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7,901 | and febrile convulsions are the most frequent com plications in infants and young children. Epistaxis, petechiae, and purpuric lesions are uncommon but may occur at any stage. Blood from epistaxis that is swallowed, vomited, or passed by rectum may be erroneously interpreted as gastrointestinal bleeding. In adults and possibly in children, underlying conditions may lead to clini cally significant bleeding. Convulsions may occur during a high temperature. Infrequently, after the febrile stage, prolonged asthe nia, mental depression, bradycardia, and ventricular extrasystoles may occur in children. In endemic areas, dengue hemorrhagic fever should be suspected in children with a febrile illness suggestive of dengue fever who experi ence hemoconcentration and thrombocytopenia. PROGNOSIS Dengue Fever The prognosis for dengue fever is good. Care should be taken to avoid the use of drugs that suppress platelet activity. Dengue Hemorrhagic Fever The prognosis of dengue hemorrhagic fever is adversely affected by a late diagnosis and delayed or improper treatment. Death has occurred in 4050 of patients with shock, but with adequate inten sive care, deaths should occur in 1 of cases. Infrequently, there 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 316 u Yellow Fever 2071 is residual brain damage as a consequence of prolonged shock or occasionally of intracranial hemorrhage. Many fatalities are caused by overhydration. PREVENTION Dengue vaccines have been under development continuously since the 1970s. One such vaccine, Dengvaxia, developed by Sanofi Pas teur, is a mixture of four chimeras, dengue virus structural genes coupled with nonstructural genes of yellow fever 17D. Dengvaxia completed phase III per protocol analyses on 32,568 children, vac cinated and controls, age 2 16 years. These studies revealed poor protection and sensitization of seronegative vaccinated children to severe breakthrough dengue but moderate protection of children vaccinated when seropositive, who experienced a reduction of hos pitalization and severe disease. Based on these data, the vaccine was endorsed by the WHO, United States, and European regulatory agencies for targeted use in individuals 9 years of age and older who have laboratory based evidence of a prior dengue infection. The vaccine has been licensed for use in 20 countries. Other dengue type 1 4 vaccines are under development. The Takeda dengue 2 chimeric tetravalent vaccine has completed phase III testing with follow up data for 2 years demonstrating strong protection against dengue 2 infection but modest protection against the other three viruses. A tetravalent dengue vaccine composed of mutagenized dengue 1, 3, and 4 and a chimeric dengue 2 virus developed by the U.S. National Institutes of Allergy and Infectious Diseases and Instituto Butantan in So Paulo, Brazil, is in the fourth year of phase III testing. Phase IIb live dengue virus human challenge data suggest this vaccine will provide solid protective immunity. Prophylaxis in the absence of vaccine consists of avoiding daytime household based mosquito bites through the use of insecticides, |
7,902 | repellents, body covering with clothing, screening of houses, and destruction of A. aegypti breeding sites. If water storage is manda tory, a tight fitting lid or a thin layer of oil may prevent egg laying or hatching. A larvicide, such as Abate (O,O thiodi p phenylene O,O,O,O tetramethyl phosphorothioate), available as a 1 sand granule formation and effective at a concentration of 1 ppm, may be added safely to drinking water. Ultra low volume spray equipment effectively dispenses the adulticide malathion from trucks or air planes for rapid intervention during an epidemic. Mosquito repel lants and other personal anti mosquito measures are effective in preventing mosquito bites in the field, forest, or jungle. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Yellow fever is an acute infection characterized in its most severe form by fever, jaundice, proteinuria, and hemorrhage. The virus is mosquito borne and occurs as urban epidemic, endemic, or jungle enzootic forms in South America and Africa. Until 1900, seasonal urban epidemics occurred in cities in temperate areas of Europe and the Americas. Urban and jungle yellow fever continues to be active in West, Central, and East Africa. ETIOLOGY Yellow fever is the prototype of the Flavivirus genus of the family Fla viviridae, which are enveloped, single stranded RNA viruses 35 50 nm in diameter. Chapter 316 Yellow Fever Scott B. Halstead Yellow fever circulates zoonotically as five genotypes: type IA in West Central Africa, type IB in South America, type II in West Africa, type III in East Central Africa, and type IV in East Africa. Types IA and IB are capable of urban transmission between human beings by Aedes aegypti. Sometime in the 1600s, A. aegypti, together with yellow fever virus, were brought to the American tropics through the African slave trade. Subsequently, yellow fever caused enormous coastal and riverine epidemics in the Atlantic and Carib bean basins until the 20th century, when the virus and its urban and sylvan mosquito cycles were identified, mosquito control methods were perfected, and a vaccine was developed. The East and East Central African genotypes have not fully entered the urban cycle and have not spread to the east coast of Africa or to the countries of Asia. EPIDEMIOLOGY Human and nonhuman primate hosts acquire the yellow fever infection by the bite of infected mosquitoes. After an incubation period of 3 6 days, virus appears in the blood and may serve as a source of infection for other mosquitoes. The virus must replicate in the gut of the mosquito and pass to the salivary gland before the mosquito can transmit the virus. Yellow fever virus is transmitted in an urban cyclehuman to A. aegypti to humanand a jungle cyclemonkey to jungle mosquitoes to monkey. Classic yellow fever epidemics in the United States, South America, the Caribbean, and parts of Europe were of the urban variety. Since 2000, West Africa has experienced five urban epidemics, including in the capi tal cities of Abidjan (Cote dIvoire), Conakry (Guinea), and Dakar (Senegal). In 20122013, |
7,903 | large outbreaks of East and EastCentral yellow fever occurred across a large, predominantly rural area of war ravaged Darfur in southwestern Sudan and in adjacent areas of northern Uganda. Beginning in 2015 and continuing to mid 2016, there were sharp outbreaks of yellow fever in and around Rwanda, Angola, and the bordering Democratic Republic of Congo, where there were 7,000 reported cases and 500 deaths. Eleven cases were imported into China by workers in Angola. In South America, all of the approximately 200 cases reported each year are jungle yel low fever. In late 2016 and continuing through 2019, a widespread zoonosis resulted in an estimated 2,237 yellow fever cases in natives and visitors to Brazil. In colonial times, urban yellow fever attack rates in White adults were very high, suggesting that subclinical infections are uncommon in this age group. Yellow fever may be less severe in children, with subclinical infection:clinical case ratios 2:1. In areas where outbreaks of urban yellow fever are common, most cases involve children because many adults are immune. Transmission in West Africa is highest during the rainy season, from July to November. In tropical forests, yellow fever virus is maintained in a transmission cycle involving monkeys and tree holebreeding mosquitoes (Haema gogus in Central and South America; the Aedes africanus complex in Africa). In the Americas, most cases involve tourists, campers, those who work in forested areas, and vacationers exposed to infected mos quitoes. In Africa, enzootic virus is prevalent in moist savanna and savanna transition areas, where other tree holebreeding Aedes vec tors transmit the virus between monkeys and humans and between humans. PATHOGENESIS Pathologic changes seen in the liver include (1) coagulative necro sis of hepatocytes in the midzone of the liver lobule, with sparing of cells around the portal areas and central veins, (2) eosinophilic degeneration of hepatocytes (Councilman bodies), (3) microvacu olar fatty change, and (4) minimal inflammation. The kidneys show acute tubular necrosis. In the heart, myocardial fiber degeneration and fatty infiltration are seen. The brain may show edema and pete chial hemorrhages. Direct viral injury to the liver results in impaired ability to perform functions of biosynthesis and detoxification; this is the central pathogenic event of yellow fever. Hemorrhage is pos tulated to result from decreased synthesis of vitamin Kdependent 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. 2072 Part XV u Infectious Diseases clotting factors and, in some cases, disseminated intravascular clot ting. The shock that occurs in patients with yellow fever appears similar to the shock associated with dengue shock syndrome and other viral hemorrhagic fevers and results at least in part from viral damage to endothelial cells. Death and severe disease rates are lower in susceptible sub Saharan African Black people than in other racial groups, suggesting existence of a resistance gene. Renal dysfunction has been attributed to hemodynamic factors |
7,904 | (pre renal failure progressing to acute tubular necrosis). CLINICAL MANIFESTATIONS In Africa, inapparent, abortive, or clinically mild infections are fre quent. Some studies suggest that children experience a milder dis ease than do adults. Abortive infections, characterized by fever and headache, may be unrecognized except during epidemics. In its classic form, yellow fever begins with a sudden onset of fever, headache, myalgia, lumbosacral pain, anorexia, nausea, and vomiting. Physical findings during the early phase of illness, when virus is present in the blood, include prostration, conjunctival injec tion, flushing of the face and neck, reddening of the tongue at the tip and edges, and relative bradycardia. After 2 3 days, there may be a brief period of remission, followed in 6 24 hours by the reappear ance of fever with vomiting, epigastric pain, jaundice, dehydration, gastrointestinal and other hemorrhages, albuminuria, hypotension, renal failure, delirium, convulsions, and coma. Death may occur after 7 10 days, with a fatality rate in severe cases approaching 50. Some patients who survive the acute phase of illness later succumb to renal failure or myocardial damage. Laboratory abnormalities include leukopenia; prolonged clotting, prothrombin, and partial thromboplastin times; thrombocytopenia; hyperbilirubinemia; elevated serum transaminase values; albuminuria; and azotemia. Hypoglycemia may be present in severe cases. Electrocardiogram abnormalities such as bradycardia and ST T changes are described. DIAGNOSIS Yellow fever should be suspected when fever, headache, vomiting, myalgia, and jaundice appear in residents of enzootic areas or in unimmunized visitors who have recently traveled (within 2 weeks before the onset of symptoms) to endemic areas. There are clinical similarities between yellow fever and dengue hemorrhagic fever. In contrast to the gradual onset of acute viral hepatitis resulting from hepatitis A, B, C, D, or E virus, jaundice in yellow fever appears after 3 5 days of high temperature and is often accompanied by severe prostration. Mild yellow fever is dengue like and cannot be distinguished from a wide variety of other infections. Jaundice and fever may occur in any of several other tropical diseases, including malaria, viral hepatitis, louse borne relapsing fever, leptospirosis, typhoid fever, rickettsial infections, certain systemic bacterial infec tions, sickle cell crisis, Rift Valley fever, Crimean Congo hemor rhagic fever, and other viral hemorrhagic fevers. Outbreaks of yellow fever always include cases with severe gastrointestinal hemorrhage. The specific diagnosis depends on the detection of the virus or viral antigen in acute phase blood samples or antibody assays. The immunoglobulin M enzyme immunoassay is particularly useful. Sera obtained during the first 10 days after the onset of symptoms should be kept in an ultra low temperature freezer (70C 94F) and shipped on dry ice for virus testing. Convalescent phase samples for antibody tests are managed by conventional means. In handling acute phase blood specimens, medical personnel must take care to avoid contaminating themselves or others on the evacuation trail (laboratory personnel and others). The postmortem diagnosis is based on virus isolation from liver or blood, identification of Coun cilman bodies in liver tissue, or detection of antigen |
7,905 | or viral genome in liver tissue. TREATMENT It is customary to keep patients with yellow fever in a mosquito free area, with use of mosquito nets if necessary. Patients are viremic during the febrile phase of the illness. Although there is no specific treatment for yel low fever, medical care is directed at maintaining the physiologic status with the following measures: (1) sponging and acetaminophen to reduce a high temperature, (2) vigorous fluid replacement of losses resulting from fasting, thirsting, vomiting, or plasma leakage, (3) correcting an acid base imbalance, (4) maintaining nutritional intake to lessen the severity of hypoglycemia, and (5) avoiding drugs that are either metabo lized by the liver or toxic to the liver, kidney, or central nervous system. COMPLICATIONS Complications of acute yellow fever include severe hemorrhage, liver failure, and acute renal failure. Bleeding should be managed by transfu sion of fresh whole blood or fresh plasma with platelet concentrates if necessary. Renal failure may require peritoneal dialysis or hemodialysis. PREVENTION Yellow fever 17D is a live attenuated vaccine with a long record of safety and efficacy. It is administered as a single 0.5 mL subcu taneous injection at least 10 days before arrival in a yellow fever endemic area. YF VAX, manufactured by Sanofi Pasteur, is licensed for use in the United States. With the exceptions noted later, indi viduals traveling to endemic areas in South America and Africa should be considered for vaccination, but the length of stay, exact locations to be visited, and environmental or occupational expo sure may determine the specific risk and individual need for vac cination. Persons traveling from yellow feverendemic to yellow feverreceptive countries may be required by national authorities to obtain a yellow fever vaccine (e.g., from South America or Africa to India). Usually, countries that require travelers to obtain a yellow fever immunization do not issue a visa without a valid immuniza tion certificate. Vaccination is valid for 10 years for international travel certification, although immunity lasts at least 40 years and probably for life. Immunoglobulin M antibodies circulate for years after administration of yellow fever vaccine. Since 1996, there have been a number of reports of yellow fever vaccineassociated viscerotropic disease with a higher risk in elderly vaccine recipients and a few cases in persons with previous thy mectomies. Yellow fever vaccine should not be administered to per sons who have symptomatic immunodeficiency diseases, are taking immunosuppressant drugs, have HIV, or have a history of thymec tomy. A recent study has shown that individuals taking maintenance corticosteroids may be successfully vaccinated. Although the vac cine is not known to harm fetuses, its administration during preg nancy is not advised. The vaccine virus may be rarely transmitted through breastfeeding. In very young children, there is a small risk of encephalitis and death after yellow fever 17D vaccination. The 17D vaccine should not be administered to infants younger than 6 months. Residence in or travel to areas of known or anticipated yellow fever activity (e.g., forested areas in |
7,906 | the Amazon basin), which puts an individual at high risk, warrants immunization of infants 6 8 months of age. Immunization of children 9 months of age and older is routinely recommended before entry into endemic areas. Immunization of persons older than 60 years of age should be weighed against their risk for sylvatic yellow fever in the American tropics and for urban or sylvatic yellow fever in Africa. Vaccination should be avoided in persons with a history of egg allergy. Alterna tively, a skin test can be performed to determine whether a serious allergy exists that would preclude vaccination. 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 317 u Ebola and Other Viral Hemorrhagic Fevers 2073 Viral hemorrhagic fevers are a loosely defined group of clinical syn dromes in which hemorrhagic manifestations are either common or especially notable during severe illness. Both the etiologic agents and the clinical features of the syndromes differ, but coagulopathy may be a common pathogenetic feature. ETIOLOGY Six of the viral hemorrhagic fevers are caused by arthropod borne viruses (arboviruses) (Table 317.1). Four are caused by togaviruses of the family Flaviviridae: Kyasanur Forest disease, Omsk hemor rhagic fever, dengue (see Chapter 315), and yellow fever (see Chapter 316) viruses. Three are caused by viruses of the family Bunyaviridae: Congo fever, Hantaan fever, and Rift Valley fever (RVF) viruses. Four are caused by viruses of the family Arenaviridae: Junin fever, Machupo fever, Guanarito fever, and Lassa fever. Two are caused by viruses in the family Filoviridae: Ebola virus and Marburg virus, enveloped, fila mentous RNA viruses that are sometimes branched, unlike any other known virus. EPIDEMIOLOGY With some exceptions, the viruses causing viral hemorrhagic fevers are transmitted to humans via a nonhuman entity. The specific ecosystem required for viral survival determines the geographic distribution of disease. Although it is commonly thought that all viral hemorrhagic fevers are arthropod borne, seven may be contracted from environ mental contamination caused by animals or animal cells or from infected humans (see Table 317.1). Laboratory and hospital infections have occurred with many of these agents. Lassa fever and Argentine and Bolivian hemorrhagic fevers are reportedly milder in children than in adults. Crimean Congo Hemorrhagic Fever Sporadic human infection with Crimean Congo hemorrhagic fever in Africa provided the original virus isolation. Natural foci are rec ognized in Bulgaria, western Crimea, and the Rostov on Don and Astrakhan regions; disease occurs in Central Asia from Kazakhstan to Pakistan. Index cases were followed by nosocomial transmission in Pakistan and Afghanistan in 1976, in the Arabian Peninsula in 1983, and in South Africa in 1984. In the Russian Federation, the vectors are ticks of the species Hyalomma marginatum and Hyalomma anatoli cum, which, along with hares and birds, may serve as viral reservoirs. Disease occurs from June to September, largely |
7,907 | among farmers and dairy workers. Kyasanur Forest Disease Human cases of Kyasanur Forest disease occur chiefly in adults in an area of Mysore State, India. The main vectors are two Ixodidae ticks, Haemaphysalis turturis and Haemaphysalis spinigera. Monkeys and forest rodents may be amplifying hosts. Laboratory infections are common. Omsk Hemorrhagic Fever Omsk hemorrhagic fever occurs throughout south central Russia and northern Romania. Vectors may include Dermacentor pictus and Der macentor marginatus, but direct transmission from moles and musk rats to humans seems well established. Human disease occurs in a springsummerautumn pattern, paralleling the activity of the vectors. This infection occurs most frequently in persons with outdoor occupa tional exposure. Laboratory infections are common. Rift Valley Fever The virus causing RVF is responsible for epizootics involving sheep, cattle, buffalo, certain antelopes, and rodents in North, Central, East, and South Africa. The virus is transmitted to domestic animals by Culex theileri and several Aedes species. Mosquitoes may serve as reservoirs by transovarial transmission. An epizootic in Egypt in 19771978 was accompanied by thousands of human infections, principally among veterinarians, farmers, and farm laborers. Smaller outbreaks occurred in Senegal in 1987, Madagascar in 1990, and Saudi Arabia and Yemen in 20002001. Humans are most often infected during the slaughter or skinning of sick or dead animals. Laboratory infection is common. Argentine Hemorrhagic Fever Before the introduction of vaccine, hundreds to thousands of cases of Argentine hemorrhagic fever occurred annually from April through July in the maize producing area northwest of Buenos Aires that reaches to the eastern margin of the Province of Cordoba. Junin virus has been isolated from the rodents Mus musculus, Akodon arenicola, and Calomys laucha. It infects migrant laborers who harvest the maize and who inhabit rodent contaminated shelters. Bolivian Hemorrhagic Fever The recognized endemic area of Bolivian hemorrhagic fever consists of the sparsely populated province of Beni in Amazonian Bolivia. Spo radic cases occur in farm families who raise maize, rice, yucca, and beans. In the town of San Joaquin, a disturbance in the domestic rodent ecosystem may have led to an outbreak of household infection caused by Machupo virus transmitted by chronically infected Calomys callo sus, ordinarily a field rodent. Mortality rates are high in young children. Venezuelan Hemorrhagic Fever In 1989, an outbreak of hemorrhagic illness occurred in the farming community of Guanarito, Venezuela, 200 miles south of Caracas. Sub sequently, in 19901991, there were 104 cases reported with 26 deaths caused by Guanarito virus. Cotton rats (Sigmodon alstoni) and cane rats (Zygodontomys brevicauda) have been implicated as likely reser voirs of Venezuelan hemorrhagic fever. Chapter 317 Ebola and Other Viral Hemorrhagic Fevers Scott B. Halstead Table 317.1 Viral Hemorrhagic Fevers MODE OF TRANSMISSION DISEASE VIRUS Tick borne Crimean Congo hemorrhagic fever (HF) Congo Kyasanur Forest disease Kyasanur Forest disease Omsk HF Omsk Mosquito borne Dengue HF Dengue (4 types) Rift Valley fever Rift Valley fever Yellow fever Yellow fever Infected animals or materials to humans Argentine HF Junin Bolivian HF Machupo Lassa fever Lassa Marburg |
7,908 | disease Marburg Ebola HF Ebola HF with renal syndrome Hantaan Patients may be contagious; nosocomial infections are common. Chikungunya virus is associated infrequently with petechiae and epistaxis. Severe hemorrhagic manifestations have been reported in some cases. 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. 2074 Part XV u Infectious Diseases Lassa Fever Lassa virus has an unusual potential for human to human spread, resulting in many small epidemics in Nigeria, Sierra Leone, and Liberia. In 2012, an outbreak of more than 1,000 cases of Lassa fever occurred in east central Nigeria. Medical workers in Africa and the United States have also contracted the disease. Patients with acute Lassa fever have been transported by international aircraft, necessitating extensive sur veillance among passengers and crews. The virus is probably main tained in nature in a species of African peridomestic rodent, Mastomys natalensis. Rodent to rodent transmission and infection of humans probably operate via mechanisms established for other arenaviruses. Marburg Disease Previously, the world experience of human infections caused by Mar burgvirus had been limited to 26 primary and 5 secondary laboratory based cases in Germany and Yugoslavia in 1967 and to small outbreaks in Zimbabwe in 1975, Kenya in 1980 and 1988, and South Africa in 1983. However, in 1999 a large outbreak occurred in the Republic of Congo, and in 2005 a still larger outbreak occurred in Uige Province, Angola, with 252 cases and 227 deaths. In laboratory and clinical set tings, transmission occurs by direct contact with tissues of the African green monkey or with infected human blood or semen. A reservoir in the African fruit bat, Rousettus aegyptiacus, has been demonstrated. Fruit bats infected with Marburg virus do not show obvious signs of illness. It appears that the virus is transmitted by close contact with fructivorous bats and by aerosol from bats. Ebola Hemorrhagic Fever Ebola virus was isolated in 1976 from a devastating epidemic involving small villages in northern Zaire and southern Sudan; smaller outbreaks have occurred subsequently. Outbreaks have initially been nosocomial. Attack rates have been highest in children from birth to 1 year of age and in persons from 15 50 years of age. The virus is in the Filovirus family and closely related to viruses in the genus Marburg virus. An Ebola virus epidemic occurred in Kikwit, Zaire, in 1995, followed by scattered outbreaks in Uganda and Central and West Africa. The virus has been recovered from chimpanzees, and antibodies have been found in other subhuman primates, which apparently acquire infection from a zoonotic reservoir in bats. The natural reservoir of Ebola is thought to be fruit bats. Reston virus, related to Ebola virus, has been recovered from Philippine monkeys and pigs and has caused subclinical infec tions in humans working in monkey colonies in the United States. In 2014, West Africa experienced the largest outbreak of Ebola virus |
