions of pregnant women, suggesting an additional role for sexual or perinatal transmission of these viruses. Breast milk does not appear to play a role in transmission of either HHV 6 or HHV 7. PATHOLOGY AND PATHOGENESIS Primary HHV 6B infection causes a viremia that can be demon strated by co culture of the patients peripheral blood mononuclear cells with mitogen stimulated cord blood mononuclear cells. HHV 6 has a recognizable cytopathic effect, consisting of the appearance of large refractile mononucleated or multinucleated cells with intracyto plasmic andor intranuclear inclusions. Infected cells exhibit a slightly prolonged life span in culture; however, lytic infection predominates. HHV 6 infection also induces apoptosis of T cells. In vitro, HHV 6 can infect a broad range of cell types, including primary T cells, monocytes, natural killer cells, dendritic cells, and astrocytes. HHV 6 has also been documented to infect B cell, megakaryocytic, endothelial, and epithe lial cell lines. Human astrocytes, oligodendrocytes, and microglia have been infected with HHV 6 ex vivo. The broad tropism of HHV 6 is consistent with the recognition that CD46, present on the surface of all nucleated cells, is a cellular receptor for HHV 6, HHV 6A in particular. CD134, a member of the TNFR superfamily, is the main entry receptor for HHV 6B and may explain some of the differences in tissue tropism noted between HHV 6A and HHV 6B. The CD4 molecule has been identified as a receptor for HHV 7. HHV 7 has been demonstrated to reactivate HHV 6 from latency in vitro, but whether this phenomenon occurs in vivo is not clear. Primary infection with HHV 6 and HHV 7 is followed by lifelong latency or persistence of virus at multiple sites. HHV 6 exists in a true state of viral latency in monocytes and macrophages. The detection of replicating HHV 6 in cultures of primary CD34 hematopoietic stem cells has also been described, suggesting that cellular differentiation is a trigger of viral reactivation. This observation is clinically significant because HHV 6 may cause either primary or reactivated infection dur ing HSCT. Additionally, HHV 6 and HHV 7 infection may be persis tent in salivary glands, and DNA of both HHV 6 and HHV 7 can be routinely detected in the saliva of both adults and children. HHV 7 can also be isolated in tissue culture from saliva, but HHV 6 cannot. HHV 6 DNA has been identified in the cerebrospinal fluid (CSF) of children, both during and subsequent to primary infection, as well as in brain tissue from immunocompetent adults at autopsy, implicating the central nervous system (CNS) as an additional important site of either viral latency or persistence. HHV 7 DNA has also been found in adult brain tissue but at a significantly lower frequency. CLINICAL MANIFESTATIONS Roseola infantum (exanthem subitum, or sixth disease) is an acute, self limited disease of infancy and early childhood. It is characterized by the |
7,790 | abrupt onset of high fever, which may be accompanied by fussi ness. The fever usually resolves acutely after 72 hours (crisis) but may gradually fade over a day (lysis) coincident with the appearance of a faint pink or rose colored, nonpruritic, 2 to 3 mm morbilliform rash on the trunk (Fig. 303.1). The rash usually lasts 1 3 days but is often described as evanescent and may be visible only for hours, spreading from the trunk to the face and extremities. Because the rash is vari able in appearance, location, and duration, it is not distinctive and may be missed. Associated signs are few but can include mild injection of the pharynx, palpebral conjunctivae, or tympanic membranes and Chapter 303 Roseola (Human Herpesviruses 6 and 7) Brenda L. Tesini Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 303 u Roseola (Human Herpesviruses 6 and 7) 2017 enlarged suboccipital nodes. In Asian countries, ulcers at the uvulo palatoglossal junction (Nagayama spots) are commonly reported in infants with roseola. High fever (mean: 39.7C 103.5F) is the most consistent find ing associated with primary HHV 6B infection. Rash detected either during the illness or following defervescence has been reported in approximately 20 of infected children in the United States. Additional symptoms and signs include irritability, inflamed tympanic membranes, rhinorrhea and congestion, gastrointestinal complaints, and encephalopathy. Symptoms of lower respiratory tract involvement such as cough are identified significantly less fre quently in children with primary HHV 6B infection than in children with other febrile illnesses. The mean duration of illness caused by primary HHV 6B infection is 6 days, with 15 of children having fever for 6 or more days. Primary infection with HHV 6B accounts for a