7,909 | disease (EVD) in history and the first transmission in a large urban area (Fig. 317.1). Countries primarily affected were Liberia, Sierra Leone, and Guinea, with imported cases reported in Nigeria, Mali, and Senegal, as well as Europe and the United States. The outbreak was caused by the Zaire Ebola virus (species of Ebola virus include the Zaire, Sudan, Bundibugyo, Reston, and Tai Forest species), which has a mortality rate of approximately 5565. As of 8 May 2016, the World Health Organization (WHO) and respective governments reported a total of 28,616 suspected cases and 11,310 deaths (39.5), though the WHO thinks that this substantially understates the magni tude of the outbreak. The outbreak had largely subsided by the end of 2015. In 20182020, an outbreak occurred in the Democratic Repub lic of the Congo, affecting more than 500 people (age 8 80 years), with a case fatality of approximately 50 (Fig. 317.2). In 2021 the Ministry of Health (MOH) in the Democratic Republic of the Congo (DRC) announced that a case of EVD had been confirmed in Biena Health Zone, North Kivu Province. Sequencing of samples suggests that this outbreak was linked to the 20182020 outbreak, likely caused by a persistent infection in a survivor that led to either a relapse or sexual transmission of the virus. EVD may occur after exposure to fruit bats or bushmeat but most often occurs through exposure to body fluids of infected individuals (blood, sweat, saliva, vomitus, diarrhea, and less often human milk or semen) (Table 317.2). Persistent infection after recovery from acute EVD has been well documented, with virus particles present in body fluids such as semen for many months in apparently healthy survi vors. Patients are infectious once they are symptomatic; the incubation period is 2 21 days (mean: 11 days). The age range in the West African epidemic was broad, but most patients were between 15 and 44 years old. Hemorrhagic Fever with Renal Syndrome The endemic area of hemorrhagic fever with renal syndrome (HFRS), also known as epidemic hemorrhagic fever and Korean hemorrhagic fever, includes Japan, Korea, far eastern Siberia, north and central China, European and Asian Russia, Scandinavia, Czechoslovakia, Romania, Bulgaria, Yugoslavia, and Greece. Although the incidence and severity of hemorrhagic manifestations and the mortality rates are lower in Europe than in northeastern Asia, the renal lesions are the same. Disease in Scandinavia, nephropathia epidemica, is caused by a different although antigenically related virus, Puumala virus, asso ciated with the bank vole, Clethrionomys glareolus. Cases occur pre dominantly in the spring and summer. There appears to be no age factor in susceptibility, but because of occupational hazards, young adult men are most frequently attacked. Rodent plagues and evidence of rodent infestation have accompanied endemic and epidemic occur rences. Hantaan virus has been detected in the lung tissue and excreta 13 14 15 Liberia Sierra Leone Guinea 16 17 18 19 20 21 2322 24 25 2726 2928 3130 3332 3534 3736 39 40 41 42 43 44 45 46 47 |
7,910 | 48 4938 Epidemiologic week 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 0 N o. o f r ep or te d ca se s Fig. 317.1 Cumulative number of Ebola virus disease cases reportedthree countries, West Africa, April 13, 2016. Reported from Sierra Leone (14,124 cases) and Liberia (10,678), followed by Guinea (3,814). (Data from the number of cases and deaths in Guinea, Liberia, and Sierra Leone during the 20142016 West Africa Ebola Outbreak. https:www.cdc.govvhfebolaoutbreaks2014 west africacase counts.html) 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 317 u Ebola and Other Viral Hemorrhagic Fevers 2075 of Apodemus agrarius coreae. Antigenically related agents have been detected in laboratory rats and in urban rat populations around the world, including Prospect Hill virus in the wild rodent Microtus penn sylvanicus in North America and sin nombre virus in the deer mouse in the southern and southwestern United States; these viruses are causes of hantavirus pulmonary syndrome (see Chapter 319). Rodent to rodent and rodent to human transmission presumably occurs via the respiratory route. CLINICAL MANIFESTATIONS Dengue hemorrhagic fever (see Chapter 315) and yellow fever (see Chapter 316) cause similar syndromes in children in endemic areas. Crimean Congo Hemorrhagic Fever The incubation period of 3 12 days is followed by a febrile period of 5 12 days and a prolonged convalescence. Illness begins suddenly with fever, severe headache, myalgia, abdominal pain, anorexia, nausea, and vomiting. After 1 2 days, the fever may subside until the patient experi ences an erythematous facial or truncal flush and injected conjunctivae. A second febrile period of 2 6 days then develops, with a hemorrhagic enanthem on the soft palate and a fine petechial rash on the chest and abdomen. Less frequently, there are large areas of purpura and bleed ing from the gums, nose, intestines, lungs, or uterus. Hematuria and proteinuria are relatively rare. During the hemorrhagic stage, there is usually tachycardia with diminished heart sounds and occasionally hypotension. The liver is usually enlarged, but there is no icterus. In protracted cases, central nervous system signs include delirium, som nolence, and progressive clouding of the consciousness. Early in the dis ease, leukopenia with relative lymphocytosis, progressively worsening thrombocytopenia, and gradually increasing anemia occur. In conva lescence there may be hearing and memory loss. The mortality rate is 250. Kyasanur Forest Disease and Omsk Hemorrhagic Fever After an incubation period of 3 8 days, both Kyasanur Forest disease and Omsk hemorrhagic fever begin with the sudden onset of fever and headache. Kyasanur Forest disease is characterized by severe myalgia, prostration, and bronchiolar involvement; it often manifests without hemorrhage but occasionally involves severe gastrointestinal bleeding. In Omsk hemorrhagic fever, there is moderate epistaxis, hematemesis, and a hemorrhagic enanthem but no profuse hemor rhage; bronchopneumonia is common. In both diseases, severe leu kopenia and thrombocytopenia, vascular dilation, increased vascular permeability, gastrointestinal hemorrhages, and |
7,911 | subserosal and inter stitial petechial hemorrhages occur. Kyasanur Forest disease may be complicated by acute degeneration of the renal tubules and focal liver damage. In many patients, recurrent febrile illness may follow an N S EW Republic of the Congo LILANGA BOBANGI MBANDAKA Mbandaka BOLOMBAWANGATA BOLENGE BIKORO INGENDE IBOKO PENDJUA KIRIINONGO NTONDO IREBU LUKOLELA BANDJAU MUSHIE Democratic Republic of the Congo Affected health zones Unaffected health zones Lakes and rivers City Bikoro Kinshasa 0 10 20 30 Miles 40 Fig. 317.2 Map of Ebola affected health zones in the Democratic Re public of the Congo (DRC), 2018. (Courtesy the Centers for Disease Control and Prevention, 2018. https:www.cdc.govvhfebolaoutbrea ksdrcdrc map.html) Table 317.2 Clinical Recommendations for Ebola Virus Infection RECOMMENDATION POPULATION INTERVENTION 1 Patients with suspected, probable, or confirmed Ebola virus disease Oral rehydration 2 Patients with suspected, probable, or confirmed Ebola virus disease who are unable to drink or who have inadequate oral intake Parenteral administration of fluids 3 Patients with suspected, probable, or confirmed Ebola virus disease Systematic monitoring and charting of vital signs and volume status 4 Patients with suspected, probable, or confirmed Ebola virus disease Serum biochemistry 5 Patients with suspected, probable, or confirmed Ebola virus disease Staffing ratio 6 Patients with suspected, probable, or confirmed Ebola virus disease Communication with family and friends 7 Patients with suspected, probable, or confirmed Ebola virus disease who are in pain Analgesic therapy 8 Patients with suspected, probable, or confirmed Ebola virus disease with high severity of illness Antibiotics Modified from Lamontagne F, Fowler RA, Adhikari NK, et al. Evidence based guidelines for supportive care of patients with Ebola virus disease. Lancet. 2018;391:700708. Table 2. 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. 2076 Part XV u Infectious Diseases afebrile period of 7 15 days. This second phase takes the form of a meningoencephalitis. Rift Valley Fever Most RVF infections have occurred in adults with signs and symp toms resembling those of dengue fever (see Chapter 315). The onset is acute, with fever, headache, prostration, myalgia, anorexia, nausea, vomiting, conjunctivitis, and lymphadenopathy. The fever lasts 3 6 days and is often biphasic. The convalescence is often prolonged. In the 19771978 outbreak, many patients died after showing signs that included purpura, epistaxis, hematemesis, and melena. RVF affects the uvea and posterior chorioretina; macular scarring, vascular occlu sion, and optic atrophy occur, resulting in permanent visual loss in a high proportion of patients with mild to severe RVF. At autopsy, extensive eosinophilic degeneration of the parenchymal cells of the liver has been observed. Argentine, Venezuelan, and Bolivian Hemorrhagic Fevers and Lassa Fever The incubation period in Argentine, Venezuelan, and Bolivian hemor rhagic fevers and Lassa fever is commonly 7 14 days; the acute illness lasts for 2 4 weeks. Clinical illnesses range from undifferentiated fever to the characteristic severe illness. Lassa fever is most often clinically severe |
7,912 | in White persons. The onset is usually gradual, with increas ing fever, headache, diffuse myalgia, and anorexia (Table 317.3). Dur ing the first week, signs frequently include a sore throat, dysphagia, cough, oropharyngeal ulcers, nausea, vomiting, diarrhea, and pains in the chest and abdomen. Pleuritic chest pain may persist for 2 3 weeks. In Argentine and Bolivian hemorrhagic fevers and less frequently in Lassa fever, a petechial enanthem appears on the soft palate 3 5 days after onset and at about the same time on the trunk. The tourniquet test may be positive. The clinical course of Venezuelan hemorrhagic fever has not been well described. In 3550 of patients, these diseases may become severe, with per sistent high temperature, increasing toxicity, swelling of the face or neck, microscopic hematuria, and frank hemorrhages from the stom ach, intestines, nose, gums, and uterus. A syndrome of hypovolemic shock is accompanied by pleural effusion and renal failure. Respira tory distress resulting from airway obstruction, pleural effusion, or congestive heart failure may occur. A total of 1020 of patients experience late neurologic involvement, characterized by intention tremor of the tongue and associated speech abnormalities. In severe cases, there may be intention tremors of the extremities, seizures, and delirium. The cerebrospinal fluid is normal. In Lassa fever, nerve deaf ness occurs in early convalescence in 25 of cases. Prolonged conva lescence is accompanied by alopecia and, in Argentine and Bolivian hemorrhagic fevers, by signs of autonomic nervous system lability, such as postural hypotension, spontaneous flushing or blanching of the skin, and intermittent diaphoresis. Laboratory studies reveal marked leukopenia, mild to moder ate thrombocytopenia, proteinuria, and, in Argentine hemorrhagic fever, moderate abnormalities in blood clotting, decreased fibrinogen, increased fibrinogen split products, and elevated serum transaminases. There is focal, often extensive eosinophilic necrosis of the liver paren chyma, focal interstitial pneumonitis, focal necrosis of the distal and collecting tubules, and partial replacement of splenic follicles by amor phous eosinophilic material. Usually, bleeding occurs by diapedesis with little inflammatory reaction. The mortality rate is 1040. Marburg Disease and Ebola Hemorrhagic Fever After an incubation period of 4 7 days, the illness begins abruptly, with severe frontal headache, malaise, drowsiness, lumbar myalgia, vomiting, nausea, and diarrhea. A maculopapular eruption begins 5 7 days later on the trunk and upper arms. It becomes generalized and often hemorrhagic and exfoliates during convalescence. The exanthem is accompanied by a dark red enanthem on the hard palate, conjunctivitis, and scrotal or labial edema. Gastrointestinal hemor rhage occurs as the severity of illness increases. Late in the illness, the patient may become tearfully depressed, with marked hyperalgesia to tactile stimuli. In fatal cases, patients become hypotensive, restless, and confused and lapse into coma. Convalescent patients may experi ence alopecia and may have paresthesias of the back and trunk. There is a marked leukopenia with necrosis of granulocytes. Dysfunction in bleeding and clotting and thrombocytopenia are universal and corre lated with the severity of disease; there are moderate abnormalities in concentrations of clotting proteins and |
7,913 | elevations of serum transami nases and amylase. Pregnant women and young children are at high risk of severe disease with a fatal outcome. The mortality rate of Mar burg disease is 2585, and the mortality rate of Ebola hemorrhagic fever 5090. High viral loads in acute phase blood samples convey a poor prognosis. Viral RNA persists in tissues long after symptoms subside, and the virus has been excreted in semen more than 1 year after recovery. Manifestations of EVD may come in stages, but most EVD begins with the sudden onset of fever accompanied by fatigue, weakness, myalgias, headache, and sore throat. This is followed by gastrointesti nal involvement, including anorexia, nausea, abdominal pain, vomit ing, and diarrhea. Hemorrhage (defined by any evidence of bleeding) is seen in more than 50 and is a serious later phase, often accompanied by vascular leakage, multiorgan failure, and death. Those who survive improve on approximately days 6 11 of EVD. One late relapse produc ing meningoencephalitis has been reported. Hemorrhagic Fever with Renal Syndrome In most cases, HFRS is characterized by fever, petechiae, mild hem orrhagic phenomena, and mild proteinuria, followed by a relatively uneventful recovery. In 20 of recognized cases, the disease may progress through four distinct phases. The febrile phase is ushered in with fever, malaise, and facial and truncal flushing. It lasts 3 8 days and ends with thrombocytopenia, petechiae, and proteinuria. The hypotensive phase of 1 3 days follows defervescence. Loss of fluid from the intravascular compartment may result in marked hemocon centration. Proteinuria and ecchymoses increase. The oliguric phase, usually 3 5 days in duration, is characterized by a low output of protein rich urine, increasing nitrogen retention, nausea, vomiting, and dehydration. Confusion, extreme restlessness, and hypertension are common. The diuretic phase, which may last for days or weeks, usually initiates clinical improvement. The kidneys show little con centrating ability, and rapid loss of fluid may result in severe dehy dration and shock. Potassium and sodium depletion may be severe. Fatal cases manifest as abundant protein rich retroperitoneal edema and marked hemorrhagic necrosis of the renal medulla. The mortality rate is 510. Table 317.3 Clinical Stages of Lassa Fever STAGE SYMPTOMS 1 (days 1 3) General weakness and malaise; high fever 39C (102.2F), constant with peaks of 4041C (104105.8F) 2 (days 4 7) Sore throat (with white exudative patches) very common; headache; back, chest, side, or abdominal pain; conjunctivitis; nausea and vomiting; diarrhea; productive cough; proteinuria; low blood pressure (systolic 100 mm Hg); anemia 3 (after 7 days) Facial edema; convulsions; mucosal bleeding (mouth, nose, eyes); internal bleeding; confusion or disorientation 4 (after 14 days) Coma and death From Richmond JK, Baglole DJ. Lassa fever: epidemiology, clinical features, and social consequences. BMJ. 2003;327:12711275. 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 317 u Ebola and Other Viral Hemorrhagic Fevers 2077 DIAGNOSIS |
7,914 | The diagnosis of these viral hemorrhagic fevers depends on a high index of suspicion in endemic areas. In nonendemic areas, histories of recent travel, recent laboratory exposure, or exposure to an earlier case should evoke suspicion of a viral hemorrhagic fever. In all viral hemorrhagic fevers, the viral agent circulates in the blood at least transiently during the early febrile stage. Togaviruses and bunyaviruses can be recovered from acute phase serum samples by inoculation into a tissue culture or living mosquitoes. Argentine, Bolivian, and Venezuelan hemorrhagic fever viruses can be isolated from acute phase blood or throat washings by intracerebral inocula tion into guinea pigs, infant hamsters, or infant mice. Lassa virus may be isolated from acute phase blood or throat washings by inoculation into tissue cultures. For Marburg disease and Ebola hemorrhagic fever, acute phase throat washings, blood, and urine may be inoculated into a tissue culture, guinea pigs, or monkeys. The viruses are readily iden tified on electron microscopy, with a filamentous structure differenti ating them from all other known agents. Specific complement fixing and immunofluorescent antibodies appear during convalescence. The virus of HFRS is recovered from acute phase serum or urine by inoculation into a tissue culture. A variety of antibody tests using viral subunits is becoming available. The serologic diagnosis depends on the demonstration of seroconversion or a fourfold or greater increase in immunoglobulin G antibody titer in acute and convalescent serum specimens collected 3 4 weeks apart. Viral RNA may also be detected in blood or tissues with the use of reverse transcriptase polymerase chain reaction analysis. The diagnosis of EVD is confirmed by enzyme linked immuno sorbent assay immunoglobulin M and polymerase chain reaction (which may need to be repeated if initially negative) testing. Criteria to aid in the diagnosis of EVD include temperature 38.6C (101.5F) plus symptoms; contact with an affected patient, the patients body fluids, or the funeral; residence in or travel to an endemic region; or a history of handling bats, rodents, or primates from an endemic area. Handling blood and other biologic specimens is hazardous and must be performed by specially trained personnel. Blood and autopsy speci mens should be placed in tightly sealed metal containers, wrapped in absorbent material inside a sealed plastic bag, and shipped on dry ice to laboratories with biocontainment safety level 4 facilities. Even rou tine hematologic and biochemical tests should be done with extreme caution. Differential Diagnosis Mild cases of hemorrhagic fever may be confused with almost any self limited systemic bacterial or viral infection. More severe cases may suggest typhoid fever; epidemic, murine, or scrub typhus; lepto spirosis; or a rickettsial spotted fever, for which effective chemothera peutic agents are available. Many of these disorders may be acquired in geographic or ecologic locations endemic for a viral hemorrhagic fever. The differential diagnosis of EVD includes malaria, typhoid, Lassa fever, influenza infection, and meningococcemia. TREATMENT Ribavirin administered intravenously is effective in reducing mortal ity rates in Lassa fever and HFRS. Further information and advice |
7,915 | about the management, control measures, diagnosis, and collec tion of biohazardous specimens can be obtained from the Centers for Disease Control and Prevention, National Center for Infectious Diseases, Viral Special Pathogens Branch, Atlanta, Georgia 30333 (470 312 0094). The therapeutic principle involved in all of these diseases, espe cially HFRS, is the reversal of dehydration, hemoconcentration, renal failure, and protein, electrolyte, or blood losses (see Table 317.2). The contribution of disseminated intravascular coagulopathy to the hemorrhagic manifestations is unknown, and the management of hemorrhage should be individualized. Transfusions of fresh blood and platelets are frequently given. Good results have been reported in a few patients after the administration of clotting factor concen trates. The efficacy of corticosteroids, aminocaproic acid, pressor amines, and adrenergic blocking agents has not been established. Sedatives should be selected with regard to the possibility of kidney or liver damage. The successful management of HFRS may require renal dialysis. Whole blood transfusions from Ebola virusimmune donors and administration of Ebola monoclonal antibodies have been shown to be effective in lowering case fatality rates. Patients suspected of having Lassa fever, Ebola fever, Marburg fever, or Congo Crimean hemorrhagic fever should be placed in a private room on standard contact and droplet precautions. Care takers should use barrier precautions to prevent skin or mucous membrane exposure. All persons entering the patients room should wear gloves, gowns, and face shields. Before exiting the patients room, caretakers should safely remove and dispose of all protec tive gear and should clean and disinfect shoes. Protocols require two person clinical care teams, one observer and one caregiver (see Centers for Disease Control and Prevention CDC website: https:www.cdc.govvhfebola). Treatment of EVD often requires an intensive care unit and man agement of multiorgan system dysfunction, including correction of hypovolemia, hyponatremia, hypokalemia, hypoalbuminemia, hypo calcemia, and hypoxia, often with renal replacement therapy as well as ventilation support (see Table 317.2). Convalescent serum and mono clonal antibodies have been employed on an experimental basis. Strict isolation and appropriate barrier protection of healthcare workers is mandatory. Several vaccines have been shown to be immunogenic, and one used late in the epidemic was protective. Epidemic control mea sures, isolation, and quarantine have been used to attempt to decrease the spread of the West African epidemic. PREVENTION A live attenuated vaccine (Candid I) for Argentine hemorrhagic fever (Junin virus) is highly efficacious. A form of inactivated mouse brain vaccine is reported to be effective in preventing Omsk hemorrhagic fever. Inactivated RVF vaccines are widely used to protect domestic animals and laboratory workers. HFRS inactivated vaccine is licensed in Korea, and killed and live attenuated vaccines are widely used in China. A vaccinia vector glycoprotein vaccine provides protection against Lassa fever in monkeys. Single doses of recombinant vesicular stomatitis virus or adenovirus type 3 vaccines containing surface glyco proteins from Ebola and Marburg viruses have been shown to protect monkeys against Ebola virus and Marburg virus disease. The vesicular stomatitis vectored Ebola vaccine was shown to be effective in prevent ing |
7,916 | Ebola cases in a ring vaccination trial in Guinea and has been used widely in outbreaks since 2018. Prevention of mosquito borne and tick borne infections includes use of repellents, wearing of tight fitting clothing that fully covers the extremities, and careful examination of the skin after exposure, with removal of any vectors found. Diseases transmitted from a rodent infected environment can be prevented through methods of rodent control; elimination of refuse and breeding sites is particularly success ful in urban and suburban areas. Patients should be isolated until they are virus free or for 3 weeks after illness. Patient urine, sputum, blood, clothing, and bedding should be disinfected. Disposable syringes and needles should be used. Prompt and strict enforcement of barrier nursing may be lifesaving. The mortality rate among medical workers contracting these diseases is 50. A few entirely asymptomatic Ebola infections result in strong antibody production. 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. 2078 Part XV u Infectious Diseases Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen and an important cause of meningitis in children and adults. Capable of crossing the placenta and infecting the fetus, LCMV is also an important cause of neurologic birth defects and encephalopathy in the newborn. ETIOLOGY LCMV is a member of the family Arenaviridae, which are enveloped, negative sense, single stranded RNA viruses. The name of the arenavi ruses is derived from arenosus, the Latin word for sandy, because of the fine granularities observed within the virion on ultra thin electron microscopic sections. EPIDEMIOLOGY Like all arenaviruses, LCMV uses rodents as its reservoir. The common house mouse, Mus musculus, is both the natural host and primary res ervoir for the virus, which is transferred vertically from one generation of mice to the next via intrauterine infection. Hamsters and guinea pigs are also potential reservoirs. Although heavily infected with LCMV, rodents that acquire the virus transplacentally often remain asymptom atic because congenital infection provides rodents with immunologic tolerance for the virus. Infected rodents shed the virus in large quantities in nasal secretions, urine, feces, saliva, and milk throughout their lives. Humans typically acquire LCMV by contacting fomites contami nated with infectious virus or by inhaling aerosolized virus. Most human infections occur during the fall and early winter, when mice move into human habitations. Humans can also acquire the virus via organ transplantation. Congenital LCMV infection occurs when a woman acquires a primary LCMV infection during pregnancy. The virus passes through the placenta to the fetus during maternal viremia. The fetus may also acquire the virus during passage through the birth canal from exposure to infected vaginal secretions. Outside of organ transplantation and vertical transmission during pregnancy, there have been no cases of human to human transmission of LCMV. LCMV is prevalent in the environment, has a great geographic |