significant burden of illness on the healthcare system; one study found that 24 of visits to emergency departments by infants between 6 and 9 months of age were because of primary HHV 6B infection. A population based study of primary HHV 6B infection confirmed that 93 of infants had symptoms and were more likely to visit a physician than noninfected infants. Fever was less likely to be present with HHV 6B infection in children younger than 6 months of age but was significantly more common in older infants and children. Much less is known about the clinical manifestations of HHV 7 infection. Primary infection with HHV 7 has been identified in a small number of children with roseola in whom the illness is indistinguish able from that caused by HHV 6B. Secondary cases of roseola caused by infection with HHV 7 have also been reported. Additionally, pri mary infection with HHV 7 may be asymptomatic or may cause a non specific febrile illness lasting approximately 3 days. LABORATORY FINDINGS The most characteristic laboratory findings noted in children with pri mary HHV 6B infection are lower mean numbers of total |
7,791 | white blood cells (8,900L), lymphocytes (3,400L), and neutrophils (4,500L) than in febrile children without primary HHV 6B infection. Similar hematologic findings have been reported during primary infection with HHV 7. Thrombocytopenia, elevated serum transaminase values, and atypical lymphocytes have also been noted sporadically in children with primary HHV 6B infection. Results of CSF analyses reported in patients with encephalitis thought to be caused by HHV 6 have been normal or demonstrated only minimal CSF pleocytosis with mild elevations of protein, espe cially early in the course of the disease, which may progress with time. Areas of hyperintense signal on T2 weighted and fluid attenu ation inversion recovery images of the hippocampus, uncus, and amygdala have been found on MRI, and increased metabolism within the hippocampus has been observed on positron emission tomogra phy scanning. DIAGNOSIS Although roseola is generally a benign self limited disease, its diagnosis can exclude other, more serious disorders that cause fever and rash. A history of 3 days of high fever in an otherwise nontoxic 10 month old infant with a blanching maculopapular rash on the trunk suggests a diagnosis of roseola. A specific diagnosis of HHV 6 is not usually necessary except in situations in which the manifestations of the infection are severe or unusual and might benefit from antiviral therapy. The diagnosis of primary infection with either HHV 6 or HHV 7 is confirmed by demonstrating the presence of actively replicating virus in the patients blood sample coupled with seroconversion. Viral culture is the gold standard method to document active viral replication. Unfortunately, culture is expensive, time consuming, and available only in research laboratories. Two other methods used to identify active HHV 6 replication are the detection of viral DNA by PCR on acellular fluids such as plasma or reverse transcriptase PCR on peripheral blood mononuclear cell samples designed to detect viral transcription and protein production. Quantitative PCR for HHV 6 genome copy numbers on various specimens is also frequently reported and is commercially available. However, the role of this methodology is not clear, as a specific value of DNA that can discriminate between patients with viremia and those who are culture negative has not been determined. Complicating the use of molecular assays for the detec tion of active replication of HHV 6 is the recognition that individuals with chromosomally integrated HHV 6 have persistent HHV 6 DNA in plasma, peripheral blood mononuclear cells, and CSF in the absence of disease and replicating virus. Serologic methods such as indirect immunofluorescence assays, enzyme linked immunosorbent assays, neutralization assays, and immunoblot have been described for the measurement of concentra tions of antibodies to HHV 6 and HHV 7 in serum or plasma and are commercially available. Although immunoglobulin M antibody is produced early in infection with HHV 6, assays designed to measure this response have not proved useful in the diagnosis of primary or reactivated infection. The absence of immunoglobulin G antibody in an infant older than 6 months of age combined with the presence of |
7,792 | replicating virus is strong evidence of primary infection with either HHV 6 or HHV 7. Alternatively, the demonstration of seroconver sion between acute and convalescent samples also confirms primary infection but is not clinically useful in the acute care setting. Unfortu nately, serologic assays have not been found reliable in the detection of HHV 6 reactivation and cannot be used to differentiate between infec tion with HHV 6A and infection with HHV 6B. Additionally, limited antibody cross reactivity has been demonstrated between HHV 6 and HHV 7, complicating the interpretation of serologic assays, especially if low titers are reported. Differential Diagnosis Primary infection with either HHV 6B or HHV 7 usually causes an undifferentiated febrile illness that may be very difficult to dis tinguish from other common viral infections of childhood. This difficulty also applies to the early stages of roseola, before the devel opment of rash. Once the rash is present, roseola may be confused with other exanthematous diseases of childhood, especially measles and rubella. Children with rubella often have a prodrome charac terized by mild illness with low grade fever, sore throat, arthralgia, A B Fig. 303.1 Roseola infantum. A, Erythematous, blanching macules and papules in an infant who had high fever for 3 days preceding de velopment of the rash. B, On closer inspection some lesions reveal a subtle peripheral halo of vasoconstriction. (From Paller AS, Mancinin AJ, eds. Hurwitz Clinical Pediatric Dermatology, 3rd ed. Philadelphia: Elsevier; 2006: p. 434) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2018 Part XV u Infectious Diseases and gastrointestinal complaints, unlike those with roseola. On physi cal examination, suboccipital and posterior auricular lymph nodes are prominent up to 1 week before the rash of rubella is evident and persist during the exanthematous phase. Additionally, the rash of rubella usually begins on the face and spreads to the chest, like that in measles. The associated symptoms of measles virus infection include cough, coryza, and conjunctivitis, with high fever coincident with the development of rash, unlike in roseola. Roseola may also be confused with scarlet fever, though the latter is rare in children younger than 2 years of age and causes a characteristic sandpaper like rash concur rent with fever. Roseola may be confused with illness caused by enterovirus infections, especially in the summer and fall months. Drug hyper sensitivity reactions may also be difficult to distinguish from roseola. Antibiotics are frequently prescribed for children with fever from roseola before the appearance of rash. A child who then demonstrates rash after the resolution of fever may erroneously be labeled as being drug allergic. COMPLICATIONS Convulsions are the most common complication of roseola and are recognized in up to one third of patients. Seizures are also the most common complication of children with documented primary HHV 6B infection, occurring in approximately 15, with a peak age of |
7,793 | 12 15 months. Children with primary HHV 6B infection are also reported to have a higher frequency of partial seizures, prolonged seizures, postictal paralysis, and repeated seizures than are children with febrile seizures not associated with HHV 6. In a study limited to children with primary HHV 6B infection and seizures, 30 of patients had prolonged seizures, 29 had focal seizures, and 38 had repeated seizures. A prospective study of children 2 35 months of age with suspected encephalitis or severe febrile illness with convulsions found that 17 had primary infection with either HHV 6 or HHV 7, and status epilepticus was the most common presentation. Among children with febrile status epilepticus (FSE), primary or reactivated infection with HHV 6B or HHV 7 has been identified in approxi mately one third. An association between recurrent seizures and reactivated or per sistent infection of the CNS by HHV 6 has also been suggested. Stud ies evaluating brain tissue specimens implicate HHV 6 in as many as 60 of patients with temporal lobe epilepsy (TLE), high viral loads being found in the hippocampus or lateral temporal lobe regions. HHV 6 is postulated to induce neuroinflammation and potential injury via innate and adaptive immune system activation as a result of the broad tissue tropism of the virus. Subsequent neuronal hyper excitability through the loss of glutamate regulatory control and increased blood brain barrier permeability have been proposed as possible mechanisms for the development of recurrent seizures based on animal models and clinical data of patients with TLE and HHV 6 DNA detected in CNS specimens. Contrary to these findings, limited clinical data suggest that there may be a decreased risk of recurrent seizures after primary infection with HHV 6 and febrile seizures than of febrile seizures from other causes. Additionally, children with FSE associated with HHV 6B and HHV 7 had similar seizure character istics and a similar proportion of electroencephalography and MRI hippocampal abnormalities as children with