7,917 | range, and infects large numbers of humans. The virus is found throughout the worlds temperate regions and probably occurs wherever the genus Mus has been introduced (which is every continent but Antarctica). An epidemiologic study found that 9 of house mice are infected and that substantial clustering occurs, where the prevalence is higher. Serologic studies demonstrate that approximately 5 of adult humans possess antibodies to LCMV, indicating prior exposure and infection. PATHOGENESIS LCMV is not a cytolytic virus. Thus unlike many other nervous system pathogens that directly damage the brain by killing host brain cells, LCMV pathogenesis involves other underlying mechanisms. Further more, the pathogenic mechanisms are different in postnatal (acquired) infection compared with prenatal (congenital) infection. A critical dif ference in the pathogenesis of postnatal versus prenatal infection is that the virus infects brain parenchyma in the case of prenatal infection but is restricted to the meninges and choroid plexus in postnatal cases. In postnatal infections, LCMV replicates to high titers in the cho roid plexus and meninges. Viral antigen within these tissues becomes the target of an acute mononuclear cell infiltration driven by CD8 T lymphocytes. The presence of lymphocytes in large numbers within the meninges and cerebrospinal fluid (CSF) leads to the symptoms of meningitis that mark acquired LCMV infection. As the lymphocytes clear the virus from the meninges and CSF, the density of lymphocytes declines and the symptoms of meningitis resolve. Thus symptoms of acquired (postnatal) LCMV infection are immune mediated and are a result of the presence of large numbers of lymphocytes. Prenatal infection likewise inflames the tissues surrounding the brain parenchyma, and this inflammation leads to some of the signs of congenital LCMV. In particular, within the ventricular system, congenital LCMV infection often leads to ependymal inflammation, which may block the egress of CSF at the cerebral aqueduct and lead to hydrocephalus. However, unlike postnatal cases, prenatal infection with LCMV includes infection of the substance of the brain rather than just the meninges or ependyma. This infection of brain parenchyma leads to the substantial neuropathologic changes typically accompa nying congenital LCMV infection. In particular, LCMV infects the mitotically active neuroblasts, located at periventricular sites. Through an unknown mechanism, the presence of the virus kills these periven tricular cells, leading to periventricular calcifications, a radiographic hallmark of this disorder. Within the fetal brain, LCMV infection of neurons and glial cells also disrupts neuronal migration, leading to abnormal gyral patterns, and interferes with neuronal mitosis, leading to microcephaly and cerebellar hypoplasia. CLINICAL MANIFESTATIONS The clinical manifestations of LCMV infection depend on whether the infection occurs prenatally or postnatally. Congenital infection with LCMV is unique, as it involves both the postnatal infection of a preg nant woman and the prenatal infection of a fetus. Acquired (Postnatal) Lymphocytic Choriomeningitis Virus Infection LCMV infection during postnatal life (during childhood or adulthood) typically consists of a brief febrile illness from which the patient fully recovers. The illness classically consists of two clinical phases. In the first phase, the symptoms are |
7,918 | those of a nonspecific viral syndrome and include fever, myalgia, malaise, nausea, anorexia, and vomiting. These symptoms usually resolve after several days but are followed by a second phase, consisting of central nervous system disease. The symp toms of this second phase are those of aseptic meningitis, including headache, fever, nuchal rigidity, photophobia, and vomiting. The entire course of the biphasic disease is typically 1 3 weeks. The clinical spectrum of LCMV infection is broad. One third of postnatal infections are asymptomatic. Other patients develop extra neural disease that extends beyond the usual symptoms and may include orchitis, pneumonitis, myocarditis, parotitis, dermatitis, alo pecia, and pharyngitis. In others, the neurologic disease may be con siderably more severe than usual and may include transverse myelitis, Guillain Barr syndrome, hydrocephalus, and encephalitis. Recovery from acquired LCMV infection is usually complete, but fatalities occa sionally occur. LCMV infections acquired via solid organ transplantation always induce severe disease. Several weeks after the transplantation, recipi ents of infected organs develop fever, leukopenia, and lethargy. After these nonspecific symptoms, the course of the disease rapidly pro gresses to multiorgan system failure and shock. These cases are almost always fatal. Congenital Lymphocytic Choriomeningitis Virus Infection LCMV infection during pregnancy can kill the fetus and induce spon taneous abortion. Among surviving fetuses, the two clinical hall marks of congenital LCMV infection are vision impairment and brain dysfunction. The vision impairment in congenital LCMV infection is a result of chorioretinitis and the formation of chorioretinal scars. The scarring is usually bilateral and most commonly located in the periphery of the fundus, but involvement of the macula also occurs. Chapter 318 Lymphocytic Choriomeningitis Virus Daniel J. Bonthius 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 318 u Lymphocytic Choriomeningitis Virus 2079 Although the retinal injuries from congenital LCMV infection are often severe, it is the brain effects that cause the greatest disability. Pre natal infection with LCMV commonly induces either macrocephaly or microcephaly. Macrocephaly after LCMV infection is almost invari ably caused by noncommunicating hydrocephalus, stemming from inflammation within the ventricular system. Microcephaly is a result of the virus induced failure of brain growth. In addition to distur bances of head size, periventricular calcifications are also cardinal fea tures of congenital LCMV infection. Although hydrocephalus, microencephaly, and periventricular cal cifications are by far the most commonly observed abnormalities of the brain in congenital LCMV, other forms of neuropathology, alone or in combination, can also occur. These include periventricular cysts, porencephalic cysts, encephalomalacia, intraparenchymal calcifica tions, cerebellar hypoplasia, and neuronal migration disturbances. Infants with congenital LCMV infection typically present during the newborn period with evidence of brain dysfunction. The most com mon signs are lethargy, seizures, irritability, and jitteriness. Within the fetus, LCMV has a specific tropism for the brain. Thus unlike many other congenital infections, LCMV usually does not induce systemic manifestations. Birthweight |
7,919 | is typically appropriate for gesta tional age. Skin rashes and thrombocytopenia, which are common in several other prominent congenital infections, are unusual in congenital LCMV infection. Hepatosplenomegaly is only rarely observed, and serum liver enzyme levels are usually normal. Auditory deficits are unusual. LABORATORY FINDINGS In acquired (postnatal) LCMV infection, the hallmark laboratory abnormality occurs during the second (central nervous system) phase of the disease and is CSF pleocytosis. The CSF typically contains hun dreds to thousands of white blood cells, almost all of which are lym phocytes. However, CSF eosinophilia may also occur. Mild elevations of CSF protein and hypoglycorrhachia are common. In congenital LCMV infection, laboratory findings in the newborn depend on whether the infant is still infected or not. If the infant still harbors the infection, then examination of the CSF may reveal a lym phocytic pleocytosis. Unlike many other congenital infections, LCMV does not typically induce elevations in liver enzymes, thrombocytope nia, or anemia. In many cases, the most reliably abnormal test is the head CT scan, which typically reveals a combination of microenceph aly, hydrocephalus, and periventricular calcifications (Fig. 318.1). DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Acute LCMV infections can be diagnosed by isolating the virus from CSF. Polymerase chain reaction has also been used to detect LCMV RNA in patients with active infections. However, by the time of birth, a baby prenatally infected with LCMV may no longer harbor the virus. Thus congenital LCMV infection is more commonly diagnosed by serologic testing. The immunofluorescent antibody test detects both immunoglobulin (Ig) M and IgG and has greater sensitivity than the more widely available complement fixation method. The immunofluo rescent antibody test is commercially available, and its specificity and sensitivity make it an acceptable diagnostic tool. A more sensitive test for detecting congenital LCMV infection is the enzyme linked immu nosorbent assay, which measures titers of LCMV IgG and IgM and is performed at the Centers for Disease Control and Prevention. For acquired (postnatal) LCMV infection, the principal items in the differential diagnosis are the other infectious agents that can induce meningitis. These include bacteria, fungi, viruses, and some other forms of pathogens. The most common viral causes of meningitis are the enteroviruses, including coxsackieviruses and echoviruses, and the arbo viruses, including La Crosse encephalitis virus and equine encephalitis virus. Unlike LCMV, which is most common in winter, the enteroviruses and arboviruses are most commonly acquired in summer and early fall. The principal items in the differential diagnosis of congenital LCMV infection are the other infectious pathogens that can cross the placenta and damage the developing fetus. These infectious agents are linked by the acronym TORCHS and include Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, and syphilis. Toxoplasmosis, Zika virus infection, and cytomegalovirus infection are particularly difficult to differentiate from LCMV, because all of these infectious agents can produce microcephaly, intracerebral calcifications, and cho rioretinitis. Although clinical clues may aid in distinguishing one con genital infection from another, definitive identification of the causative infectious agent usually requires |
7,920 | laboratory data, including cultures and serologic studies. COMPLICATIONS Complications in children with congenital LCMV infection are nonspe cific and include the medical problems that commonly arise in scenarios involving ventriculoperitoneal shunts, severe seizure disorders, and static encephalopathy. These complications include shunt failure or infection, aspiration pneumonia, injuries from falls, and joint contractures. TREATMENT There is no specific treatment for acquired or congenital LCMV infection. An effective antiviral therapy for LCMV infection has not yet been developed. Ribavirin is active against LCMV and other arena viruses in vitro, but its utility in vivo is unproven. Immunosuppressive therapy, if present, should be reduced. Supportive Care Children with hydrocephalus from congenital LCMV infection often require placement of a ventriculoperitoneal shunt during infancy for treatment of hydrocephalus. Seizures often begin during early post natal life, are often difficult to control, and require administration of multiple antiepileptic medications. The mental retardation induced by congenital LCMV infection is often profound. In most cases, affected children should be referred for educational intervention during early life. The spasticity accompanying congenital LCMV infection is often severe. Although physical therapy can help to maintain the range of motion and minimize painful spasms and contractures, implantation of a baclofen pump is often helpful. PROGNOSIS The great majority of patients with postnatally acquired LCMV infec tion have a full recovery with no permanent sequelae. Rarely, postnatal infections induce hydrocephalus and require shunting. Rarer yet, post natal LCMV infection is fatal. In contrast to the usual benign outcome of postnatal infections, prenatal infections typically lead to severe and permanent disability. Fig. 318.1 Head CT scan from a 2 mo old microcephalic baby with congenital lymphocytic choriomeningitis virus infection. The scan re veals enlargement of the lateral ventricles (LV) and periventricular cal cifications (arrows). 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. 2080 Part XV u Infectious Diseases In children with congenital LCMV infection, brain function is nearly always impaired and chorioretinitis is invariably present. Mental retar dation, cerebral palsy, ataxia, epilepsy, and blindness are common neu rologic sequelae. However, children with congenital LCMV infection have diverse outcomes. All children with the combination of microen cephaly and periventricular calcifications are profoundly neurologically impaired. Blindness, medically refractory epilepsy, spastic quadriparesis, and mental retardation are typical of this group. However, other chil dren with congenital LCMV infection who do not have the combination of microencephaly and periventricular calcifications often have a more favorable outcome, with less severe motor, mental, and vision impair ments. Children with isolated cerebellar hypoplasia may be ataxic but have only mild or moderate mental retardation and vision loss. PREVENTION No vaccine exists to prevent LCMV infection. However, measures can be taken to reduce the risk of infection. Because rodents, especially house mice, are the principal reservoir of LCMV, people can reduce their risk of contracting the virus by minimizing their exposure to the secretions and excretions |
7,921 | of mice. This can be accomplished most effec tively by eliminating cohabitation with mice. Congenital LCMV infec tion will not occur unless a woman contracts a primary infection with LCMV during pregnancy. Thus women should be especially careful to avoid contact or cohabitation with mice during pregnancy. Pregnant women should also avoid contact with pet rodents, especially mice and hamsters. These facts should be stressed during prenatal visits. Acquisition of LCMV from solid organ transplantation represents a substantial risk to organ recipients. Prospective donors with LCMV meningitis or encephalitis pose a clear risk for transmitting a fatal infection to recipients. Healthcare providers, transplantation centers, and organ procurement organizations should be aware of the risks posed by LCMV and should consider LCMV in any potential donor with signs of aseptic meningitis but no identified infectious agent. The risks and benefits of offering and receiving organs from donors with possible LCMV infection should be carefully considered. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 319 Hantavirus Pulmonary Syndrome Scott B. Halstead Hantavirus pulmonary syndrome (HPS) is caused by multiple closely related hantaviruses that have been identified from the western United States, with sporadic cases reported from the eastern United States (Fig. 319.1) and Canada and important foci of disease in several coun tries in South America. HPS is characterized by a febrile prodrome followed by the rapid onset of noncardiogenic pulmonary edema and hypotension or shock. Sporadic cases in the United States caused by related viruses may manifest with renal involvement. Cases in Argen tina and Chile sometimes include severe gastrointestinal hemorrhag ing; nosocomial transmission has been documented in this geographic region only. ETIOLOGY Hantaviruses are a genus in the family Bunyaviridae, which are lipid enveloped viruses with a negative sense RNA genome composed of three unique segments. Several pathogenic viruses that have been recognized within the genus include Hantaan virus, which causes the severe disease; hemorrhagic fever with renal syndrome (HFRS), seen primarily in mainland Asia (see Chapter 317); Dobrava virus, the cause of a form of HFRS seen primarily in the Balkans; Puumala virus, which causes a milder disease with a high proportion of subclinical infections prevalent in northern Europe; and Seoul virus, which results in mod erate HFRS and is transmitted predominantly in Asia by urban rats or worldwide by laboratory rats. Prospect Hill virus, a hantavirus that is widely disseminated in meadow voles in the United States, is not known to cause human disease. There are an increasing number of case reports of European hantaviruses causing HPS. HPS is associated with sin nombre virus, isolated from deer mice, Pero myscus maniculatus, in New Mexico. The multiple HPS like agents in the Northern Hemisphere isolated to date belong to a single genetic group of hantaviruses and are associated with rodents of the family Muridae, sub family Sigmodontinae. These rodent species are restricted to the Ameri cas, suggesting that HPS may be a Western Hemisphere disease. EPIDEMIOLOGY Persons acquiring HPS generally have a history of recent outdoor expo sure or |
7,922 | live in an area with large populations of deer mice. Clusters of cases have occurred among individuals who have cleaned houses that were rodent infested. P. maniculatus is one of the most common North American mammals and, where found, is frequently the dominant member of the rodent community. About half of the average of 30 cases seen annually occurs between the months of May and July. Patients are almost exclusively 12 70 years of age; 60 of patients are 20 39 years of age. Rare cases are reported in children younger than 12 years of age. Two thirds of patients are male, probably reflecting their greater outdoor activities. It is not known whether almost complete absence of disease in young children is a reflection of innate resistance or simply lack of expo sure. Evidence of human to human transmission has been reported in Argentine outbreaks. As of January 2017, 728 cases of hantavirus disease have been reported in the United States since surveillance began in 1993. Hantaviruses do not cause apparent illness in their reservoir hosts, which remain asymptomatically infected for life. Infected rodents shed virus in saliva, urine, and feces for many weeks, but the duration of shedding and the period of maximum infectivity are unknown. The presence of infectious virus in saliva, the sensitivity of these animals to parenteral inoculation with hantaviruses, and field observations of infected rodents indicate that biting is important for rodent to rodent transmission. Aerosols from infective saliva or excreta of rodents are implicated in the transmission of hantaviruses to humans. Persons visiting animal care areas housing infected rodents have been infected Cases of hantavirus disease per State of reporting 0 15 16 50 50 Fig. 319.1 Total number of confirmed cases of hantavirus pulmonary syndrome, by state reporting, United States, 1993 2016. N 728 as of January 2017. (From Viral Special Pathogens Branch, Centers for Disease Control and Prevention. http:www.cdc.govhantavirussurveillance reporting state.html) 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 320 u Rabies 2081 after exposure for as little as 5 minutes. It is possible that hantaviruses are spread through contaminated food and breaks in skin or mucous membranes; transmission to humans has occurred by rodent bites. Person to person transmission is distinctly uncommon but has been documented in Argentina. PATHOGENESIS HPS is characterized by sudden and catastrophic pulmonary edema, resulting in anoxia and acute heart failure. The virus is detected in pulmonary capillaries, suggesting that pulmonary edema is the con sequence of a T cell attack on virus infected capillaries. The disease severity is predicted by the level of acute phase viremia titer. A useful hamster model of HPS is available. CLINICAL MANIFESTATIONS HPS is characterized by a prodrome and a cardiopulmonary phase. The mean duration after the onset of prodromal symptoms to hospi talization is 5.4 days. The mean duration of symptoms to death |
7,923 | is 8 days (median: 7 days; range: 2 16 days). The most common prodromal symptoms are fever and myalgia (100); cough or dyspnea (76); gas trointestinal symptoms, including vomiting, diarrhea, and midabdom inal pain (76); and headache (71). The cardiopulmonary phase is heralded by progressive cough and shortness of breath. The most com mon initial physical findings are tachypnea (100), tachycardia (94), and hypotension (50). Rapidly progressive acute pulmonary edema, hypoxia, and shock develop in most severely ill patients. Pulmonary vascular permeability is complicated by cardiogenic shock associated with increased vascular resistance. The clinical course of the illness in patients who die is characterized by pulmonary edema accompanied by severe hypotension, frequently terminating in sinus bradycardia, electromechanical dissociation, ventricular tachycardia, or fibrillation. Hypotension may be progressive even with adequate oxygenation. HPS virus is excreted in the urine during the acute illness phase, and survi vors may demonstrate evidence of chronic renal damage. DIAGNOSIS The diagnosis of HPS should be considered in a previously healthy patient presenting with a febrile prodrome, acute respiratory distress, and thrombocytopenia who has had outdoor exposure in the spring and sum mer months. A specific diagnosis of HPS is made by serologic tests that detect hantavirus immunoglobulin M antibodies. The early appearance of immunoglobulin G antibodies signals probable recovery. Hantavirus antigen can be detected in tissue by immunohistochemistry and ampli fication of hantavirus nucleotide sequences detected by reverse tran scriptase polymerase chain reaction. The state health department or the Centers for Disease Control and Prevention should be consulted to assist in the diagnosis, epidemiologic investigations, and outbreak control. Laboratory Findings Laboratory findings include leukocytosis (median: 26,000 cellsL), an elevated hematocrit resulting from hemoconcentration, throm bocytopenia (median: 64,000 cellsL), prolonged prothrombin and partial thromboplastin times, elevated serum lactate dehydrogenase concentration, decreased serum protein concentrations, proteinuria, and microscopic hematuria. Patients who die often experience dis seminated intravascular coagulopathy, including frank hemorrhage and exceptionally high leukocyte counts. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes adult respiratory distress syndrome, pneumonic plague, psittacosis, severe mycoplasmal pneumonia, influ enza, leptospirosis, inhalation anthrax, rickettsial infections, pulmo nary tularemia, atypical bacterial and viral pneumonia, legionellosis, meningococcemia, and other sepsis syndromes. The key determinant in the diagnosis of HPS is throm bocyt openia. TREATMENT Management of patients with hantavirus infection requires mainte nance of adequate oxygenation and careful monitoring and support of cardiovascular function. The pathophysiology of HPS somewhat resembles that of dengue shock syndrome (see Chapter 315). Pressor or inotropic agents, such as dobutamine, should be administered in combination with judicious volume replacement to treat symptomatic hypotension or shock while avoiding exacerbation of the pulmonary edema. Intravenous ribavirin, which is lifesaving if given early in the course of HFRS and is effective in preventing death in the hamster model, has not yet been demonstrated to be of value in HPS. Further information and advice about management, control mea sures, diagnosis, and collection of biohazardous specimens can be obtained from the Centers for Disease Control and Prevention, National Center for Infectious Diseases, Viral Special Pathogens Branch, |
7,924 | Atlanta, Georgia 30333 (470 312 0094). PROGNOSIS In some geographic areas, fatality rates for HPS have been 50. Severe abnormalities in hematocrit, white blood cell count, lactate dehydro genase value, and partial thromboplastin time and a high viral load predict death with high specificity and sensitivity. The early appearance of immunoglobulin G antibodies may signal a hopeful prognosis. PREVENTION Avoiding contact with rodents is the only preventive strategy against HPS. Rodent control in and around the home is important. Barrier nurs ing is advised, and biosafety level 3 facilities and practices are recom mended for laboratory handling of blood, body fluids, and tissues from suspect patients or rodents, because the virus may be aerosolized. How ever, to date, there are no cases of person to person transmission of HPS. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 320 Rabies Rodney E. Willoughby Jr. Rabies virus is a bullet shaped, negative sense, single stranded, enveloped RNA virus from the family Rhabdoviridae, genus Lyssa virus. There are 17 species of Lyssavirus, divided into three antigenic phylogroups. Rabies vaccines and immunoglobulins are active against phylogroup I viruses. The classic rabies virus (phylogroup I, genotype 1) is distributed worldwide and naturally infects a large variety of ani mals. The other genotypes are more geographically confined, with none found in the Americas. Six Lyssavirus genotypes are associated with rabies in humans, although genotype 1 accounts for the great majority of cases. Within genotype 1, different lineages are specific to animal reservoirs, although cross species transmission can occur. Cosmopolitan dog, vampire bat, and insectivorous bat lineages in the Americas cause overlapping but distinct clinical syndromes and vary in immunogenicity, affecting survival. EPIDEMIOLOGY Rabies is present on all continents except Antarctica. Rabies predomi nantly afflicts underaged, poor, and geographically isolated popula tions. Approximately 59,000 cases of human rabies occur in Africa and Asia annually. Rabies virus can infect any mammal or bird, but true animal reservoirs that maintain the presence of rabies virus in the population are limited to terrestrial carnivores and bats. Worldwide, transmission from dogs accounts for 90 of human cases. In Africa and Asia, other animals serve as prominent reservoirs, such as jackals, mongooses, and raccoon dogs. In the United States, raccoons are the most infected wild animal along the eastern seaboard. Three lineages 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. 2082 Part XV u Infectious Diseases of skunk rabies are endemic in the Midwest (north and south) and California, gray foxes harbor rabies in Arizona and Texas, red foxes and arctic foxes harbor rabies in Alaska, and mongooses carry rabies in Puerto Rico. Rabies occurs infrequently in livestock. Among Ameri can domestic pets, infected cats outnumber infected dogs, probably because cats frequently prowl unsupervised and are not uniformly sub ject to vaccine laws. Rabies is rare in small mammals, including mice, squirrels, and rabbits; to date, |