FSE not associated with HHV 6B or HHV 7, suggesting a shared pathogenesis to other etiolo gies of FSE. Case reports and small patient series have described additional complications in children with primary HHV 6B infection, including encephalitis, acute disseminated demyelination, autoimmune enceph alitis, acute cerebellitis, hepatitis, and myocarditis. Late developing long term sequelae, including developmental disabilities and autistic like features, are reported rarely in children who have CNS symptoms during primary HHV 6B infection. Reactivation of HHV 6 has been reported in several different popu lations with and without disease with the use of various methods of detection. The best documentation of HHV 6 reactivation has been in immunocompromised hosts, especially those patients who have under gone HSCT. Such reactivation occurs in approximately 50 of patients, typically at 2 4 weeks after transplantation, and the risk of reactiva tion is associated with a lack of donor derived HHV 6specific T cell immunity. Many of the clinical complications seen following HSCT have been associated with HHV 6B reactivation, including fever, rash, delayed engraftment of platelets |
7,794 | or monocytes, and graft versus host disease, with variable degrees of support in the literature for each. HHV 6 reactivation has been associated with worse overall survival compared with HSCT recipients who did not experience reactivation. HHV 6B reactivation has also been reported as a cause of encephali tis in both immunocompetent and immunocompromised hosts. A dis tinct syndrome of posttransplant acute limbic encephalitis (PALE) has been described primarily in patients following HSCT, especially cord blood stem cell transplantation; it is characterized by short term memory dysfunction, confusion, and insomnia, with seizures noted either clinically or on prolonged electroencephalography monitoring. HHV 6B DNA has been identified in the CSF in the majority of these patients, with additional evidence of reactivation by detection of HHV 6B DNA in plasma. HHV 6 proteins were identified in the astrocytes of the hippocampus in one postmortem specimen, consistent with active HHV 6B infection at the time of death. The development of PALE is associated with increased mortality and long term neurocognitive sequelae. TREATMENT Supportive care is usually all that is needed for infants with rose ola. Parents should be advised to maintain hydration and may use antipyretics if the child is especially uncomfortable with the fever. Specific antiviral therapy is not recommended for routine cases of primary HHV 6B or HHV 7 infection. Unusual or severe manifes tations of primary or presumed reactivated HHV 6B infection such as encephalitisPALE, especially in immunocompromised patients, may benefit from treatment. Ganciclovir, foscarnet, and cidofovir all demonstrate inhibitory activity against HHV 6 in vitro, simi lar to their activity against cytomegalovirus. Case reports suggest that all three drugs, alone or in combination, can decrease HHV 6 viral replication, as evidenced by decreased viral loads in plasma and CSF. However, clinical data regarding efficacy are sparse and contradictory, with no randomized trials to guide use. Additionally, in vitro resistance of HHV 6 to all three drugs has been described. Despite these drawbacks, treatment with ganciclovir or foscarnet as first line agents has been recommended for a minimum of 3 weeks in patients with PALE. Foscarnet appears to be most likely to have activity against HHV 7 on the basis of in vitro testing, but no clini cal data are available. PROGNOSIS Roseola is generally a self limited illness associated with complete recovery. The majority of children with primary infections with HHV 6B and HHV 7 also recover uneventfully without sequelae. Although seizures are a common complication of primary infection with HHV 6B and HHV 7, the risk of recurrent seizures does not appear to be higher than that associated with other causes of simple febrile seizures. PREVENTION Primary infections with HHV 6 and HHV 7 are widespread through out the human population with no current means of interrupting transmission. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights |
7,795 | reserved. Chapter 304 u Human Herpesvirus 8 2019 Human herpesvirus 8 (HHV 8) is an oncogenic virus identified in tis sue specimens from patients with Kaposi sarcoma (KS). Because of this association, it is also known as Kaposi sarcomaassociated herpesvi rus. HHV 8 is the etiologic agent of two additional lymphoproliferative disorders: primary effusionbased lymphoma (PEL) and multicen tric Castleman disease (MCD). ETIOLOGY HHV 8 is a 2 human herpesvirus similar to Epstein Barr virus. The virus contains a large DNA genome encoding 85 95 unique pro teins. Infection is followed by both lytic and latent viral states, with different degrees of viral replication associated with distinct disease manifestations. EPIDEMIOLOGY The prevalence of infection with HHV 8 varies both geographically and by population and roughly matches the epidemiology of KS. HHV 8 infection is endemic in Africa and parts of South America, with infec tion rates of up to 3060 by adolescence. Seroprevalence 20 has also been found in regions bordering the Mediterranean. In contrast, infection rates 5 are noted in North America, Central Europe, and Asia. However, within geographic regions, the prevalence of infection varies with risk behaviors, with rates of 3075 being found among men who have sex with men in North America and Europe. HHV 8 DNA can be detected in saliva, blood, semen, and tissues. Based on large scale epidemiologic studies and the high prevalence of viral shed ding in oral secretions, saliva is believed to be the major mode of trans mission. Other less common routes of HHV 8 transmission include blood transfusion, bone marrow transplantation, and solid organ transplantation. Vertical transmission and transmission via breast milk may occur in regions where HHV 8 is highly endemic, but the risk appears low. PATHOLOGY AND PATHOGENESIS HHV 8 contains multiple genes that affect cell cycle regulation and the host immune response. Viral proteins interfere with the func tion of the tumor suppressor molecules, induce the expression of proangiogenesis factors, and lead to upregulation of the rapamycin pathway target, which is instrumental in the control of cell growth and metabolism. HHV 8 also encodes a homolog of human inter leukin 6, which can bind and activate cytokine receptors and serve as a host cell autocrine growth factor. Additionally, viral proteins are associated with the constitutive expression of the transcription factor nuclear factor B. All of these proteins may be potential targets for therapeutic intervention. CLINICAL MANIFESTATIONS Although subclinical infection appears to be common, symptomatic primary HHV 8 infection has been described in immunocompetent children. Patients commonly have fever and a maculopapular rash or a mononucleosis like syndrome, with full recovery the rule. In immu nocompromised patients, primary infection has been associated with fever, rash, splenomegaly, pancytopenia, and lymphoid hyperplasia and may be quite severe. Additionally, preliminary data suggest that transfusion associated primary infection with HHV 8 is associated with an increased risk of mortality. Even in regions with high rates of seroprevalence, the develop ment of KS is uncommon. KS has several different clinical forms; each includes |
7,796 | multifocal, angiogenic lesions arising from vascular endothelial cells infected with HHV 8. Classic KS is an indolent disorder seen in elderly men with limited involvement of the skin of the lower extremities. Endemic KS is more aggressive, occurring in children and young people, primarily in Africa, and can include visceral involvement as well as widespread cutaneous lesions (patches, plaques, or nodules). Posttransplantation KS and AIDS related KS are the most severe forms, with disseminated lesions, often in the gastrointestinal tract and lungs, with or without cuta neous findings. Primary effusionbased lymphoma is a rare disease caused by HHV 8 that is seen most commonly in HIV infected individuals. It consists of lymphomatous invasion of the serosal surfaces of the pleura, pericardium, and peritoneum. Similarly, multicentric Castleman disease is an unusual lymphoproliferative disorder characterized by anemia, thrombocytopenia, generalized lymphadenopathy, and consti tutional symptoms and is frequently associated with HHV 8 infection and a high degree of viral replication. DIAGNOSIS Serologic assays, including immunofluorescence and enzyme linked immunosorbent assays, are the primary methods of diagnosing infection with HHV 8. However, testing has limited sensitivity, specificity, and reproducibility and is primarily a research tool with no universally recognized standard assays. Additionally, the loss of antibodies over time, referred to as seroreversion, has been described, further complicating serodiagnosis. Immunohistochemis try and molecular methods are available for the detection of HHV 8 in tissue samples and are used in the diagnosis of KS, PEL, and MCD, alongside their disease specific clinical manifestations. Nucleic acid testing of blood and other body fluids is also available but has a limited diagnostic role. TREATMENT Treatment for KS, PEL, and MCD is multifaceted and includes attempts to control malignant proliferations with traditional chemotherapeutic regimens and biologic agents as well as agents aimed at specific cel lular pathways targeted by HHV 8 proteins. Combined antiretrovi ral therapy (ART) is a mainstay of both prevention and therapy for HHV 8related disease in HIV infected patients. In HIV associated KS, treatment with ART alone is often used for the control of mild (i.e., cutaneous) disease, whereas ART plus chemotherapy is used for more severe disease. In transplantation associated KS, the first line of treat ment includes decreasing immunosuppression, often in association with a switch from calcineurin inhibitors to sirolimus (rapamycin) to block the mammalian target of rapamycin pathway. Severe disease fre quently requires the use of traditional chemotherapy as well. The role of specific antiherpesvirus antiviral treatment is unclear. Valganciclovir and ganciclovir treatment have been associated with decreased viral replication and rates of development of KS in HIV infected individu als. However, results of using antivirals in the treatment of established disease have been generally disappointing. The prognosis for PEL tends to be poor despite the use of traditional chemotherapy, whereas ritux imab (anti CD20)based therapy has been highly successful for MCD treatment. However, relapse and the development of lymphoma after treatment can still occur. Rituximab treatment may also worsen con current KS without additional agents. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for |
7,797 | Bibliography. Chapter 304 Human Herpesvirus 8 Brenda L. Tesini Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2020 Part XV u Infectious Diseases Influenza viral infections cause a broad array of respiratory illnesses that are responsible for significant morbidity and mortality in children dur ing seasonal epidemics. Influenza A viruses also have the potential to cause global pandemics, which can happen when a new (novel) influ enza A virus emerges and transmits efficiently from person to person. ETIOLOGY Influenza viruses are large, single stranded RNA viruses belonging to the family Orthomyxoviridae, which includes three genera (or types): A, B, and C. Influenza A and B viruses are the primary human patho gens causing seasonal epidemics, whereas influenza virus type C is a sporadic cause of predominantly mild upper respiratory tract illness. Influenza A viruses are further divided into subtypes based on two sur face proteins that project as spikes from the lipid envelope, the hem agglutinin (HA) and neuraminidase (NA) proteins (Fig. 305.1). Strain variants are identified by antigenic differences in their HA and NA and are designated by the geographic area from which they were originally isolated, isolate number, and year of isolationfor example, influenza AVictoria3612011(H3N2). The HA and NA antigens from influenza B and C viruses do not receive subtype designations, because there is less variation among influenza B and C antigens. However, influenza B viruses can be further broken down into lineages, with recent examples including the BYamagata and BVictoria lineages. EPIDEMIOLOGY Influenza has generally been thought to be transmitted primarily via respiratory droplets, but transmission through contact with secre tions and small particle aerosols may also occur. The typical incuba tion period ranges from 1 to 4 days, with an average of 2 days. Healthy adults are generally considered potentially infectious from a day before symptoms develop until 5 7 days after becoming ill. Children with pri mary influenza infection have higher influenza viral loads and more prolonged viral shedding than adults; therefore children may be able to infect others for a longer time. Influenza outbreaks occur commonly in schools and childcare settings. Healthcare associated influenza infec tions can also occur in healthcare settings, and outbreaks in long term care facilities and hospitals may cause significant morbidity. In the United States, seasonal influenza viruses can be detected year round, but circulating viruses are most common during the fall and winter. Transmission through a community is rapid, with the highest incidence of illness occurring within 2 3 weeks of introduction. Antigenic Variation Influenza A and B viruses contain a genome consisting of 8 single stranded RNA segments. Minor changes within a subtype continually occur through point mutations during viral replication, particularly in the HA gene, and result in new influenza strains of the same HA type. This phenomenon, termed antigenic drift, occurs in both influenza A and B viruses. Variation in |