7,925 | no animal to human transmission from these animals has been documented. The epidemiology of human rabies in the United States is dominated by cryptogenic bat rabies. Bats are migratory in the spring and fall; rabid bats are identified in every state of the union except Hawaii. In almost all cases of bat associated human rabies in the United States, there was no history of a bat bite. Among inhabitants of the Peru vian Amazon region who have exposure to rabies infected vampire bats, there are some who have rabies virusneutralizing antibodies. Antibody positive patients remember bat bites but do not recall symp toms of rabies. In the United States, 30,000 episodes of rabies postexposure pro phylaxis (PEP) occur annually. Between one and three endemic human cases are diagnosed annually, half postmortem. There have been five outbreaks of rabies associated with solid organ and corneal transplantation. TRANSMISSION Rabies virus is found in large quantities in the saliva of infected ani mals, and transmission occurs almost exclusively through inoculation of the infected saliva through a bite or scratch from a rabid mammal. Approximately 3550 of people who are bitten by a known rabies infected animal and receive no PEP contract rabies. The transmission rate is increased if the victim has suffered multiple bites and if the inoculation occurs in highly innervated parts of the body such as the face and the hands. Infection does not occur after exposure of intact skin to infected secretions, but virus may enter the body through intact mucous membranes. Claims that spelunkers may experience rabies after inhaling bat excreta have come under doubt, although inhala tional exposure can occur during laboratory accidents. No case of nosocomial transmission to a healthcare worker has been documented to date, but caregivers of a patient with rabies are advised to use full barrier precautions. The virus is rapidly inactivated in the environment, and contamination of fomites is not a mechanism of spread. PATHOGENESIS After inoculation, rabies virus replicates slowly and at low levels in mus cle or skin. This slow initial step likely accounts for the diseases long incubation period. The virus then enters the peripheral motor nerve, using the nicotinic acetylcholine receptor and possibly other receptors for entry. Once in the nerve, the virus travels by fast axonal transport, crossing synapses roughly every 12 hours. Rapid dissemination occurs throughout the brain and spinal cord before symptoms appear. Infec tion of the dorsal root ganglia is apparently futile but causes charac teristic radiculitis. Infection concentrates in the brainstem, accounting for autonomic dysfunction and relative sparing of cognition. Despite severe neurologic dysfunction with rabies, histopathology reveals lim ited damage, inflammation, or apoptosis. The pathologic hallmark of rabies, the Negri body, is composed of clumped viral nucleocapsids that create cytoplasmic inclusions on routine histology. Negri bodies can be absent in documented rabies virus infection. Rabies may be a metabolic disorder of neurotransmission; tetrahydrobiopterin defi ciency in human rabies causes severe deficiencies in dopamine, norepi nephrine, and serotonin. After infection of the central nervous |
7,926 | system, the virus travels anterograde through the peripheral nervous system to virtually all innervated organs, further exacerbating dysautonomia. It is through this route that the virus infects the salivary glands. Many victims of rabies die from uncontrolled cardiac dysrhythmia in the first week of objective signs of rabies. Deficiency of tetrahydrobiopterin, an essential cofactor for neuronal nitric oxide synthase, is predicted to lead to spasm of the basilar arter ies. Onset of vasospasm has been confirmed in a few patients within 5 8 days of the first hospitalization, at about the time coma supervenes in the natural history. Metabolites in cerebrospinal fluid (CSF) con sistent with ketogenesis are associated with demise. Immune response to rabies is delayed, usually evident 4 14 days after onset of clinical signs. Immune response to rabies varies by lineage; antibody responses in CSF are often inferior to those in serum. Common complications include complete heart block in dog rabies and cerebral edema in bat rabies. CLINICAL MANIFESTATIONS The incubation period for rabies is 1 3 months. In severe wounds to the head, symptoms may occur within 5 days after exposure, and occa sionally the incubation period can extend to 8 years. Rabies has two principal clinical forms, but these overlap in practice. Encephalitic or furious rabies is extrapolated from carnivores and begins with non specific symptoms, including fever, sore throat, malaise, headache, nausea and vomiting, and weakness. Symptoms are often accompanied by paresthesia and pruritus at or near the site of the bite. The patient begins to demonstrate symptoms of encephalitis, with agitation, sleep disturbance, or depressed mentation. Characteristically, patients with rabies encephalitis initially have periods of lucidity alternating with periods of profound encephalopathy. Hydrophobia and aerophobia are the cardinal signs of rabies; they are unique to humans and are not universal or specific. Phobic spasms are manifested by agitation and fear created by being offered a drink or fanning of air in the face, which in turn produce choking and aspiration through spasms of the pharynx, neck, and diaphragm. Seizures are rare and should point to an alternative diagnosis; orofacial dyskinesias and myoclonus may be confused with seizures. Severe dysautonomia is common, and cardiac arrests occur in 25 of patients in the first week of hospitalization. The illness is relentlessly progressive. There is a dissociation of brain elec trical activity with findings of brainstem coma caused by anterograde denervation. Death almost always occurs within 1 2 days of hospital ization in developing countries and by 18 days of hospitalization with intensive care. Paralytic or dumb rabies, extrapolated from herbivores, is seen much less frequently and is characterized principally by fevers and ascending motor weakness affecting both the limbs and the cranial nerves. Most patients with paralytic rabies also have some element of encephalopathy as the disease progresses subacutely. Case reports suggest that milder forms of rabies encephalitis may exist, and 45 rabies survivors are known. Rabies should be considered earlier and more frequently than current practice to improve outcomes. DIFFERENTIAL DIAGNOSIS The differential diagnosis |
7,927 | of rabies encephalitis includes all forms of severe cerebral infections, tetanus, and some intoxications and envenomations. Rabies can be confused with autoimmune (antiN methyl d aspartate receptor, NMDAR) encephalitis, other infectious forms of encephalitis, psychiatric illness, drug abuse, and conversion disorders. Paralytic rabies is frequently confused with Guillain Barr syndrome. The diagnosis of rabies is frequently delayed in Western countries because of the unfamiliarity of the medical staff with the infection. These considerations highlight the need to pursue a his tory of contact with an animal belonging to one of the known res ervoirs for rabies or to establish a travel history to a rabies endemic region. DIAGNOSIS The Centers for Disease Control and Prevention (CDC) require complementary tests to confirm a clinically suspected case of rabies. The virus can be grown both in cell culture and after animal injec tion, but these methods are slow. Pan lyssavirus reverse transcription polymerase chain reaction is 90 sensitive for the diagnosis of rabies when done on skin and iteratively in saliva. Rabies antigen is detected 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 320 u Rabies 2083 through immunofluorescence of saliva or biopsies of hairy skin or brain. Corneal impressions are not recommended. Rabies specific antibody can be detected in serum or CSF samples, but most patients die while seronegative. Antirabies antibodies are present in the sera of patients who have received an incomplete course of the rabies vaccine, precluding a meaningful interpretation in this setting. Recent treatment with intravenous immunoglobulin may result in a false positive antibody test. Antibody in CSF is rarely detected after vaccination and is considered diagnostic of rabies regardless of immunization status. CSF abnormalities in cell count, glucose, and protein content are minimal and not diagnostic. MRI findings in the brain are late. TREATMENT AND PROGNOSIS Rabies is generally fatal. Conventional critical care yielded 6 survivors from 79 attempts since 1990. Seventeen of 103 patients survived with use of the Milwaukee Protocol (MP) (http:www.mcw.edurabies); neurologic outcomes are poor in half of patients. Neither rabies immu noglobulin (RIG) nor rabies vaccine provides benefit once symptoms have appeared. Among 10 survivors of rabies after use of rabies vac cine, 7 had poor neurologic outcomes. Among seven vaccine nave survivors, two had poor outcomes. Antiviral treatments have not been effective; favipiravir has been administered to eight patients with mod est clinical effect. Ribavirin and RIG delay the immune response and should be avoided. In contrast, appearance of the normal antibody response by 7 days is associated with clearance of salivary viral load and survival. PREVENTION Primary prevention of rabies infection includes vaccination of domes tic animals and education to avoid wild animals, stray animals, and animals with unusual behavior. Immunization and Fertility Control of Animal Reservoirs The introduction of routine rabies immunization for domestic pets in the United States and Europe during the |
7,928 | middle of the 20th century virtually eliminated infection in dogs. Dog rabies has now been almost eliminated from the Americas; residual cases concentrate in the Carib bean and Bolivia. In the 1990s, control efforts in Europe and North America shifted to immunization of wildlife reservoirs of rabies, where rabies was newly emerging. These programs employed bait laced with either an attenuated rabies vaccine or a recombinant rabies surface gly coprotein inserted into vaccinia, distributed by air or hand into areas inhabited by rabid animals. Human contact with vaccine laden bait has been infrequent. Adverse events after such contact have been rare, but the vaccinia vector poses a threat to the same population at risk for vac cinia itself, namely, pregnant women, immunocompromised patients, and people with atopic dermatitis. Mass culling of endemic reservoirs has never worked; vaccination and fertility control stop outbreaks. Bats are ubiquitous and very important for insect control. Less than 1 of free flying bats but 8 of downed bats and bats found in dwellings are rabid. Postexposure Prophylaxis Only one case of rabies has been documented in a person in the United States receiving the recommended schedule of PEP since introduction of modern cellular vaccines in the 1970s. Given the incubation period for rabies, PEP is a medical urgency, not emergency. The relevance of rabies for most pediatricians centers on evaluating whether an animal exposure warrants PEP (Fig. 320.1). The decision to proceed ultimately depends on the local epidemiol ogy of animal rabies as determined by active surveillance programs, information that can be obtained from local and state health depart ments. In general, bats, raccoons, skunks, coyotes, and foxes should be considered rabid unless proven otherwise through euthanasia and testing of brain tissue, whereas bites from small herbivorous animals (squirrels, hamsters, gerbils, chipmunks, rats, mice, and rabbits) can be discounted. The response to bites from a pet, particularly a dog, cat, or ferret, depends on local surveillance statistics and on whether the animal is vaccinated and available for observation. Areas free of canine lineage of rabies virus may still have rabid dogs and cats through wild life transmission. The approach to nonbite bat exposures is controversial. In response to the observation that most cases of rabies in the United States have been caused by bat variants and that most affected patients had no rec ollection of a bat bite, the CDC has recommended that rabies PEP be considered after any physical contact with bats and when a bat is found in the same room as persons who may not be able to accurately report a bite, assuming that the animal is unavailable for testing. Such people include young children, the mentally disabled, and intoxicated individuals. Other nonbite contacts (e.g., handling a carcass, exposure to an animal playing with a carcass, or coming into contact with blood or excreta from a potentially rabid animal) usually do not require PEP. In all instances of a legitimate exposure, effort should be made to recover the animal for quarantine and |
7,929 | observation or brain examina tion after euthanasia. Testing obviates the need for PEP more than half the time. In most instances, PEP can be deferred until the results of observation or brain histology are known. In dogs, cats, and ferrets, symptoms of rabies always occur within several days of viral shedding; therefore in these animals a 10 day observation period is sufficient to eliminate the possibility of rabies. No duration of time between exposure and onset of symptoms should preclude rabies prophylaxis. Rabies PEP is most effective when applied expeditiously. Nevertheless, the series should be initiated in the asymptomatic person as soon as possible, regardless of the length of time since the bite. Rabies vaccine and RIG are contraindicated once symptoms develop. The first step in rabies PEP is to cleanse the wound thoroughly. Soapy water is sufficient to inactivate an enveloped virus, and its effectiveness is supported by broad experience. Other commonly used disinfectants, such as iodine containing preparations, are virucidal and should be used in addition to soap when available. Probably the most important aspect of this component is that the wound is cleansed with copious volumes of disinfectant. Primary closure is avoided; wounds may be bacterially infected as well, so cosmetic repair should follow. Antibiot ics and tetanus prophylaxis (see Chapter 257) should be applied with the use of usual wound care criteria. Schedules and indications for administration of rabies vaccine and human derived rabies immunoglobulin (HRIG) are available at the CDC website (https:www.cdc.govvaccineshcpacip recsvacc specificrabies.html). These do not harmonize fully with international recommendations by the World Health Organization that seek greater efficiencies in PEP and use of RIG after dog bites. The second component of rabies PEP consists of passive immuniza tion with RIG. Most failures of PEP are attributed to not using RIG. HRIG, the formulation used in industrialized countries, is adminis tered at a dose of 20 IUkg. Globally, the World Health Organization recommends that as much of the dose is infused around the wound as possible. In the United States, where bat rabies dominates, the remain der is injected intramuscularly in a limb distant from the one injected with the killed vaccine. Like other immunoglobulin preparations, RIG interferes with the take of live viral vaccines for at least 4 months after administration of the RIG dose. A more concentrated formulation of HRIG is available, which may be more suitable for bites on the face and digits to minimize risk of compartment syndrome after injection. HRIG is not available in many parts of the developing world. Modern preparations of equine RIG are associated with fewer side effects than prior products composed of crude horse serum. Regrettably, for a large segment of the worlds population, no passive immunization product is available at all, so preexposure prophylaxis (PreRP) should be con sidered. Monoclonal antibody products are in clinical trials and may alleviate this deficiency. The third component of rabies PEP is immunization with inacti vated vaccine. In most of the world, cell based vaccines have replaced |
7,930 | previous preparations. Two formulations currently are available in the United States, namely, RabAvert (Chiron Behring Vaccines, Maharash tra, India), a purified chick embryo cellcultivated vaccine, and Imovax 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. 2084 Part XV u Infectious Diseases Rabies (Aventis Pasteur, Bridgewater, NJ), cultivated in human diploid cell cultures. In both children and adults, both vaccines are adminis tered intramuscularly in a 1 mL volume in the deltoid or anterolateral thigh on days 0, 3, 7, and 14 after presentation. Injection into the gluteal area is associated with a blunted antibody response, so this area should not be used. The rabies vaccines can be safely administered during pregnancy. In most persons the vaccine is well tolerated; most adverse effects are related to booster doses. Pain and erythema at the injection site occur commonly, and local adenopathy, headache, and myalgias occur in 1020 of patients. Approximately 5 of patients who receive the human diploid cell vaccine experience an immune complexmedi ated allergic reaction, including rash, edema, and arthralgias, several days after a booster dose. The World Health Organization has approved schedules using smaller amounts of vaccine, administered intrader mally, that are immunogenic and protective, but none is approved for use in the United States. Other cell culturederived rabies virus vaccines are available in the developing world. A few countries still produce nerve tissuederived vaccines; these preparations are poorly immunogenic, and cross reactivity with human nervous tissue may occur, producing severe neurologic symptoms even in the absence of rabies infection. Prompt travel to a clinic or country to obtain modern rabies vaccine is advised instead. Preexposure Prophylaxis The killed rabies vaccine can be given to prevent rabies in persons at high risk for exposure to wild type virus, including laboratory person nel working with rabies virus, veterinarians, and others likely to be exposed to rabid animals as part of their occupation. PreEP should be considered for persons traveling to a rabies endemic region where there is a credible risk for a bite or scratch from a rabies infected ani mal, particularly if there is likely to be a shortage of RIG or cell cul turebased vaccine. Rabies vaccine as part of the routine vaccine series is under investigation in some countries. The schedule for PreEP con sists of two intramuscular injections on days 0, and 7; other schedules are available globally. PEP in the patient who has received PreEP or a prior three doses of PEP consists of two doses of vaccine (one each on days 0 and 3) and does not require RIG. Immunity from PreEP wanes after several years and requires boosting if the potential for exposure to rabid animals recurs. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 320.1 Algorithm for evaluating a child for rabies postexposure prophylaxis. This and any other algorithm should be used in concert with local |
7,931 | epidemiologic information regarding the incidence of animal rabies in any given location. NoYes Bite, scratch, or mucous membrane contact from a mammal Squirrels, hamsters, gerbils, chipmunks, rat, mice, rabbits Consult local health officials. Quarantine animal for 10 days. Signs of rabies? Animal available for observation? Dog, cat, ferret Animal available for testing? PEP No PEP PEP PEP No PEP Consult local health officials Domestic animals: dogs, cats, ferrets Wildlife: bats, raccoons, skunks, foxes, coyotes In some locations: livestock No PEP Contact health department for testing. Testing positive? No Yes Yes Yes Yes Yes No No No NoYes NoYes No Chapter 321 Polyomaviruses Bijal A. Parikh Human polyomaviruses (PyV) comprise a unique group of viruses that cause disease in immunocompromised individuals but not in the healthy immune competent host. The two best studied human PyV, BK PyV and JC PyV, are acquired relatively early in life and gener ally cause no clinical disease, despite occasional bouts of asymptomatic viral shedding. PyV associated sequelae become especially relevant in the setting of posttransplant renal graft failure and hemorrhagic cystitis in the case of BK PyV and neurologic disease for JC PyV reac tivation. The number of human PyV has expanded dramatically, with discovery of up to 12 additional viruses. Two PyV, designated KI virus and WU virus, can be detected in respiratory samples from children; however, their disease associations are not as well established outside of a few case reports. Exceptions include Merkel cell or MC PyV and trichodysplasia spinulosa associated or TS PyV, yet their relevance in the pediatric population is limited. Current knowledge regarding BK PyV and JC PyV epidemiology and disease associations with special emphasis on diagnostic and clinical management of pediatric popula tions is summarized next. GENOMIC ORGANIZATION PyV are nonenveloped, icosahedral virions of 40 45 nm in diameter. The genomes are circular double stranded DNA composed of approximately 5,000 base pairs. The type member of the parent family, Polyomaviridae, is simian virus 40 (SV40). Translation of proteins occurs from both early and late transcripts, transcribed in opposite directions from the noncoding control region (NCCR). The host range of PyV is very broad, having been isolated from a variety of mammals, birds, and even fish. However, PyV are strictly species specific; thus human PyV only infect humans. PyV EPIDEMIOLOGY Almost 90 of adults have been infected with BK PyV by their third decade; only 20 of children are seropositive for BK PyV by age 3, 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 321 u Polyomaviruses 2085 climbing to 80 by age 7. Approximately 5070 of adults are sero positive for JC PyV, and children show even lower seroprevalence rates, with less than 30 positive by age 7. Both BK PyV and JC PyV are pri marily respiratory tract infections with subsequent spread to the kid neys and the central nervous system |
7,932 | (CNS), respectively. Tropism for BK PyV has been demonstrated to be the bladder urothelium and renal tubular cells, where lifelong latency is likely established. In contrast, the primary tropism for JC PyV includes the CNS and lymphoid and renal tissue. MC PyV is found and shed from skin, although little is known about its acquisition. BK PyV BK PyV was first detected in the urine from a renal allograft recipient suffering from ureteral stenosis with the initials BK. In the immuno competent host, BK PyV may never result in any observable clinical disease. However, in the immunocompromised, BK PyV reactivation can lead to serious consequences. Immune suppression can either be iatrogenic after transplantation or constitutional, such as with inher ited immune deficiency syndromes. In renal transplant recipients, interstitial nephritis, renal dysfunction, and ultimately graft failure can develop. In hematopoietic stem cell transplant (HSCT) recipients, reactivation can lead to hemorrhagic cystitis. Although the incidence of such symptomatic complications is rare, BK PyV must be proac tively managed through careful monitoring and alteration of immu nosuppressive regimens. Although the most common complication after pediatric kidney transplantation continues to be graft failure caused by chronic rejec tion, infections of the transplanted organ can also promote graft dysfunction. Common infectious complications placing pediatric recipients at risk for graft failure include EBV, CMV, BK PyV, and JC PyV. Fortunately, with current monitoring and interventions, the inci dence of pediatric transplants that will fail as a result of nephropathy correlating with BK PyV infection is very low. Nearly two thirds of pediatric renal transplant recipients show evi dence of BK viruria (virus in the urine), with one fifth showing viremia (virus in the blood). BK virusassociated nephropathy (BKVAN) can initially manifest as rising creatinine and is diagnosed definitively through core renal biopsies. However, because the nephropathy can be focal, a single unaffected core specimen does not exclude disease. In the core biopsy, BKVAN is characterized by tubular injury with cel lular enlargement, epithelial necrosis, erosion of tubular basement membranes, and intranuclear inclusion bodies in epithelial cells. If untreated, tubular necrosis and sclerosing allograft nephropathy can lead to irreversible renal impairment and rejection. Importantly, reduction of immunosuppression in viremic patients has been highly effective in limiting rejection caused by BKVAN. Rates of BKVAN in the pediatric population have been estimated at around 5, and approximately 0.5 of renal transplant recipients will lose their graft because of BKVAN. Laboratory evidence of BK PyV infection is best achieved through a microscopic urine examination, followed by molecular (poly merase chain reaction PCRbased) quantitative analysis of urine and plasma (Table 321.1). Depending on the method and analyte, a wide range of sensitivity and specificity has been reported. Detection of haufen, which are viral aggregates that can be detected only by electron microscopy, is nearly 100 sensitive and specific but requires special equipment. An alternative diagnostic approach includes microscopic examination for the presence of decoy cells (urothelial cells containing abundant viral particles) in the urine; however, sensi tivity is poor, and thus |