7,798 | antigenic composition of influenza virus surface proteins occurs almost yearly, which confers a selective advan tage to a new strain and contributes to annual epidemics. For this rea son, the formulation of the influenza vaccine is reviewed each year and updated as needed. Less frequent but more dramatic major changes in virus subtype can occur, resulting in a new influenza A subtype to which most people have little to no immunity. This process is called antigenic shift and can occur through reassortment of viral gene segments when there is simultaneous infection by more than one strain of influenza in a single host, or by direct adaptation of an animal virus to a human host. Anti genic shift occurs in influenza A viruses, which have multiple avian and mammalian hosts acting as reservoirs for diverse strains. Through the process of reassortment, potentially any of 18 HA and 11 NA proteins currently known to reside in influenza A viruses of nonhuman hosts could be introduced into humans, who may have little existing immunologic cross protection to emerging viruses. A global pandemic can result if an influenza A virus with a novel HA or NA enters a nonimmune human population and acquires the capac ity for sustained and efficient transmission between people. Four major global pandemics have occurred since 1900: in 1918 caused by an influenza A(H1N1) virus, 1957 caused by an influenza A(H2N2) virus, 1968 caused by an influenza A(H3N2) virus, and 2009 caused by an influenza A virus designated A(H1N1)pdm09. The most severe influenza pandemic in recorded history occurred in 1918, when the virus was estimated to have killed at least 50 million people. The 1918 pandemic virus was likely the result of direct adaptation of an avian influenza virus to the human host, rather than from reassortment. The 2009 pandemic virus stemmed from reassortment of genes from swine, avian, and human viruses (Fig. 305.2). This resulted in the emergence of a novel influenza A(H1N1)pdm09 virus that spread quickly from North America across the globe and replaced the previously circulating seasonal H1N1 viruses. Several novel influenza viruses, all originating in animals, have also caused outbreaks of human infections. Avian influenza A(H5N1), a virulent avian influenza virus that was first identified in 1997, has caused more than 880 documented cases in 19 countries, with a mor tality rate over 50. A novel avian influenza A(H5N6) with a case fatal ity rate of 40, emerged in China in 2014, causing infection in at least Chapter 305 Influenza Viruses Flor M. Munoz Hemagglutinin Neuraminidase M2 ion channel RNP Fig. 305.1 Graphical representation of influenza virus. The key at bottom identifies the surface protein constituents: the hemagglutinin, neuraminidase, matrix protein 2 (M2) ion channel, and ribonucleopro tein (RNP). (From Centers for Disease Control and Prevention Public Health Image Library, Image ID11822. https:phil.cdc.govDetails.as px?pid11822; courtesy CDCDouglas Jordan and Dan Higgins, 2009.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses |
7,799 | without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 305 u Influenza Viruses 2021 60 people. Another avian influenza, A(H7N9) virus, has caused more than 1,500 documented cases and is also highly virulent. This virus first caused an outbreak of human infections in China during the spring of 2013, with annual epidemics in China occurring in subsequent years. During the first four yearly epidemics, infection was fatal in approxi mately 40 of documented cases. In addition, novel influenza A variant viruses have caused human infections (Table 305.1). These include H3N2v viruses, which caused 372 confirmed human infections in the United States from 2011 to 2016 and were primarily transmitted through swine contact at agri cultural fairs. Influenza viruses that normally circulate in swine are designated variant (v) viruses when detected in humans, and H3N2v and other variant viruses, including H1N1v and H1N2v, continue to be detected and sporadically infect humans with prolonged exposure to infected pigs. In contrast to avian influenza A(H5N1), A(H5N6), and A(H7N9) viruses, variant viruses generally cause mild illness and have been primarily detected in children. However, none of these viruses has exhibited sustained, efficient human to human transmission. Seasonal Influenza An estimated 11,000 45,000 children younger than 18 years of age are hospitalized annually in the United States as a result of seasonal influenza associated complications, with approximately 6,000 26,000 hospitalizations in children younger than 5 years of age. Since 2004, the annual number of reported influenza associated pediatric deaths in the United States has ranged from 37 to 199 during regular influ enza seasons (358 were reported to have occurred during the 2009 H1N1 pandemic). Influenza disproportionately