7,933 | examination for decoy cells is not the preferred screening method. More commonly, PCR testing for BK genomic DNA from urine and plasma is employed. Although highly sensi tive for BK PyV, the specificity of single time point molecular tests for predicting renal nephropathy is low, as asymptomatic individuals can intermittently shed virus without progression to renal disease. There fore the presence of isolated BK viruria is not sufficient to diagnose infection leading to renal impairment. Accurate quantification of BK PyV in plasma and urine is essential for standardized care across transplant centers with broadly applied thresholds for intervention. The first WHO international standard for BK PyV was made available to enable interassay comparisons in 2016. In 2020, the first molecular platform to obtain FDA clearance for quan titative BK PyV testing included plasma and urine for monitoring renal transplant recipients based on the use of the WHO standard. No single guideline exists for routine monitoring for BKVAN in either pediatric or adult populations, and thus transplant centers need to design strategies that best fit their local prevalence rates. One proposed guideline suggests urine screening monthly in the first months after transplant, then every 3 months for 2 years, and then annually in years 3, 4, and 5. If viruria exceeds 1 107 copiesmL, then biopsy should be performed with a concomitant reduction in immunosuppression. In addition, plasma levels exceeding 1 104 copiesmL should also prompt a biopsy and reduction in immuno suppression. Centers may include routine renal biopsies to monitor for overall graft health, and these may also be used to evaluate for BKVAN. Although there are no direct antiviral treatments for BK PyV, the primary clinical parameter shown to have the greatest effect on preventing long term kidney damage and rejection is careful adjust ment of the dose of immunosuppression. This adjustment allows the bodys natural immunity, specifically the T cell compartment, to effectively reduce the viral burden. However, decreasing immu nosuppression comes at a risk of graft rejection if not cautiously approached. A growing body of literature is beginning to emerge that reevaluates the anecdotal successes of specific treatments, including cidofovir (CDV) and leflunomide. These two drugs have shown effi cacy in culture conditions, yet clinical utility remains unproven. The antibiotic class of fluoroquinolones has also demonstrated in vitro activity without a subsequent sustained clinical effect. Finally, both intravenous immunoglobulin (IVIG) and cyclosporine A have shown equally limited effects in clinical trials. In summary, the cur rent treatment options rely heavily on early and accurate detection of infection followed by an appropriately titered dose reduction in immunosuppressive drugs. In pediatric HSCT recipients, a common association between BK PyV shedding and hemorrhagic cystitis (HC) has been clinically observed. HC can occur in one fifth to one third of pediatric patients after HSCT; however, it rarely results in death. Unfortunately, the long term sequelae of fibrosis and bladder contracture can lead to significant morbidity. After HSCT, either early onset (within 1 week) or late onset (2 8 weeks) HC may |
7,934 | occur, with the timing providing insight into the pathogenic process. Early onset HC appears to be a result of direct urothelial damage from conditioning agents (cyclophosphamide, Table 321.1 Recommendations for Patients with BK PyVAssociated Nephropathy SCREENING DIAGNOSIS MONITORING Cytology Poor sensitivity Decoy cells, Haufen Poor sensitivity Molecular Routine BK PyV PCR after renal transplant BK viremia 10,000 copiesmL Follow until viral loads trend lower Pathology Institution specific for the frequency of kidney biopsy Kidney allograft biopsy with characteristic changes and positive immunohistochemistry (IHC) demonstrating viral antigen Institution specific for the frequency of kidney biopsy 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. 2086 Part XV u Infectious Diseases Table 321.2 Recommendations for Patients with BK PyVAssociated Hemorrhagic Cystitis SCREENING DIAGNOSIS MONITORING Clinical Suspect with anemia, thrombocytopenia, dysuria, or urinary obstruction after HSCT Cystitislower abdominal pain Follow clinical resolution Cytology Gross hematuria Gross hematuria No recommendations Molecular No recommendations BK viruria 10,000,000 copiesmL busulfan, radiation) before transplant, independent of any infectious process, whereas the more commonly observed late onset HC occurs around the time of engraftment. Although primarily associated with BK PyV, the differential diagnosis for late onset HC also includes JC PyV, CMV, and adenovirus. All causes of HC must be carefully con sidered for effective clinical management. Diagnosis of HC requires a triad of findings: cystitis, gross hematu ria, and urine BK PyV loads 7 log10 copiesmL (Table 321.2). Cur rent guidelines do not recommend screening for BK PyV after HSCT, citing a lack of effective prophylactic treatment. However, long term sequelae of renal impairment greater than 2 years after transplant have been described, and therefore routine monitoring may need to eventu ally be considered. The presence of BK PyV in the urine occurs in the majority of HSCT recipients and is therefore neither specific nor predictive of BK PyV HC. Although not as sensitive, the presence of virus in plasma of 3 log10 copiesmL is seen in two thirds of recipients with BK PyV HC, and diminution of viremia correlates strongly with resolu tion of HC. For individuals with severe HC, standard treatment includes hyperhydration and diuretics. Bladder irrigation may be necessary to avoid renal damage and clotting. Less severe cases will spontaneously resolve in a few weeks. Unlike with renal transplantation, reduction of immunosuppression carries a large risk for potentially life threatening graft versus host disease (GVHD) and so is not considered to be the initial treatment approach. Additionally, if thrombocytopenia and anemia are present, appropriate transfusions should be initiated to maintain adequate blood counts. The role of CDV in treating or pre venting HC in the context of HSCT remains controversial, and thus professional society guidelines currently do not recommend its routine use. JC PyV JC PyV was first detected in the brain of a patient with Hodgkin lym phoma with the initials JC. JC PyV can be acquired by |
7,935 | the respira tory route and through ingestion from contaminated surfaces, food, and water and ultimately establishes latency in the kidneys, brain, and various lymphoid organs. In renal transplant recipients, JC PyV can be shed in the urine but only rarely causes nephropathy. After HSCT, HC from BK PyV is far more likely than from JC PyV. Conversely, only JC PyV infects the oligodendrocytes of the CNS and is responsible for progressive multifocal leukoencephalopathy (PML). PML is a fatal demyelinating disease that results from the lysis of specific glial cells in afflicted immunocompromised individuals. In patients with hema tologic malignancy, autoimmune disorders, or HIV infection leading to decreased cellular immunity, JC PyV reactivation can lead to PML. In immunocompetent adults, PML is a feared consequence of mono clonal antibody treatments for multiple sclerosis. However, the litera ture for JC PyV infection in the pediatric population is sparse, with the majority of studies provided as case reports. As a result, many of the clinical guidelines for screening, diagnosis, and therapy must be extended from the adult literature. The more common clinical manifestations of PML in children are similar to what has been observed in adults and includes hemipare sis, ataxia, dysarthria, and seizures. Evaluation for PML is primarily through radiologic imaging, with primary findings consistent with characteristic asymmetric white matter lesions. The diagnosis of PML is established through molecular detection of viral DNA in the cere brospinal fluid (CSF) or viral proteins on a brain biopsy (Table 321.3). Unlike with BK PyV, there are no quantitative thresholds because any amount of virus in the CSF is considered abnormal. Although the sensitivity for detection in pediatric cases is under 60, the specific ity is near 100; therefore a positive PCR result can be considered diagnostic. Remarkably, the CSF cell counts and protein and glucose levels are typically normal. Cases without molecular evidence may still be termed possible PML based on neurologic and radiologic findings. Treatment for PML is primarily through reversing the underlying cause of immune dysfunction. Adults with advanced HIV infection should be treated with antiretroviral therapy (ART), but the efficacy of ART for resolution of PML in children is not well documented. It is important for the clinician to be aware of a rare but serious com plication after HIV suppression promoting a paradoxical increase in JC PyVmediated damage. This phenomenon has been termed PML immune reconstitution inflammatory syndrome and can often be treated with steroids. Unfortunately, the prognosis for PML in chil dren is grim, with most patients succumbing to the disease within 6 months. It remains to be seen if absolute viral load or specific radio logic and clinical findings might be used to better predict outcomes in children. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 321.3 Recommendations for Patients with JCV PyVProgressive Multifocal Leukoencephalopathy SCREENING DIAGNOSIS MONITORING Clinical Suspect in an immunosuppressed patient with subacute neurologic findings Imaging No recommendations Characteristic MRI findings No recommendations Molecular No recommendations Positive CSF PCR for JC PyV Pathology No recommendations |
7,936 | Brain biopsy with characteristic lesions and positive IHC demonstrating viral 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. Chapter 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2087 Advances in research and major improvements in the treatment and management of HIV infection have brought about a substantial decrease in the incidence of new HIV infections and AIDS in children. Globally, from 20002015, there has been an estimated 70 decline in new infections in children age 0 14 years, largely the result of antiret roviral treatment (ART) of HIV infected pregnant individuals for the prevention of vertical transmission. Of adults and children with HIV infection, 70 live in sub Saharan Africa, where the disease continues to have a devastating impact (Fig. 322.1). Children experience more rapid disease progression than adults, with up to half of untreated chil dren dying within the first 2 years of life. This rapid progression is cor related with a higher viral burden and faster depletion of infected CD4 lymphocytes in infants and children than in adults. Accurate diagnos tic tests and the early initiation of potent drugs to inhibit HIV replica tion have dramatically increased the ability to prevent progression and control this disease. ETIOLOGY HIV 1 and HIV 2 are members of the Retroviridae family and belong to the Lentivirus genus, which includes cytopathic viruses causing diverse diseases in several animal species. The HIV 1 genome con tains two copies of single stranded RNA that is 9.2 kb in size. At both ends of the genome there are identical regions, called long terminal repeats, which contain the regulation and expression genes of HIV. The remainder of the genome includes three major sections: the GAG region, which encodes the viral core proteins (p24 capsid protein: CA, p17 matrix protein: MA, p9, and p6, which are derived from the precursor p55); the POL region, which encodes the viral enzymes (i.e., reverse transcriptase p51, protease p10, and integrase p32); and the ENV region, which encodes the viral envelope proteins (gp120 and gp41, which are derived from the precursor gp160). Other regulatory proteins, such as transactivator of transcription (tat: p14), regulator of virion (rev: p19), negative regulatory factor (nef: p27), viral protein r (vpr: p15), viral infectivity factor (vif: p23), viral protein u (vpu in HIV 1: P16), and viral protein x (vpx in HIV 2: P15), are involved in transactivation, viral messenger RNA expression, viral replication, induction of cell cycle arrest, promotion of nuclear import of viral reverse transcription complexes, downregulation of the CD4 receptors and class I major histocompatibility complex (MHC), proviral DNA synthesis, and virus release and infectivity (Fig. 322.2). The HIV tropism to the target cell is determined by its envelope gly coprotein (Env). Env consists of two components: the surface, heavily glycosylated subunit, gp120 protein and the associated transmembrane subunit glycoprotein gp41. Both gp120 and gp41 |
7,937 | are produced from the precursor protein gp160. The glycoprotein gp41 is very immu nogenic and is used to detect HIV 1 antibodies in diagnostic assays; gp120 is a complex molecule that includes the highly variable V3 loop. This region is immunodominant for neutralizing antibodies. The heterogeneity of gp120 presents major obstacles in establishing an Chapter 322 Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Ericka V. Hayes Fig. 322.1 Estimated number of people living with HIV in 2016 by WHO region. Data from WHO 2017 report. (Courtesy World Health Organiza tion, 2017. Global Health Observatory (GHO) data. http:www.who.intghohivepidemicstatuscasesallen) 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. 2088 Part XV u Infectious Diseases effective HIV vaccine. The gp120 glycoprotein also carries the binding site for the CD4 molecule, the most common host cell surface recep tor of T lymphocytes. This tropism for CD4 T cells is beneficial to the virus because of the resulting reduction in the effectiveness of the host immune system. Other CD4 bearing cells include macrophages and microglial cells. The observations that CD4 cells are also infected by HIV and that some CD4 T cells are resistant to such infections suggests that other cellular attachment sites are needed for the interac tion between HIV and human cells. Several chemokines serve as co receptors for the envelope glycoproteins, permitting membrane fusion and entry into the cell. Most HIV strains have a specific tropism for one of the chemokines, including the fusion inducing molecule CXCR 4, which acts as a co receptor for HIV attachment to lymphocytes, and CCR 5, a chemokine receptor that facilitates HIV entry into mac rophages. Several other chemokine receptors (CCR 3) have also been shown in vitro to serve as virus co receptors. Other mechanisms of attachment of HIV to cells use nonneutralizing antiviral antibodies and complement receptors. The Fab portion of these antibodies attaches to the virus surface, and the Fc portion binds to cells that express Fc receptors (macrophages, fibroblasts), thus facilitating virus transfer into the cell. Other cell surface receptors, such as the mannose binding protein on macrophages or the DC specific, C type lectin (DC SIGN) on dendritic cells, also bind to the HIV 1 envelope glycoprotein and increase the efficiency of viral infectivity. Cell to cell transfer of HIV without formation of fully formed particles is a more rapid mechanism of spreading the infection to new cells than is direct infection by the virus. After viral attachment, gp120 and the CD4 molecule undergo con formational changes, and gp41 interacts with the fusion receptor on the cell surface (Fig. 322.3). Viral fusion with the cell membrane allows entry of viral RNA into the cell cytoplasm. This process involves acces sory viral proteins (nef, vif) and binding of cyclophilin A (a host cel lular protein) to the capsid protein (p24). A number of HIV drugs that target |
7,938 | the viral fusioncell entry of the virus have been developed. The p24 protein is involved in virus uncoating, recognition by restriction factors, and nuclear importation and integration of the newly created viral DNA. Viral DNA copies are then transcribed from the virion RNA through viral reverse transcriptase enzyme activity, which builds the first DNA strand from the viral RNA and then destroys the viral RNA and builds a second DNA strand to produce double stranded cir cular DNA (see Fig. 322.3). The HIV 1 reverse transcriptase is error prone and lacks error correcting mechanisms. Thus many mutations arise, creating a wide genetic variation in HIV 1 isolates even within an individual patient. Many of the drugs used to fight HIV infection were designed to block the reverse transcriptase action. The circular DNA is transported into the cell nucleus, using viral accessory proteins such as vpr, where it is integrated (with the help of the virus integrase) into the host chromosomal DNA and referred to as the provirus (see Fig. 322.3). Drugs have been developed that block this integration step. The provirus has the advantage of latency, because it can remain dor mant for extended periods, making it extremely difficult to eradicate. The infected CD4 T cells that survive long enough to revert to resting memory state become the HIV latent reservoir where the virus persists RNA Lipid bilayer Protein Function p10 p15 p17 p24 p32 gp41 p51p66 gp120 Protease, processes the gag and pol polyproteins Viral replication Matrix protein Capsid structural protein Viral cDNA integration Transmembrane protein Reverse transcriptase Surface protein Fig. 322.2 The human immunodeficiency virus and associated pro teins and their functions. Fig. 322.3 HIV life cycle showing the sites of action and different classes of antiretroviral drugs. (Adapted from Ralston SH, Penman ID, Strachan MWJ, Hobson R, eds. Davidsons Principles and Practice of Medicine, 23rd ed. London: Elsevier, 2018.) 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2089 indefinitely even in patients who respond favorably to potent ART. The molecular mechanisms of this latency are complex and involve unique biologic properties of the latent provirus (e.g., absence of tat, epigenetic changes inhibiting HIV gene expression) and the nature of the cellu lar host (e.g., absence of transcription factors such as nuclear factor B). Integration usually occurs near active genes, which allow a high level of viral production in response to various external factors such as an increase in inflammatory cytokines (by infection with other patho gens) and cellular activation. Depending on the relative expression of the viral regulatory genes (tat, rev, nef), the proviral DNA may encode production of the viral RNA genome, which, in turn, leads to produc tion of viral proteins necessary for viral assembly. HIV 1 transcription is followed by translation (see Fig. 322.3). A capsid polyprotein is |
7,939 | cleaved to produce the virus specific protease (p10), among other products. This enzyme is critical for HIV 1 assem bly because it cleaves the long polyproteins into the proper functional pieces. Several HIV 1 antiprotease drugs have been developed, target ing the increased sensitivity of the viral protease, which differs from the cellular proteases. The regulatory protein vif is active in virus assembly and Gag processing. The RNA genome is then incorporated into the newly formed viral capsid that requires zinc finger domains (p7) and the matrix protein (MA: p17). The matrix protein forms a coat on the inner surface of the viral membrane, which is essential for the budding of the new virus from the host cells surface. As new virus is formed, it buds through specialized membrane areas, known as lipid rafts, and is released. The virus release is facilitated by the viroporin vpu, which induces rapid degradation of newly synthesized CD4 molecules that impede viral budding. In addition, vpu counteracts host innate immu nity (e.g., hampering natural killer T cell activity). Full length sequencing of the HIV 1 genome demonstrated three different groups (M main, O outlier, and N non M, non O), prob ably occurring from multiple zoonotic infections from primates in dif ferent geographic regions. The same technique identified eight groups of HIV 2 isolates. Group M diversified to nine subtypes (or clades A to D, F to H, J, and K). In each region of the world, certain clades pre dominate, for example, clade A in Central Africa, clade B in the United States and South America, clade C in South Africa, clade E in Thailand, and clade F in Brazil. Although some subtypes were identified within group O, none was found in any of the HIV 2 groups. Clades are mixed in some patients as a result of HIV recombination, and some crossing between groups (i.e., M and O) has been reported. HIV 2 has a similar life cycle to HIV 1 and is known to cause infec tion in several monkey species. Subtypes A and B are the major causes of infection in humans, but rarely cause infection in children. HIV 2 differs from HIV 1 in its accessory genes (e.g., it has no vpu gene but contains the vpx gene, which is not found in HIV 1). It is most preva lent in western Africa, but increasing numbers of cases are reported from Europe and southern Asia. The diagnosis of HIV 2 infection is more difficult because of major differences in the genetic sequences between HIV 1 and HIV 2. Thus several of the standard confirmatory assays (immunoblot), which are HIV 1 specific, may give indetermi nate results with HIV 2 infection. If HIV 2 infection is suspected, a combination screening test that detects antibody to HIV 1 and HIV 2 peptides should be used. In addition, the rapid HIV detection tests have been less reliable in patients suspected to be dually infected with HIV 1 and HIV 2, because of |
7,940 | lower antibody concentrations against HIV 2. HIV 2 viral loads also have limited availability. Notably, HIV 2 infection demonstrates a longer asymptomatic stage of infection and slower declines of CD4 T cell counts and is less efficiently transmit ted vertically than HIV 1, likely related to lower levels of viremia with HIV 2. EPIDEMIOLOGY In 2022, the World Health Organization (WHO) estimated that 2.6 million children younger than 19 years of age worldwide were living with HIV 1 infection, with 270,000 new infections annually. Nearly 90 of these children 0 9 years of age live in sub Saharan Africa. From 20102022, there has been a 58 reduction in infection in children 0 9 years of age, reflecting steady expansion of services to prevent perinatal transmission of HIV to infants globally. Over the same period there has been a 46 reduction in new cases 10 19 years of age. Notably, there were still 100,000 deaths worldwide of children 19 years of age with HIV in 2020. As of 2022, an estimated 13.9 million children have been orphaned by AIDS (i.e., having at least one parent die from AIDS). Globally, the vast majority of HIV infections in early childhood are the result of vertical transmission. In the United States, approximately 11,700 children, adolescents, or young adults were reported to be living with perinatally acquired HIV infection in 2014. The number of U.S. children with AIDS diagnosed each year increased from 19841992 but then declined by more than 95 to 100 cases annually by 2003, largely from the success of prenatal screening and perinatal combina tion antiretroviral treatment (cART) of HIV infected pregnant indi viduals and infants. From 20142018, there were 507 infants born with perinatally acquired HIV in the United States and Puerto Rico, declin ing 54 over that interval, with 65 infants being born infected in 2018. As of 2019, the overall rate of perinatally acquired HIV infection in the United States was 0.8 per 100,000 births. Children of racial and ethnic minority groups are overrepresented, particularly non Hispanic Blacks, who had a rate of 2.9 per 100,000 births in 2019. Race and eth nicity are not risk factors for HIV infection but more likely reflect other social determinants of health that may be predictive of an increased risk for HIV infection, such as lack of educational and economic opportu nities as well as decreased access and barriers to healthcare. As of 2017, Florida, Illinois, Texas, Virginia, California, Tennessee, and Maryland are the states with the highest numbers of perinatally acquired cases of HIV in the United States. Adolescents (13 24 years of age) constitute an important growing population of newly infected individuals; in 2018, 21 of all new HIV infections in the United States occurred in this age group, with 81 of youth cases occurring in young males who have sex with males (MSM). It is estimated that 50 of HIV positive youth, the highest rate of any age group, are unaware of their diagnosis. Considering the long latency period |