affects children with specific chronic conditions, such as underlying pulmonary, cardiac, or neurologic and neuromuscular disorders. Very young children, especially those younger than 2 years of age, and children with chronic medical conditions are more likely to develop severe influenza related complications, including viral and bacterial pneumonia, hospitaliza tion, respiratory failure, and death. However, although children with underlying medical conditions are at higher risk of complications, many healthy children are hospitalized with influenza, and nearly half of pediatric influenza associated deaths are in children that have no known underlying medical condition. Influenza also causes a substantial burden of disease in outpatient settings. It contributes to an estimated 600,000 to 2,500,000 outpatient medical visits annually in children younger than 5 years of age and has been identified in 1025 of outpatient visits among all children with respiratory symptoms during influenza season. Influenza may also be underdiagnosed. Many who seek medical care for influenza do not have laboratory testing performed and do not receive a diagno sis of influenza. Every year, three or four influenza virus types or sub types typically co circulate, including influenza A(H3N2), influenza A(H1N1), and two types of B viruses. Although one subtype usually predominates in any given season, it is difficult to predict which will be predominant. Thus the influenza vaccine varies annually and contains three or four antigens representing the expected circulating types. |
7,800 | PATHOGENESIS Influenza viruses infect the respiratory tract epithelium, primarily the ciliated columnar epithelial cells, by using the HA to attach to sialic acid residues. After viral entry into cells, virus replication occurs usually within 4 6 hours, and new virus particles are assembled and released to infect neighboring cells. With primary infection, virus replication continues for 10 14 days. Influenza virus causes a lytic infection of the respiratory epithelium with loss of ciliary function, decreased mucus Fig. 305.2 Host and lineage origins for the gene seg ments of the 2009 A(H1N1) virus. HA, Hemagglutinin; M, matrix gene; NA, neuraminidase; NP, nucleoprotein; NS, nonstructural gene; PA, polymerase acidic; PB1, poly merase basic 1; PB2, polymerase basic 2. Color of gene segment in circle indicates host. (From Garten RJ, Davis CT, Russell CA, et al. Antigenic and genetic character istics of swine origin 2009 A(H1N1) influenza viruses cir culating in humans. Science. 2009;3255937:197201.) Gene segments, hosts, and years of introduction Triple reassortant Classical swine Eurasian swine PB2, PA PB2, PA PB1 PB1 HA, NP, NS NA, M HA, NP, NS 2009 A(H1N1) PB2 PB1 PA HA NP NA M NS NA, M PB1 1998 1968 1998 1918 1979 Table 305.1 Subtypes of Novel Influenza A Viruses and Clinical Syndromes in Human Infections LPAI VIRUSES HPAI VIRUSES VARIANT VIRUSES Conjunctivitis H7N2, H7N3, H7N7, H10N7 H7N3, H7N7 H1N1v, H3N2v Upper respiratory tract illness H6N1, H7N2, H7N3, H7N9, H9N2, H10N7 H5N1, H5N6, H7N7 H1N1v, H1N2v, H3N2v Lower respiratory tract disease, pneumonia H7N2, H7N9, H9N2, H10N8 H5N1, H5N6, H7N7, H7N9 H1N1v, H3N2v Respiratory failure, acute respiratory distress syndrome H7N9, H10N8 H5N1, H5N6, H7N7, H7N9 H1N1v, H3N2v Multiorgan failure H7N9, H10N8 H5N1, H5N6, H7N7, H7N9 Encephalopathy or encephalitis H7N9 H5N1 Fatal outcomes H7N9, H9N2, H10N8 H5N1, H5N6, H7N7, H7N9 H1N1v, H3N2v Variant viruses of swine origin. High mortality in reported cases: about 40 for LPAI H7N9, about 50 for HPAI H5N1, and about 70 for HPAI H5N6. HPAI, Highly pathogenic avian influenza; LPAI, low pathogenic avian influenza. From Uyeki TM, Katz JM, Jernigan DB. Novel influenza A viruses and pandemic threats. Lancet. 2017;389:21722174. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2022 Part XV u Infectious Diseases production, and desquamation of the epithelial layer. These changes permit secondary bacterial invasion, either directly through the epithe lium or, in the case of the middle ear space, through obstruction of the normal drainage through the eustachian tube. The exact immune mechanisms involved in termination of primary infection and protection against reinfection are complex. Induction of cytokines that inhibit viral replication, such as interferon and tumor necrosis factor, as well as other host defenses, such as cell mediated immune responses and local and humoral antibody defenses, all likely play a role. Secretory immunoglobulin A antibodies produced by the respiratory mucosa are thought to be an effective and immediate response generated during influenza infection. Serum |
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