7,941 | between the time of infection and the development of clinical symptoms, reliance on AIDS case definition surveillance data significantly underrepresents the impact of the disease in adolescents. Based on a median incubation period of 8 12 years, it is estimated that 1520 of all patients with AIDS acquired HIV infection between 13 and 19 years of age. Risk factors for HIV infection vary by sex in adolescents. Whereas 9193 of males between the ages of 13 and 24 years with HIV acquire infection through sex with other males, 9193 of adolescent females with HIV are infected through heterosexual contact. Adolescent racial and ethnic minority populations are overrepresented, especially among females. Another important group are transgender individuals. Trans gender women in the United States have 49 times the odds of contract ing HIV compared to the general population; transgender men have rates that are lower than in transgender women but still significantly higher than the rate in the general population. Transgender individuals unfortunately have many barriers to accessing and receiving appropri ate transgender sensitive care and HIV testing and treatment that must be addressed. Transmission Transmission of HIV 1 occurs via sexual contact, parenteral exposure to blood, or vertical transmission from pregnant individual to child via exposure to vaginal secretions during birth or via breast milk. The primary route of infection in the pediatric population (15 years) is vertical transmission. Rates of vertical transmission of HIV have var ied in high and low resource countries; the United States and Europe have documented transmission rates in untreated pregnant individuals of 1230, whereas transmission rates in Africa and Haiti have been higher (2552), likely because of more advanced disease and the presence of co infections. Perinatal treatment of HIV infected preg nant persons with antiretroviral drugs has dramatically decreased the transmission rate to 2. Vertical transmission of HIV can occur before delivery (intra uterine), during delivery (intrapartum), or after delivery (postpar tum through breastfeeding). Although intrauterine transmission 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. 2090 Part XV u Infectious Diseases has been suggested by identification of HIV by culture or polymerase chain reaction (PCR) in fetal tissue as early as 10 weeks, statistical modeling data suggest that the majority of in utero transmissions likely occur in late gestation, when the vascular integrity of the placenta weakens and microtransfusions across the maternalfetal circulation occur. It is generally accepted that 2030 of infected newborns are infected in utero, because this percentage of infants has laboratory evidence of infection (positive viral culture or PCR) within the first week of life. Some studies have found that viral detec tion soon after birth is also correlated with an early onset of symptoms and rapid progression to AIDS, consistent with more long standing infection during gestation. A higher percentage of HIV infected children acquire the virus intrapartum, evidenced by the fact that |
7,942 | 7080 of infected infants do not demonstrate detectable virus until after 1 week of age. The mecha nism of transmission appears to be mucosal exposure to infected blood and cervicovaginal secretions in the birth canal, and intrauterine con tractions during active labordelivery may also increase the risk of late microtransfusions. Breastfeeding is the least common route of vertical transmission in resource rich nations but is responsible for as much as 40 of perinatal infections in resource limited countries. The risk of an infant acquiring HIV through breastfeeding is 1520 over 2 years without parental cART or infant prophylaxis. Both free and cell associated viruses have been detected in breast milk from HIV infected individuals. The risk for transmission through breastfeeding for indi viduals not on suppressive cART is approximately 916 in individu als with established infection but is 2953 in those who acquire HIV postnatally, suggesting that the viremia experienced by the breastfeed ing individual during primary infection at least triples the risk for transmission. Where replacement feeding is readily available and safe, it is recommended that the parent substitute infant formula for breast milk if they are known to be HIV infected and not on suppressive cART or are at risk for ongoing sexual or parenteral exposure to HIV. How ever, the WHO recommends that in resource limited countries where other diseases (diarrhea, pneumonia, malnutrition) substantially contribute to a high infant mortality rate, the benefit of breastfeeding outweighs the risk for HIV transmission, and HIV infected persons in developing countries should exclusively breastfeed their infants for at least the first 6 months of life, ideally with parent on suppressive cART. Recently, infant feeding recommendations for breastfeeding (or chestfeeding) persons with HIV in resource rich settings have evolved as well, given that the risk of transmission via breastfeeding from an individual on suppressive cART is very low (1) (see Prevention for more discussion). Several risk factors influence the rate of vertical transmission: preg nant parent viral load at delivery, preterm delivery (34 weeks gesta tion), and low antenatal CD4 count. The most important variable is the level of viremia; the odds of transmission may be increased more than twofold for every log10 increase in viral load at delivery. Elective cesar ean delivery has been shown to decrease transmission by 87 if used in conjunction with zidovudine therapy in the pregnant individual and infant. However, because these data predated the advent of cART (also called highly active antiretroviral therapy HAART), the additional benefit of cesarean section is negligible if the viral load is 1,000 cop iesmL. It should be noted that rarely (0.1), transmission may occur with viral loads 50 copiesmL. Transfusions of infected blood or blood products have historically accounted for 36 of all pediatric AIDS cases. The period of highest risk was between 1978 and 1985, before the availability of HIV anti bodyscreened blood products. Whereas the prevalence of HIV infec tion in individuals with hemophilia treated before 1985 was as high as 70, heat treatment of factor VIII |
7,943 | concentrate and HIV antibody screening of donors has virtually eliminated HIV transmission in this population. Donor screening has dramatically reduced, but not elimi nated, the risk for blood transfusionassociated HIV infection: nucleic acid amplification testing of minipools (pools of 16 24 donations) per formed on antibody nonreactive blood donations (to identify dona tions made during the window period before seroconversion) reduced the residual risk of transfusion transmitted HIV 1 to approximately 1 in 2 million blood units. However, in many resource limited countries, screening of blood is not uniform, and the risk for transmitting HIV infection via transfusion remains in these settings. Although HIV can be isolated rarely from saliva, it is in very low titers (1 infectious particlemL) and saliva has not been implicated as a transmission vehicle. Studies of hundreds of household contacts of HIV infected individuals have found that the risk for household HIV transmission is essentially nonexistent. Only a few cases have been reported in which urine or feces (possibly devoid of visible blood) have been proposed as a possible vehicle of HIV transmission, though these cases have not been fully verified. In the pediatric population, sexual transmission is infrequent, but a small number of cases resulting from sexual abuse have been reported. Sexual contact is the major route of transmission in the adolescent population (13 years), accounting for the vast majority of cases. Infec tion via shared needles with IV drug use is seen in this population, but much less frequently. PATHOGENESIS HIV infection affects most of the immune system and disrupts its homeostasis (see Fig. 322.3). In most cases, the initial infection is caused by low amounts of a single founder virus. Therefore disease may be prevented by drug prophylaxis or vaccine. When the mucosa serves as the portal of entry for HIV, the first cells to be affected are the dendritic cells. These cells collect and process antigens introduced from the periphery and transport them to the lymphoid tissue. HIV does not infect the dendritic cell but binds to its DC SIGN surface molecule, allowing the virus to survive until it reaches the lymphatic tissue. In the lymphatic tissue (e.g., lamina propria, lymph nodes), the virus selectively binds to cells expressing CD4 molecules on their surface, primarily helper T lymphocytes (CD4 T cells) and cells of the monocyte macrophage lineage. Other cells bearing CD4, such as microglia, astrocytes, oligodendroglia, and placental tissue containing villous Hofbauer cells, may also be infected by HIV. Additional factors (co receptors) are necessary for HIV fusion and entry into cells. These factors include the chemokines CXCR 4 (fusion) and CCR 5. Other chemokines (CCR1, CCR3) may be necessary for the fusion of cer tain HIV strains. Several host genetic determinants affect the suscep tibility to HIV infection, the progression of disease, and the response to treatment. These genetic variants vary in different populations. A deletion in the CCR 5 gene that is protective against HIV infection (CCR 532) is relatively common in individuals of European descent but is |
7,944 | rare in individuals of African descent. Several other genes that regulate chemokine receptors, ligands, the MHC, and cytokines also influence the outcome of HIV infection. Usually, CD4 lymphocytes migrate to the lymphatic tissue in response to viral antigens and then become activated and proliferate, making them highly susceptible to HIV infection. This antigen driven migration and accumulation of CD4 cells within the lymphoid tissue may contribute to the generalized lymphadenopathy characteristic of acute HIV infection in adults and adolescents. HIV preferentially infects the very cells that respond to it (HIV specific memory CD4 cells), accounting for the progressive loss of these cells and the subsequent loss of control of HIV replication. The continued destruction of memory CD4 cells in the gastrointes tinal tract (in the gut associated lymphoid tissue or GALT) leads to reduced integrity of the gastrointestinal epithelium followed by leak age of bacterial particles into the blood and increased inflammatory response, which cause further CD4 cell loss. When HIV replication reaches a threshold (usually within 3 6 weeks from the time of infec tion), a burst of plasma viremia occurs. This intense viremia causes acute HIV infection, formerly known as acute retroviral syndrome which can present similar to influenza or mononucleosis (fever, rash, pharyngitis, lymphadenopathy, malaise, arthralgia, fatigue, cytope nias, elevated liver enzymes) in 5070 of infected adolescents and adults; this syndrome is not typically seen in infants. With establish ment of a cellular and humoral immune response within 2 4 months, the viral load in the blood declines substantially, and patients enter a phase characterized by a lack of symptoms and a return of CD4 cells to only moderately decreased levels. Typically, adult patients who are not treated eventually progress to achieve a virologic set point (steady state), usually ranging from 10,000 100,000 during this clinical latency. 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2091 This is in contrast to untreated infants with vertically acquired HIV who have viral loads that are much higher, resulting in faster CD4 count declines and earlier onset of significant immunodeficiency. HIV rapidly responds to the immune system pressure by developing a genetically complex population (quasi species) that successfully evades the immune system. In addition, inappropriate use of ART increases the ability of the virus to diverge even further by selecting for mutants with fitness or resistance advantages in the presence of subtherapeutic drug levels. Early HIV 1 replication in children has no apparent clini cal manifestations. Whether tested by virus isolation or by PCR for viral nucleic acid sequences, fewer than 40 of HIV 1infected infants demonstrate evidence of the virus at birth. The viral load increases by 1 4 months, and essentially all perinatally HIV infected infants have detectable HIV 1 in peripheral blood by 4 months of age, except for those who |
7,945 | may acquire infection via ongoing breastfeeding. In adults, the long period of clinical latency (typically 8 12 years) is not indicative of viral latency. In fact, there is a very high turnover of virus and CD4 lymphocytes (more than a billion cells per day), gradu ally causing deterioration of the immune system, marked by deple tion of CD4 cells. Several mechanisms for the depletion of CD4 cells in adults and children have been proposed, including HIV mediated single cell killing, formation of multinucleated giant cells of infected and uninfected CD4 cells (syncytia formation), virus specific immune responses (natural killer cells, antibody dependent cellular cytotoxic ity), superantigen mediated activation of T cells (rendering them more susceptible to infection with HIV), autoimmunity, and programmed cell death (apoptosis). The viral burden is greater in the lymphoid organs than in the peripheral blood during the asymptomatic period. As the virions and their immune complexes migrate through the lymph nodes, they are trapped in the network of dendritic follicular cells. Because the ability of HIV to replicate in T cells depends on the state of activation of the cells, the immune activation that takes place within the microenvi ronment of the lymph nodes in HIV disease serves to promote infection of new CD4 cells, as well as subsequent viral replication within these cells. Monocytes and macrophages can be productively infected by HIV yet resist the cytopathic effect of the virus and, with their long lifespan, explain their role as reservoirs of HIV and as effectors of tissue damage in organs such as the brain. In addition, they reside in anatomic viral sanctuaries where current treatment agents are less effective. The innate immune system responds almost immediately after HIV 1 infection by recognizing the viral nucleic acids, once the virus fuses to the infected cell, by the toll like receptor 7. This engagement leads to activation of pro inflammatory cytokines and interferon (IFN ), which blocks virus replication and spread. The virus uses its Nef protein to downregulate the expression of MHC and non MHC ligands to reduce the natural killer (NK) cellmediated anti HIV activity. It also modulates NK cell differentiation and maturation, dys regulates cytokine production, and increases apoptosis. Although the mechanism by which the innate system triggers the adaptive immune responses is not yet fully understood, cell mediated and humoral responses occur early in the infection. CD8 T cells play an important role in containing the infection. These cells produce various ligands (macrophage inflammatory proteins 1 and 1, RANTES), which suppress HIV replication by blocking the binding of the virus to the co receptors (CCR 5). HIV specific cytotoxic T lymphocytes (CTLs) develop against both the structural (ENV, POL, GAG) and regulatory (tat) viral proteins. The CTLs appear at the end of the acute infection, as viral replication is controlled by killing HIV infected cells before new viruses are produced and by secreting potent antiviral factors that compete with the virus for its receptors (CCR 5). Neutralizing antibod ies appear later in the |
7,946 | infection and seem to help in the continued sup pression of viral replication during clinical latency. There are at least two possible mechanisms that control the steady state viral load level during the chronic clinical latency. One mechanism may be the limited availability of activated CD4 cells, which prevent a further increase in the viral load. The other mechanism is the development of an active immune response, which is influenced by the amount of viral antigen and limits viral replication at a steady state. There is no general consen sus about which of these two mechanisms is more important. The CD4 cell limitation mechanism accounts for the effect of ART, whereas the immune response mechanism emphasizes the importance of immune modulation treatment (cytokines, vaccines) to increase the efficiency of immune mediated control. A group of cytokines that includes tumor necrosis factor (TNF ), TNF , interleukin 1 (IL 1), IL 2, IL 3, IL 6, IL 8, IL 12, IL 15, granulocyte macrophage colony stimulating fac tor, and macrophage colony stimulating factor plays an integral role in upregulating HIV expression from a state of quiescent infection to active viral replication. Other cytokines such as IFN , IFN , and IL 13 exert a suppressive effect on HIV replication. Certain cytokines (IL 4, IL 10, IFN , transforming growth factor ) reduce or enhance viral replication depending on the infected cell type. The interactions among these cytokines influence the concentration of viral particles in the tissues. Plasma concentrations of cytokines need not be elevated for them to exert their effect, because they are produced and act locally in the tissues. The activation of virtually all the cellular components of the immune system (i.e., T and B cells, NK cells, and monocytes) plays a significant role in the pathologic aspects of HIV infection. Further understanding of their interactions during the infection will expand our treatment options. Commonly, HIV isolated during the clini cal latency period grows slowly in culture and produces low titers of reverse transcriptase. These isolates from earlier in clinical latency use CCR 5 as their co receptor. By the late stages of clinical latency, the isolated virus is phenotypically different. It grows rapidly and to high titers in culture and uses CXCR 4 as its co receptor. The switch from CCR 5 receptor to CXCR 4 receptor increases the capacity of the virus to replicate, to infect a broader range of target cells (CXCR 4 is more widely expressed on resting and activated immune cells), and to kill T cells more rapidly and efficiently. As a result, the clinical latency phase is over and progression toward AIDS is noted. The progression of disease is related temporally to the gradual disruption of lymph node architecture and degeneration of the follicular dendritic cell network with loss of its ability to trap HIV particles. The virus is freed to recir culate, producing high levels of viremia and an increased disappear ance of CD4 T cells during the later stages of disease. The |
7,947 | clinical course of HIV infection shows substantial heterogene ity. This variation is determined by both viral and host factors. HIV viruses that use co receptor CXCR 4 in the course of the infection are associated with an accelerated deterioration of the immune system and more rapid progression to AIDS. In addition, several known host genetic determinants (e.g., variants in the human leukocyte antigen region, polymorphisms in the CCR 5 region such as CCR 532) affect disease course. There are likely additional host and viral factors yet to be identified that contribute to the variable course of HIV infection in individuals, as well. Three distinct patterns of disease are described in children. Approximately 1525 of HIV infected newborns in high resource settings present with a rapid progression course, with onset of AIDS and symptoms during the first few months of life and a median survival time of 6 9 months if untreated. In resource limited settings, the majority of HIV infected newborns will have this rapidly progress ing disease course. It has been suggested that if intrauterine infection coincides with the period of rapid expansion of CD4 cells in the fetus, the virus could effectively infect the majority of the bodys immuno competent cells. The normal migration of these cells to the marrow, spleen, and thymus would result in efficient systemic delivery of HIV, unchecked by the immature immune system of the fetus. Thus infec tion would be established before the normal ontogenic development of the immune system, causing more severe impairment of immu nity. Most children in this group have detectable virus in the plasma (median level: 11,000 copiesmL) in the first 48 hours of life. This early evidence of viral presence suggests that the newborn was infected in utero. The viral load rapidly increases, peaking by 2 3 months of age (median: 750,000 copiesmL) and staying high for at least the first 2 years of life. Sixty percent to 80 of perinatally infected newborns in high resource settings present with a slower progression of disease, with a median survival time of 6 years representing the second pattern of disease. Many patients in this group have a negative PCR result in the first week of life and are therefore considered to be infected intrapar tum. In a typical patient, the viral load rapidly increases, peaking by 2 3 months of age (median: 100,000 copiesmL) and then slowly declines 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. 2092 Part XV u Infectious Diseases over a period of 24 months. The slow decline in viral load is in sharp contrast to the rapid decline after primary infection seen in adults. This observation can be explained only partially by the immaturity of the immune system in newborns and infants. The third pattern of disease occurs in 5 of perinatally infected children, referred to as long term survivors |
7,948 | or long term nonpro gressors, who have minimal or no progression of disease with rela tively normal CD4 counts and very low viral loads for longer than 8 years. Mechanisms for the delay in disease progression include effec tive humoral immunity andor CTL responses, host genetic factors (e.g., human leukocyte antigen profile), and infection with an attenu ated (defective gene) virus. A subgroup of the long term survivors called elite survivors or elite suppressors has no detectable virus in the blood and may reflect different or greater mechanisms of protection from disease progression. Note that both groups warrant long term close follow up because later in their course they may begin to progress with their disease. HIV infected children have changes in the immune system that are similar to those in HIV infected adults. Absolute CD4 cell depletion may be less dramatic because infants normally have a relative lympho cytosis. A value of 750 CD4 cellsL in children younger than 1 year of age is indicative of severe CD4 depletion and is comparable to 200 CD4 cellsL in adults. Lymphopenia is relatively rare in perinatally infected children and is usually only seen in older children or those with end stage disease. Although cutaneous anergy is common during HIV infection, it is also frequent in healthy children younger than 1 year of age, and thus its interpretation is difficult in infected infants. The deple tion of CD4 cells also decreases the response to soluble antigens such as in vitro mitogens phytohemagglutinin and concanavalin A. Polyclonal activation of B cells occurs in most children early in the infection, as evidenced by elevation of immunoglobulins IgA, IgM, IgE, and, particularly, IgG (hypergammaglobulinemia), with high levels of antiHIV 1 antibody. This response may reflect both dys regulation of the T cell suppression of B cell antibody synthesis and active CD4 enhancement of the B lymphocyte humoral response. As a result, the antibody response to routine childhood vaccinations may be abnormal. The B cell dysregulation precedes the CD4 depletion in many children and may serve as a surrogate marker of HIV infection in symptomatic children in whom specific diagnostic tests (PCR, culture) are not available or are too expensive. Despite the increased levels of immunoglobulins, some children lack specific antibodies or protective antibodies. Hypogammaglobulinemia is very rare (1). Central nervous system (CNS) involvement is more common in pediatric patients than in adults. Macrophages and microglia play an important role in HIV neuropathogenesis, and data show that astro cytes may also be involved. Although the specific mechanisms for encephalopathy in children are not yet clear, the developing brain in young infants is affected by at least two mechanisms. The virus itself may directly infect various brain cells or cause indirect damage to the nervous system by the release of cytokines (IL 1, IL 1, TNF , IL 2) or reactive oxygen damage from HIV infected lymphocytes or macrophages. CLINICAL MANIFESTATIONS The clinical manifestations of HIV infection vary widely among infants, children, and adolescents. In most infants, |
7,949 | physical examination at birth is normal. Initial symptoms may be subtle, such as lymphadenopathy and hepatosplenomegaly, or nonspecific, such as failure to thrive, chronic or recurrent diarrhea, respiratory symptoms, or oral thrush, and may be distinguishable only by their persistence. Whereas systemic and pul monary findings are common in the United States and Europe, chronic diarrhea, pneumonia, wasting, and severe malnutrition predominate in Africa. Clinical manifestations found more commonly in children than adults with HIV infection include recurrent bacterial infections, chronic parotid swelling, lymphocytic interstitial pneumonitis (LIP), and early onset of progressive neurologic deterioration; note that chronic parotid swelling and LIP are associated with a slower progression of disease. The Centers for Disease Control and Prevention (CDC) Surveillance Case Definition for HIV infection is based on the age specific CD4 T lymphocyte count or the CD4 T lymphocyte percentage of total lymphocytes (Table 322.1), except when a stage 3defining opportu nistic illness (Table 322.2) supersedes the CD4 data. Age adjustment of the absolute CD4 count is necessary because counts that are rela tively high in normal infants decline steadily until age 6 years, when they reach adult norms. The CD4 count takes precedence over the CD4 T lymphocyte percentage, and the percentage is considered only if the count is unavailable. Infections Approximately 20 of AIDS defining illnesses in children are recur rent bacterial infections caused primarily by encapsulated organisms such as Streptococcus pneumoniae and Salmonella as a result of dis turbances in humoral immunity. Other pathogens, including Staphy lococcus, Enterococcus, Pseudomonas aeruginosa, and Haemophilus influenzae, and other gram positive and gram negative organisms may also be seen. The most common serious infections in HIV infected children are bacteremia, sepsis, and bacterial pneumonia, accounting for more than 50 of infections in these patients. Meningitis, urinary tract infections, deep seated abscesses, and bonejoint infections occur less frequently. Milder recurrent infections, such as otitis media, sinus itis, and skin and soft tissue infections, are very common and may be chronic with atypical presentations. Opportunistic infections are generally seen in children with severe depression of the CD4 count. In adults, these infections often repre sent reactivation of a latent infection acquired early in life. In contrast, young children generally have primary infection and often have a more fulminant course of disease reflecting the lack of prior immunity. In addition, infants 1 year of age have a higher incidence of developing stage 3defining opportunistic infections and mortality rates compared with older children and adults even at higher CD4 counts, reflect ing that the CD4 count may overpredict the immune competence in young infants. This principle is best illustrated by Pneumocystis jir oveci pneumonia (formerly Pneumocystis carinii), the most common opportunistic infection in the pediatric population (see Chapter 290). The peak incidence of Pneumocystis pneumonia occurs at age 3 6 Table 322.1 HIV Infection Stage Based on Age Specific CD4 T Lymphocyte Count or CD4 T Lymphocyte Percentage of Total Lymphocytes STAGE AGE ON DATE OF CD4 T LYMPHOCYTE TEST 1 Yr 1 5 Yr 6 |
7,950 | Yr CELLSL CELLSL CELLSL 1 1,500 34 1,000 30 500 26 2 750 1,499 26 33 500 999 22 29 200 499 14 25 3 750 26 500 22 200 14 Stage is based primarily on the CD4 T lymphocyte count. The CD4 T lymphocyte count takes precedence over the CD4 T lymphocyte percentage, and the percentage is considered only if the count is missing. From Centers for Disease Control and Prevention. Revised surveillance case definition for HIV infectionUnited States, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(No RR 3):110. 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2093 months in the setting of undiagnosed perinatally acquired HIV infec tion, with the highest mortality rate in children younger than 1 year of age regardless of CD4 count. Aggressive approaches to treatment have improved the outcome substantially. Although the overall incidence of opportunistic infections has markedly declined since the era of combi nation ART, opportunistic infections still occur in patients with severe immunodepletion as the result of unchecked viral replication, which often accompanies poor ART adherence. The classic clinical presentation of Pneumocystis pneumonia includes an acute onset of fever, tachypnea, dyspnea, and marked hypoxemia; in some children, more indolent development of hypoxemia may pre cede other clinical or x ray manifestations. In some cases, fever may be absent or low grade, particularly in more indolent cases. Chest x ray findings most commonly consist of interstitial infiltrates or diffuse alveolar disease, which rapidly progresses. Chest x ray in some cases can have very subtle findings and can mimic the radiologic appearance of viral bronchiolitis. Nodular lesions, streaky or lobar infiltrates, or pleural effusions may occasionally be seen. The diagnosis is established by demonstration of P. jiroveci with appropriate staining of induced sputum or bronchoalveolar fluid lavage; rarely, an open lung biopsy is necessary. Bronchoalveolar lavage and open lung biopsy have sig nificantly improved sensitivity (7595) for Pneumocystis testing than induced sputum (2040), such that if an induced sputum is negative, it does not exclude the diagnosis. PCR testing on respiratory specimens is also available and is more sensitive than microscopy but also has less specificity; it is also not widely available. The first line therapy for Pneumocystis pneumonia is trimethoprim sulfamethoxazole (TMP SMX) (15 20 mgkgday of the TMP component divided every 6 hours intravenously) with adjunctive corti costeroids for moderate to severe disease, usually defined as if the Pao2 is 70 mm Hg while breathing room air. After improvement, therapy with oral TMP SMX should continue for a total of 21 days while the corticosteroids are weaned. An alternative therapy for Pneumocystis pneumonia includes intravenous administration of pentamidine (4 mgkgday). Other regimens such as TMP plus dapsone, clindamycin plus primaquine, or atovaquone are used as alternatives in adults but have not been widely used in children |
7,951 | to date. Nontuberculous mycobacteria (NTM), with Mycobacterium avium intracellulare complex (MAC) being most common, may cause disseminated disease in HIV infected children who are severely immu nosuppressed. The incidence of MAC infection in ARTnave children 6 years with 100 CD4 cellsL is estimated to be as high as 10, but effective cART that results in viral suppression makes MAC infections rare. Disseminated MAC infection is characterized by fever, malaise, weight loss, and night sweats; diarrhea, abdominal pain, and, rarely, intestinal perforation or jaundice (a result of biliary tract obstruction by lymphadenopathy) may also be present. Labs may be notable for sig nificant anemia. The diagnosis is made by the isolation of MAC from blood, bone marrow, or tissue; the isolated presence of MAC in the stool does not confirm a diagnosis of disseminated MAC. Treatment can reduce symptoms and prolong life but is at best only capable of sup pressing the infection if severe CD4 depletion persists. Therapy should include at least two drugs: clarithromycin or azithromycin and etham butol. A third drug (rifabutin, rifampin, ciprofloxacin, levofloxacin, or amikacin) may be added to decrease the emergence of drug resistant isolates. Careful consideration of possible drug interactions with anti retroviral agents is necessary before initiation of disseminated MAC therapy. Drug susceptibilities should be ascertained, and the treatment regimen should be adjusted accordingly in the event of an inadequate clinical response to therapy. Because of the great potential for toxicity with most of these medications, surveillance for adverse effects should be ongoing. Less commonly, NTM infections, including lymphadenitis, osteomyelitis, tenosynovitis, and pulmonary disease, can also be seen. Oral candidiasis is the most common fungal infection seen in HIV infected children. Oral nystatin suspension (2 5 mL qid) is often effec tive. Clotrimazole troches or fluconazole (3 6 mgkg orally qd) are effective alternatives. Oral thrush progresses to involve the esophagus in as many as 20 of children with severe CD4 depletion, present ing with symptoms such as anorexia, dysphagia, vomiting, and fever. Treatment with oral fluconazole for 7 14 days generally results in rapid improvement in symptoms. Fungemia rarely occurs, usually in the set ting of indwelling venous catheters, and up to 50 of cases may be caused by non albicans species. Disseminated histoplasmosis, coccidi oidomycosis, and cryptococcosis are rare in pediatric patients but may occur in endemic areas. Parasitic infections such as intestinal cryptosporidiosis and micro sporidiosis and rarely isosporiasis or giardiasis are other opportunistic infections that cause significant morbidity. Although these intestinal infections are usually self limited in healthy hosts, they cause severe chronic diarrhea in HIV infected children with low CD4 counts, often leading to malnutrition. Nitazoxanide therapy is partially effec tive at improving cryptosporidia diarrhea, but immune reconstitution with cART is the most important factor for clearance of the infection. Albendazole has been reported to be effective against most microspo ridia (excluding Enterocytozoon bieneusi and Vittaforma corneae), and TMP SMX appears to be effective for isosporiasis. Systemic fumagillin can be used to treat Enterocytozoon and Vittaforma. Viral infections, |
7,952 | especially with the herpesvirus group, pose signifi cant problems for HIV infected children. HSV causes recurrent gingi vostomatitis, which may be complicated by local and distant cutaneous dissemination. Primary varicella zoster virus infection (chickenpox) may be prolonged and complicated by bacterial superinfections or Table 322.2 Stage 3Defining Opportunistic Illnesses in HIV Infection Bacterial infections, multiple or recurrent Candidiasis of bronchi, trachea, or lungs Candidiasis of esophagus Cervical cancer, invasive Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (1 mo duration) Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age 1 mo Cytomegalovirus retinitis (with loss of vision) Encephalopathy attributed to HIV Herpes simplex: chronic ulcers (1 mo duration) or bronchitis, pneumonitis, or esophagitis (onset at age 1 mo) Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (1 mo duration) Kaposi sarcoma Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis of any site, pulmonary, disseminated, or extrapulmonary Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jiroveci (previously known as Pneumocystis carinii) pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain, onset at age 1 mo Wasting syndrome attributed to HIV Only among children age 6 yr. Only among adults, adolescents, and children age 6 yr. Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy and HIV wasting syndrome, are described in the following references: Centers for Disease Control and Prevention. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Recomm Rep. 1994;43(No. RR 12); Centers for Disease Control and Prevention. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(No. RR 17). From Centers for Disease Control and Prevention. Revised surveillance case definition for HIV infectionUnited States, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(No RR 3):110. 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. 2094 Part XV u Infectious Diseases visceral dissemination, including pneumonitis. Recurrent, atypical, or chronic episodes of herpes zoster are often debilitating and require prolonged therapy with acyclovir; in rare instances, varicella zoster virus has developed a resistance to acyclovir, requiring the use of fos carnet. Disseminated cytomegalovirus infection occurs in the setting of severe CD4 depletion (50 CD4 cellsL for 6 years) and may involve single or multiple organs. Retinitis, pneumonitis, esophagitis, gastritis with pyloric obstruction, hepatitis, colitis, and encephalitis have been reported, but these complications are rarely seen if cART is given. Ganciclovir and foscarnet are the drugs of choice and are often given together in children with sight threatening cytomegalovirus retinitis. Intraocular injections of foscarnet or intraocular ganciclovir implants plus oral valganciclovir have also been efficacious in adults and older children with cytomegalovirus retinitis. Measles may occur despite immunization |
7,953 | and may present without the typical rash. It often disseminates to the lung or brain with a high mortality rate in these patients. HIV infected children with low CD4 counts can also develop extensive cutaneous molluscum contagiosum infection. Respiratory viruses such as respiratory syncytial virus and adenovirus may pres ent with prolonged symptoms and persistent viral shedding. In parallel with the increased prevalence of genital tract human papillomavirus infection, cervical intraepithelial neoplasia and anal intraepithelial neoplasia also occur with increased frequency among HIV 1infected adult females compared with HIV seronegative females. The relative risk for cervical intraepithelial neoplasia is 5 10 times higher for HIV 1 seropositive females. Multiple modalities are used to treat human pap illomavirus (HPV) infection (see Chapter 313), although none is uni formly effective and the recurrence rate is high among HIV 1infected persons. Prevention with appropriate vaccinations in patients whose CD4 counts are above threshold is recommended, including mumps measles rubella (MMR), varicella vaccine, and HPV vaccine (see Sup portive Care section). Appropriate therapy with antiretroviral agents may result in immune reconstitution inflammatory syndrome (IRIS), which is characterized by an increased inflammatory response from the recov ered immune system to subclinical opportunistic infections (e.g., Mycobacterium infection, herpes simplex virus (HSV) infection, toxo plasmosis, cytomegalovirus (CMV) infection, Pneumocystis infection, cryptococcal infection). This condition is more commonly observed in patients with progressive disease and severe CD4 T lymphocyte depletion. Patients with IRIS develop fever and worsening of the clini cal manifestations of the opportunistic infection or new manifestations (e.g., enlargement of lymph nodes, pulmonary infiltrates), typically within the first few weeks after initiation of ART. Determining whether the symptoms represent IRIS, worsening of a current infection, a new opportunistic infection, or drug toxicity can be challenging. If the syndrome does represent IRIS, adding nonsteroidal antiinflamma tory agents or corticosteroids may alleviate the inflammatory reaction, although the use of corticosteroids is usually reserved for severe cases. The inflammation may take weeks or months to subside. In most cases, continuation of cART while treating the opportunistic infection (with or without antiinflammatory agents) is sufficient. If opportunistic infection is suspected before the initiation of ART, appropriate antimi crobial treatment should be started before starting cART, particularly in the case of cryptococcal meningitis. Central Nervous System The incidence of CNS involvement in perinatally infected children is as high as 5090 in resource limited settings but significantly lower in resource rich settings, with a median onset at 19 months of age. Mani festations may range from subtle developmental delay to progressive encephalopathy with loss or plateau of developmental milestones, cog nitive deterioration, impaired brain growth resulting in acquired micro cephaly, and symmetric motor dysfunction. Encephalopathy may be the initial manifestation of the disease or may present much later when severe immune suppression occurs. With progression, marked apathy, spasticity, hyperreflexia, and gait disturbance may occur, as well as loss of language and oral, fine, andor gross motor skills. The encephalopa thy may progress intermittently, with periods of deterioration followed by transiently stable plateaus. |
7,954 | Older children may exhibit behavioral problems and learning disabilities. Associated abnormalities identified by neuroimaging techniques include cerebral atrophy in up to 85 of children with neurologic symptoms, increased ventricular size, basal ganglia calcifications, and, less frequently, leukomalacia. Fortunately, since the advent of cART, the incidence rate of encepha lopathy has dramatically declined to as low as 0.08 in 2006. However, as HIV infected children progress through adolescence and young adulthood, other subtle manifestations of CNS disease are evident, such as cognitive deficits, attention problems, and psychiatric disor ders. Living with a chronic, often stigmatizing, disease; parental loss; and the requirement for lifelong pristine medication adherence com pounds these issues, making it challenging for these youth as they inherit responsibility for managing their disease as adults. Focal neurologic signs and seizures are unusual and may imply a comorbid pathologic process such as a CNS tumor, opportunistic infection, or stroke. CNS lymphoma may present with new onset focal neurologic findings, headache, seizures, and mental status changes. Characteristic findings on neuroimaging studies include a hyperdense or isodense mass with variable contrast enhancement or a diffusely infiltrating contrast enhancing mass. CNS toxoplasmo sis is exceedingly rare in young infants but may occur in vertically HIV infected adolescents and is typically associated with serum anti toxoplasma IgG as a marker of infection. Other opportunistic infec tions of the CNS are rare and include infection with CMV, JC virus (progressive multifocal leukoencephalopathy), HSV, Cryptococcus neoformans, and Coccidioides immitis. Although the true incidence of cerebrovascular disorders (both hemorrhagic and nonhemorrhagic strokes) is unclear, 610 of children from large clinical series have been affected. Respiratory Tract Recurrent upper respiratory tract infections such as otitis media and sinusitis are very common. Although the typical pathogens (S. pneu moniae, H. influenzae, Moraxella catarrhalis) are most common, unusual pathogens such as P. aeruginosa, yeast, and anaerobes may be present in chronic infections and result in complications such as inva sive sinusitis and mastoiditis. LIP is the most common chronic lower respiratory tract abnormal ity reported to the CDC for HIV infected children; historically this occurred in approximately 25 of HIV infected children, although the incidence has declined in the cART era. LIP is a chronic process with nodular lymphoid hyperplasia in the bronchial and bronchiolar epithe lium, often leading to progressive alveolar capillary block over months to years. It has a characteristic chronic diffuse reticulonodular pattern on chest radiography rarely accompanied by hilar lymphadenopathy, allowing a presumptive diagnosis to be made radiographically before the onset of symptoms. There is an insidious onset of tachypnea, cough, and mild to moderate hypoxemia with normal auscultatory findings or minimal rales. Progressive disease presents with symptomatic hypoxemia, which usually resolves with oral corticosteroid therapy, accompanied by digital clubbing. Several studies suggest that LIP is a lymphoproliferative response to a primary Epstein Barr virus infec tion in the setting of HIV infection. It is also associated with a slower immunologic decline. Most symptomatic HIV infected children experience at least one episode of pneumonia during their disease. |
7,955 | S. pneumoniae is the most common bacterial pathogen, but P. aeruginosa and other gram negative bacterial pneumonias may occur in end stage disease and may produce acute respiratory failure and death. Rarely, severe recurrent bacterial pneumonia results in bronchiectasis. Pneumocystis pneu monia is the most common opportunistic infection, but other patho gens, including CMV, Aspergillus, Histoplasma, and Cryptococcus, can cause pulmonary disease. Infection with common respiratory viruses, including respiratory syncytial virus, parainfluenza, influenza, and adenovirus, may occur simultaneously and have a protracted course and prolonged period of viral shedding from the respiratory tract. Infection with SARS CoV 2 may also occur, without clear evidence of increased morbidity relative to children without HIV infection. 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2095 Pulmonary and extrapulmonary tuberculosis (TB) has been reported with increasing frequency in HIV infected children in low resource countries, although it is considerably more common in HIV infected adults. Because of drug interactions between rifampin and ritonavir based ART and poor tolerability of the combination of multiple drugs required, treatment of TBHIV co infection is particularly challenging in children. Cardiovascular System Cardiac dysfunction, including left ventricular hypertrophy, left ven tricular dilation, reduced left ventricular fractional shortening, and or heart failure occurred in 1839 of HIV infected children in the pre cART era; among those affected, a lower nadir CD4 percentage and a higher viral load were associated with lower cardiac function. However, a more current evaluation of HIV infected children taking long term cART found that echocardiographic findings were closer to normal and none had symptomatic heart disease, suggesting that cART has a cardioprotective effect. What is still unclear is whether an increased rate of premature cardiovascular disease that has been seen in adults will be seen in children who have disease or treatment related hyperlipidemia, and prospective studies are needed to assess this risk. Because of this risk, regular monitoring of cholesterol and lipids, as well as education regarding a heart healthy lifestyle and diet, is an important part of pediatric HIV care. Gastrointestinal and Hepatobiliary Tract Oral manifestations of HIV disease include erythematous or pseudo membranous candidiasis, periodontal disease (e.g., ulcerative gingivi tis or periodontitis), salivary gland disease (i.e., swelling, xerostomia), and, rarely, ulcerations or oral hairy leukoplakia. Gastrointestinal tract involvement is common in HIV infected children. A variety of patho gens can cause gastrointestinal disease, including bacteria (Salmonella, Campylobacter, Shigella, MAC), protozoa (Giardia, Cryptosporidium, Isospora, microsporidia), viruses (CMV, HSV, rotavirus), and fungi (Candida). MAC and the protozoal infections are most severe and protracted in patients with severe CD4 cell depletion. Infections may be localized or disseminated and affect any part of the gastrointestinal tract from the oropharynx to the rectum. Oral or esophageal ulcer ations, either viral in origin or idiopathic, are painful and often inter fere with eating. |
7,956 | AIDS enteropathy, a syndrome of malabsorption with partial villous atrophy not associated with a specific pathogen, has been postulated to be a result of direct HIV infection of the gut. Disac charide intolerance is common in HIV infected children with chronic diarrhea. The most common symptoms of gastrointestinal disease are chronic or recurrent diarrhea with malabsorption, abdominal pain, dyspha gia, and failure to thrive. Prompt recognition of weight loss or poor growth velocity in the absence of diarrhea is critical. Linear growth impairment is often correlated with the level of HIV viremia. Supple mental enteral feedings should be instituted, either by mouth or with nighttime nasogastric tube feedings in cases associated with more severe chronic growth problems; placement of a gastrostomy tube for nutritional supplementation may be necessary in severe cases. The wasting syndrome, defined as a loss of 10 of body weight, is not as common as failure to thrive in pediatric patients, but the resulting malnutrition is associated with a grave prognosis. Chronic liver inflam mation evidenced by fluctuating serum levels of transaminases with or without cholestasis is relatively common, often without identification of an etiologic agent. Cryptosporidial cholecystitis is associated with abdominal pain, jaundice, and elevated glutamyltransferase. In some patients, chronic hepatitis caused by CMV, hepatitis B, hepatitis C, or MAC may lead to portal hypertension and liver failure. Several of the antiretroviral drugs or other drugs such as didanosine, protease inhibi tors (PIs), nevirapine, and dapsone may also cause reversible elevation of transaminases. Pancreatitis with increased pancreatic enzymes with or without abdominal pain, vomiting, and fever may be the result of drug therapy (e.g., with pentamidine, didanosine, or stavudine) or, rarely, opportu nistic infections such as MAC or CMV. Renal Disease Nephropathy is an unusual presenting symptom of HIV infection, more commonly occurring in older symptomatic children. A direct effect of HIV on renal epithelial cells has been suggested as the cause, but immune complexes, hyperviscosity of the blood (secondary to hyperglobulinemia), and nephrotoxic drugs are other possible factors. A wide range of histologic abnormalities has been reported, including focal glomerulosclerosis, mesangial hyperplasia, segmental necrotiz ing glomerulonephritis, and minimal change disease. Focal glomeru losclerosis generally progresses to renal failure within 6 12 months, but other histologic abnormalities in children may remain stable without significant renal insufficiency for prolonged periods. Nephrotic syn drome is the most common manifestation of pediatric renal disease, with edema, hypoalbuminemia, proteinuria, and azotemia with nor mal blood pressure. Cases resistant to steroid therapy may benefit from cyclosporine therapy. Polyuria, oliguria, and hematuria have also been observed in some patients. Skin Manifestations Many cutaneous manifestations seen in HIV infected children are inflam matory or infectious disorders that are not unique to HIV infection. These disorders tend to be more disseminated and respond less consistently to conventional therapy than in the uninfected child. Seborrheic dermatitis or eczema that is severe and unresponsive to treatment may be an early nonspecific sign of HIV infection. Recurrent or chronic episodes of HSV, herpes zoster, molluscum contagiosum, flat |
7,957 | warts, anogenital warts, and candidal infections are common and may be difficult to control. Allergic drug eruptions are also common, in particular related to nonnucleoside reverse transcriptase inhibitors; they generally respond to withdrawal of the drug but also may resolve spontaneously without drug interruption; rarely, progression to Stevens Johnson syndrome has been reported. Epidermal hyperkeratosis with dry, scaling skin is frequently observed, and sparse hair or hair loss may be seen in the later stages of the disease. Hematologic and Malignant Diseases Anemia occurs in 2070 of HIV infected children, more commonly in children with AIDS. The anemia may be a result of chronic infec tion, poor nutrition, autoimmune factors, virus associated conditions (hemophagocytic syndrome, parvovirus B19 red cell aplasia), or the adverse effect of drugs (zidovudine). Leukopenia occurs in almost 30 of untreated HIV infected chil dren, and neutropenia often occurs. Multiple drugs used for treatment or prophylaxis for opportunistic infections, such as Pneumocystis pneu monia (TMP SMX), MAC, and CMV (ganciclovir), or antiretroviral drugs (zidovudine) may also cause leukopenia andor neutropenia. In cases in which therapy cannot be changed, treatment with subcutane ous granulocyte colony stimulating factor may be necessary. Thrombocytopenia has been reported in 1020 of patients. The etiology may be immunologic (i.e., circulating immune complexes or antiplatelet antibodies) or, less commonly, from drug toxicity, or idiopathic. cART may also reverse thrombocytopenia in ART nave patients. In the event of sustained severe thrombocytopenia (10,000 plateletsL), treatment with intravenous immunoglobulin or anti D immune globulin offers temporary improvement in most patients already taking cART. If ineffective, a course of steroids may be an alter native, but consultation with a hematologist should be sought. Defi ciency of clotting factors (factors II, VII, IX) is not rare in children with advanced HIV disease and corrects with vitamin K. A novel disease of the thymus has been observed in a few HIV infected children. These patients were found to have characteristic anterior mediastinal multilocular thymic cysts without clinical symp toms. Histologic examination shows focal cystic changes, follicular hyperplasia, and diffuse plasmacytosis and multinucleated giant cells. Treatment with cART may result in resolution, and spontaneous invo lution occurs in some cases. Malignant diseases have been reported infrequently in HIV infected children, representing only 2 of AIDS defining illnesses. Non Hodgkin lymphoma (including Burkitt lymphoma), primary CNS lymphoma, 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. 2096 Part XV u Infectious Diseases leiomyosarcoma are the most commonly reported neoplasms among HIV infected children. Epstein Barr virus is associated with most lym phomas and with all leiomyosarcomas (see Chapter 301). Kaposi sar coma, which is caused by human herpesvirus 8, occurs frequently among HIV infected adults but is exceedingly uncommon among HIV infected children in resource rich settings (see Chapter 304). DIAGNOSIS AND TESTING All infants born to HIV infected individuals test antibody positive at birth because |
7,958 | of passive transfer of HIV antibody across the placenta during gestation; therefore antibody should not be used to establish the diagnosis of HIV in an infant. Most uninfected infants without ongoing exposure (i.e., who are not breastfed) lose antibodies against HIV between 6 and 18 months of age and are known as serorevert ers. Because a small proportion of uninfected infants continue to test HIV antibody positive for up to 24 months of age, positive IgG anti body tests, including the rapid tests, cannot be used to make a defini tive diagnosis of HIV infection in infants younger than 24 months. The presence of IgA or IgM anti HIV in the infants circulation can indicate HIV infection, because these immunoglobulin classes do not cross the placenta; however, IgA and IgM anti HIV assays have been both insen sitive and nonspecific and therefore are not valuable for clinical use. In any child older than 24 months of age, demonstration of IgG antibody to HIV by a repeatedly reactive enzyme immunoassay and confirma tory HIV PCR establishes the diagnosis of HIV infection. Certain dis eases (e.g., syphilis and autoimmune diseases) may cause false positive or indeterminate results in antibody testing. In such cases, specific viral diagnostic tests must be done. Several rapid HIV tests are currently available with sensitivity and specificity better than those of the standard enzyme immunoassay. Many of these tests require only a single step that allows test results to be reported within less than 30 minutes. Performing rapid HIV test ing on individuals during delivery or immediately after birth is cru cial for the care of HIV exposed newborns whose birth parents HIV status was unknown during pregnancy. A positive rapid test must be confirmed by a second different rapid test (testing different HIV associated antibodies) or by HIV RNA PCR (viral load). Given the earlier detection of fourth generation HIV enzyme linked immuno sorbent assay (ELISA) testing (p24 antigen HIV 1, HIV 2 IgG and IgM antibodies), Western blots are not appropriate to confirm testing because the fourth generation assays can be positive before the West ern blot becomes positive (i.e., in acute infection). In acute infection, patients may have only a positive p24 antigen with negative antibod ies on confirmatory testing; these patients should have HIV RNA PCR performed to confirm acute infection (or establish that the p24 antigen result was a false positive test). In infants who are at risk of exposure to HIV 2 infection (e.g., born to an HIV infected person from West Africa or who has a partner with HIV from West Africa), a rapid test that can detect both HIV 1 and HIV 2 should be used. However, if the HIV testing is negative or the Western blot test reveals an unusual pattern, further diagnostic tests should be considered. In addition, they should be tested with an HIV 2specific DNA PCR assay. Viral diagnostic assays, such as HIV DNA or RNA PCR, are more useful in young infants, allowing a definitive |
7,959 | diagnosis in most infected infants by 1 4 months of age. By 4 months of age, HIV PCR testing identifies all infected nonbreastfed infants. Historically, HIV DNA PCR testing was the preferred virologic assay over HIV RNA PCR testing in high resource settings for young infants because of what was thought to be a modest advantage in detecting intrapartum acquired infection for DNA PCR in the first month of life. An FDA approved HIV DNA PCR test is no longer commercially available in the United States, but other assays exist; however, the sensitivity and specificity of noncom mercial HIV 1 DNA tests (using individual laboratory reagents) may differ from the sensitivity and specificity of the prior FDA approved commercial test. HIV RNA PCR is recommended for non subtype B viruses or group O infections, which are not common in the United States. It should be noted that PCR results can be affected by ART in both the birthing parent and the infant, serving as the rationale for the recommendation for testing 2 6 weeks after completing prophylaxis in high risk newborns (Fig. 322.4) Almost 40 of infected newborns have positive DNA PCR test results in the first 2 days of life, with 90 testing positive by 2 weeks of age. The commercially available HIV 1 assays are not designed for quantification of HIV 2 RNA and thus should not be used to monitor patients with this infection. Viral diagnostic testing should be performed within the first 12 24 hours of life for high risk infants (i.e., those born to individuals without sustained virologic suppression, a late cART start, or a diagnosis with acute or primary HIV during the pregnancy); the tests can identify almost 40 of intrauterine HIV infected children. Birth testing is optional in low risk infants. Additional testing should be done at 2 3 weeks of age, 4 8 weeks of age, and 4 6 months of age. For higher risk infants, addi tional virologic diagnostic testing should be done at 2 to 6 weeks after cessation of ARV prophylaxis (i.e., at 8 12 weeks of life) (see Fig. 322.4). Breastfed infants should have PCR testing performed per testing sched ule based on their risk through 4 months of age; an additional test should be done between the 4 to 8 week test and the 4 to 6 month test if the gap between tests is more than 3 months. Breastfed infants should then be tested every 3 months while breastfeeding continues and then at 4 6 weeks, 3 months, and 6 months after cessation of breastfeeding regard less of age to identify those who may become infected at the end of lacta tion by the HIV infected individual (see Fig. 322.4). A positive virologic assay (i.e., detection of HIV by PCR) suggests HIV infection and should be confirmed by a repeat test on a second specimen as soon as possible because false positive tests can occur. A confirmed diagnosis of HIV infection can be made with two |
7,960 | positive virologic test results obtained from different blood samples. HIV infec tion can be presumptively excluded in nonbreastfed infants with two or more negative virologic tests (one at age 14 days and one at age 4 weeks), one negative virologic test (i.e., negative RNA or DNA) at age 8 weeks done at least 2 weeks after discontinuation of multidrug Birth Low risk High risk Breast fed After cessation of breastfeeding NAT NAT NAT NAT NAT NAT NAT NAT NAT NAT NAT NAT NAT NAT NAT NATNAT 2 weeks 3 weeks 4 weeks 8 weeks 10 weeks 12 weeks 4 months 6 months q 3 months Fig. 322.4 Recommended virologic testing schedules for infants exposed to HIV by perinatal HIV transmission risk and breastfed infants. See Table 322.7 for definitions of low and high risk. For higher risk infants, additional virologic diagnostic testing should be done at birth and 2 6 wk after cessation of ARV prophylaxis (i.e., at 8 10 wk of life). For breastfed infants, an additional virologic test should be performed between the 1 to 2 mo and 4 to 6 mo time points if the gap between tests is 3 mo. NAT, Nucleic acid test. (Content adapted from Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States. https:clinicalinfo.hiv.govsites defaultfilesguidelinesdocumentsperinatal hivguidelines perinatal.pdf) 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2097 empirical therapy or prophylaxis, or one negative HIV antibody test at age 6 months. Definitive exclusion of HIV infection in nonbreast fed infants is based on two or more negative virologic tests, with one obtained at age 1 month (done 2 6 weeks after the cessation of mul tidrug empirical therapy or prophylaxis) and one at age 4 months, or two negative HIV antibody tests from separate specimens obtained at age 6 months. Documentation of seroreversion (loss of antibody) at 12 18 month of age is no longer routinely recommended for non breastfed infants meeting definitive exclusion criteria who have had no known or suspected postnatal HIV exposure. Infants 18 months who have postnatal HIV exposure, including new HIV infection of breast feeding parent, premasticated feedings, sexual abuse, contaminated blood product, or percutaneous exposure, should have HIV PCR based testing to determine infection status. Children 18 months of age with no HIV perinatal exposure history with these postnatal expo sures should be tested with HIV antibodyantigen testing. Note that HIV antibodyantigen testing should not be used for diagnosis in the perinatally exposed child until age 24 months. Any child or adoles cent suspected of HIV infection should be tested with age appropriate testing with the caveat that if acute infection is suspected, additional HIV PCR testing may be required to establish the diagnosis. TREATMENT The currently available therapies do not |
7,961 | eradicate the virus and cure the patient; instead they suppress the virus for extended periods and change the course of the disease to a chronic process. It is now recom mended that all children be started on cART, regardless of viral load, CD4 count, or clinical status at diagnosis. Treatment should be initi ated within 7 days of diagnosis, with counseling and support for adher ence. Because cART therapy changes as new drugs become available, decisions regarding therapy should be made in consultation with an expert in pediatric HIV infection. The following principles form the basis for cART: 1. Uninterrupted HIV replication causes destruction of the immune system and progression to AIDS. 2. The magnitude of the viral load predicts the rate of disease progres sion, and the CD4 cell count reflects the risk of opportunistic infec tions and HIV infection complications. 3. cART, which includes at least three drugs with at least two different mechanisms of action, should be the initial treatment. Potent com bination therapy that suppresses HIV replication to an undetectable level restricts the selection of ART resistant mutants; drug resistant strains are the major factor limiting successful viral suppression and delay of disease progression. 4. The goal of sustainable suppression of HIV replication is best achieved by the simultaneous initiation of combinations of antiret roviral drugs to which the patient has not been exposed previously and to which the patients virus does not have cross resistance. 5. Drug related interactions and toxicities should be minimized as much as possible. 6. Adherence to the complex drug regimens is crucial for a successful outcome. Very rarely, treatment may need to be deferred on a case by case basis based on clinical or psychosocial factors that may affect adher ence with the caregivers and child. In these children, virologic, immu nologic, and clinical status should be closely monitored at least every 3 4 months. Combination Therapy As of February 2023, 21 individual ART drugs, 22 co formulated com bination tablets, one injectable long acting combination regimen, as well as two pharmacokinetic boosters were approved by the FDA for use in HIV infected adults and adolescents. Of the 21 individual drugs, 19 were approved for at least some portion of the pediatric popula tion (0 12 years of age), with many but not all of them available as a liquid, powder, or small tabletcapsule (Table 322.3). ART drugs are categorized by their mechanism of action, such as preventing viral entrance into CD4 T cells, inhibiting the HIV reverse transcriptase or protease enzymes, or inhibiting integration of the virus into the human DNA (see Fig. 322.3). Within the reverse transcriptase inhibi tors, a further subdivision can be made: nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (see Fig. 322.3). The NRTIs have a structure similar to that of the building blocks of DNA (e.g., thymidine, cytosine). When incorporated into DNA, they act as chain terminators and block further incorporation of nucleosides, preventing viral DNA synthesis. Among |
7,962 | the NRTIs, thymidine analogs (e.g., zidovudine) are found in higher concentrations in activated or dividing cells, produc ing 99 of the HIV virion population, and nonthymidine analogs (e.g., lamivudine and emtricitabine) have more activity in resting cells, which account for 1 of the HIV virions but may serve as a reservoir for HIV. Suppression of replication in both populations is important for long term viral control. NNRTIs (i.e., nevirapine, efavirenz, etra virine, rilpivirine, doravirine) act differently than NRTIs. They attach to the reverse transcriptase and cause a conformational change, reduc ing the activity of the enzyme (see Fig. 322.3). The PIs are potent agents that act farther along the viral replicative cycle. They bind to the site where the viral long polypeptides are cut into individual, mature, and functional core proteins that produce the infectious virions before they leave the cell (see Fig. 322.3). The virus entry into the cell is a com plex process that involves several cellular receptors and fusion. Sev eral drugs have been developed to prevent this process (see Fig. 322.3). The fusion inhibitor enfuvirtide (T 20), which binds to viral gp41, causes conformational changes that prevent fusion of the virus with the CD4 cell and entry into the cell; with the common use of integrase inhibitors, this medication is now used very rarely. Two entry inhib iting drugs are now approved for use only in treatment experienced adult patients with multidrug resistant HIV infection. Fostemsavir is an attachment inhibitor prodrug of temsavir that works by blocking CD4 binding to gp120; ibalizumab is a humanized monoclonal anti body (mAb) that acts as a postattachment inhibitor and prevents the HIV connection to co receptors CCR 5 or CXCR 4. Maraviroc is an example of a selective CCR 5 co receptor antagonist that blocks the attachment of the virus to this chemokine (an essential process in the viral binding and fusion to the CD4 cells). Integrase inhibitors (INS TIs) (i.e., raltegravir, dolutegravir, elvitegravir, bictegravir) block the enzyme that catalyzes the incorporation of the viral genome into the hosts DNA (see Fig. 322.3). By targeting different points in the viral life cycle and stages of cell activation and by delivering drug to all tissue sites, maximal viral sup pression is achievable. Combinations of three drugs consisting of a two NRTI backbone of (1) a guanosine or thymidine analog NRTI (abacavir or zidovudine) or tenofovir and (2) a nonthymidine ana log NRTI (lamivudine or emtricitabine) to suppress replication in both active and resting cells added to (3) a ritonavir boosted PI (lopinavir, atazanavir, or darunavir), an NNRTI (efavirenz, nevirapine, rilpivirine, or etravirine), or an INSTI (raltegravir, dolutegravir, elvitegravir, or bictegravir) can produce prolonged suppression of the virus. The use of three drugs from three different classes generally should be avoided but may be necessary in children with highly resistant viruses; these regimens should be chosen only by an HIV specialist with expert pharmacist input. For adult patients with established virologic suppression, some combination therapies pare down to just two drugs. |
7,963 | Combination treatment increases the rate of toxicities (see Table 322.3), and complex drug drug interac tions occur among many of the antiretroviral drugs, particularly with the pharmacokinetic boosters ritonavir and cobicistat. Many PIs are inducers or inhibitors of the cytochrome P450 system and are there fore likely to have serious interactions with multiple drug classes, including nonsedating antihistamines and psychotropic, vasocon strictor, antimycobacterial, cardiovascular, anesthetic, analgesic, and gastrointestinal drugs (cisapride). Whenever new medications are added to an ART regimen, especially a PI or cobicistat containing regimen, a pharmacist andor HIV specialist should be consulted to address possible drug interactions. The inhibitory effect of ritonavir (a PI) on the cytochrome P450 system is exploited, and small doses of the drug are added to several other PIs (e.g., lopinavir, atazana vir, darunavir) to slow their metabolism by the P450 system and to 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. 2098 Part XV u Infectious Diseases Table 322.3 Summary of Antiretroviral Therapies Available in 2023 DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS NUCLEOSIDENUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS Class adverse effects: Lactic acidosis with hepatic steatosis, particularly for older members of the class Abacavir (Ziagen, ABC): tablet: 300 mg; oral solution: 20 mgmL Epzicom: combination of lamivudine, ABC (300, 600 mg) Triumeq: combination of ABC, lamivudine, dolutegravir (600, 300, 50 mg) Triumeq PD: combination of ABC, lamivudine, dolutegravir (60, 30, 5 mg) Children: Full term 1 mo: 2 mg kgdose bid Full term 1 mo to 3 mo: 4 mg kgdose bid 3 mo to 13 yr: 8 mgkgdose bid (max: 300 mg bid) 25 kg: 300 mg bid Children with stable CD4 counts and undetectable viral load 6 mo while taking ABC can transition to 16 mgkg once daily (max: 600 mg) Children 25 kg, adolescents and adults: 300 mg bid or 600 mg qd Epzicom (25 kg): 1 tablet qd Triumeq: 1 tablet qd Triumeq PD (10 kg to 25 kg): Must be dispersed in 20 mL of water, not swallowed whole, cut, or chewed 10 kg to 14 kg: 4 tablets qd 14 kg to 20 kg: 5 tablets qd 20 kg to 25 kg: 6 tablets qd Common: nausea, vomiting, anorexia, fever, headache, diarrhea, rash Less common: hypersensitivity reactions, which can be fatal Rare: lactic acidosis with hepatic steatosis, pancreatitis, elevated triglycerides, myocardial infarction Genetic screening for HLAB5701 must be done before initiation of ABC containing treatment. If test is positive, avoid ABC. Once daily dosing is not preferred with liquid formulations. Can be given with or without food Do not restart ABC in patients who had hypersensitivity like symptoms (e.g., flulike symptoms). Oral solution does not require refrigeration. Abacavir should never be used for postexposure prophylaxis (PEP). Emtricitabine (Emtriva, FTC): capsule: 200 mg; oral solution: 10 mgmL Truvada: combination of FTC, tenofovir disoproxil fumarate (TDF) (200, 300 mg) Truvada Low Strength: combinations |
7,964 | of FTCTDF (100, 150 mg); (133, 200 mg); (167, 250 mg) Descovy: combinations of FTC, tenofovir alafenamide (TAF) (200, 25 mg); (120, 15 mg) Atripla: combination of FTC, TDF, efavirenz (EFV) (200, 300, 600 mg) Biktarvy: combinations of FTC, TAF, bictegravir (BIC) (200, 25, 50 mg); (120, 15, 30 mg) Complera: combination of FTC, TDF, rilpivirine (RPV) (200, 300, 25 mg) Odefsey: combination of FTC, TAF, RPV (200, 25, 25 mg) Stribild: combination of FTC, TDF, elvitegravir (EVG), cobicistat (COBI) (200, 300, 150, 150 mg) Genvoya: combination of FTC, TAF, EVG, COBI (200, 10, 150, 150 mg) Symtuza: combination of FTC, TAF, darunavir (DRV), COBI (200, 10, 800, 150 mg) Infants: 0 3 mo: 3 mgkg qd Children 3 mo to 17 yr, oral solution: 6 mgkg (max: 240 mg) qd 33 kg, adolescents and adults: 200 mg capsule or 240 mg solution qd 14 to 25 kg: Biktarvy (120, 15, 30 mg), Descovy (120, 15 mg): 1 tablet qd 25 kg: Biktarvy (200, 25, 50 mg), Genvoya: 1 tablet qd 25 kg to 35 kg: Descovy (200 mg, 25 mg) but cannot pair with boosted PI or COBI: 1 tablet qd 35 kg: Complera, Odefsey, Descovy (200, 25 mg): 1 tablet qd 35 kg, SMR 4 or 5: Stribild: 1 tablet qd 40 kg Atripla, Symtuza: 1 tablet qd SMR Sexual maturity rating Common: headache, insomnia, diarrhea, nausea, skin discoloration (hyperpigmentation of palms, soles) Less common: lactic acidosis with hepatic steatosis, neutropenia Patient should be tested for hepatitis B virus (HBV) before starting because HBV exacerbation can occur when emtricitabine is discontinued. Some combination drugs may have food requirements. Oral solution should be refrigerated if temperature above 25C (77F) and for long term storage. COBI is a pharmacokinetic enhancer (boosting agent) used to optimize drug levels; it is not interchangeable with ritonavir. It can alter renal tubular secretion of Cr, resulting in elevated Cr with normal GFR. Note FTC oral solution is less bioavailable and has a max dose of 240 mg, whereas the max dose for capsules is 200 mg. 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2099 Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS Lamivudine (Epivir, Epivir HBV, 3TC): tablet: 150 (scored), 300 mg (Epivir, generic), 100 mg (Epivir HBV); Solution: 5 mgmL (Epivir HBV), 10 mgmL (Epivir) Combivir: combination of ZDV, lamivudine (300, 150 mg) Cimduo: combination of 3TC, TDF (300 mg, 300 mg) Delstrigo: combination of 3TC, TDF, doravirine (DOR) (300, 300, 100 mg) Dovato: combination of 3TC, DTG (300, 50 mg) Symfi: combination of 3TC, TDF, EFV (300, 300, 600 mg) Symfi Lo: combination of 3TC, TDF, EFV (300, 300, 400 mg) Temixys: combination of 3TC, TDF (300, 300 mg) Epzicom and Triumeq, Triumeq PD combination (see |
7,965 | abacavir) Neonates (32 wk gestational age through 4 wk of age for term infants): 2 mgkgdose bid 4 wk to 3 mo: 4 mgkgdose bid 3 mo to 3 yr: 5 mgkgdose bid (max: 150 mg) 3 yr: 5 mgkgdose bid (max: 150 mg) or 10 mgkgdose qd (max: 300 mg) For 14 kg with scored tablet (150 mg) 14 to 20 kg: 75 mg bid or 150 mg qd (if 3 yr) 20 to 25 kg: 75 mg qAM and 150 mg qPM or 225 mg qd (if 3 yr) 25 kg: 150 mg bid or 300 mg qd Children should be switched to once daily dosing of lamivudine (oral solution or tablets) from twice daily dosing at 3 yr if clinically stable for 36 wk with an undetectable viral load and stable CD4 count Adolescents and adults: Combivir, (30 kg): 1 tablet bid Cimduo (35 kg): 1 tablet qd Epzicom (25 kg): 1 tablet qd Triumeq (25 kg): 1 tablet qd Triumeq PD: see abacavir Symfi (40 kg), Symfi Lo (35 kg and SMR 4 or 5): 1 tablet qd on empty stomach Temixys (35 kg): 1 tablet qd Dovato: 1 tablet qd in children who meet minimum body weight as part of a three drug regimen Child and adolescent 35 kg and virologically suppressed: Delstrigo: 1 tablet qd SMR Sexual maturity rating Common: headache, nausea Less common: pancreatitis, peripheral neuropathy, lactic acidosis with hepatic steatosis, lipodystrophy No food restrictions for lamivudine alone but some restrictions with combination drugs Patient should be tested for hepatitis B virus (HBV) before starting because HBV exacerbation can occur when lamivudine is discontinued. M184V mutation for this drug decreases viral fitness and can be advantageous to maintain including inducing AZT hypersusceptibility. Tenofovir alafenamide (Vemlidy, TAF) Descovy: combinations of TAF, FTC (25, 200 mg); (15, 120 mg) Genvoya: combination of TAF, FTC, EVG, COBI (10, 200, 150, 150 mg) Odefsey: combination of TAF, FTC, RPV (25, 200, 25 mg) Biktarvy: combinations of TAF, FTC, BIC (25, 200, 50 mg); (15, 120, 30 mg) Symtuza: combination of TAF, FTC, DRV, COBI (10, 200, 800, 150 mg) 2 yr 14 kg to 25 kg: Biktarvy (15, 120, 30 mg): 1 tablet qd Descovy (15, 120 mg): 1 tablet qd 25 kg: Biktarvy (25, 200, 50 mg), Descovy (25, 200 mg), Genvoya: 1 tablet qd 25 kg but 35 kg: Descovy but cannot pair with boosted PI: 1 tablet qd 35 kg: Descovy: 1 tablet qd 35 kg and 12 yr: Odefsey: 1 tablet qd 40 kg (adult dose) Symtuza: 1 tablet qd Common: headache, diarrhea, nausea, asthenia, increased serum lipids Newer version of TDF that has less renal and bone toxicity. Baseline serum creatinine still recommended before starting. Screen for HBV before TAF is started, because exacerbation of hepatitis may occur when TAF is discontinued. Concentrates in cells more so than TDF Continued 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. |
7,966 | No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS Tenofovir disoproxil fumarate (Viread, TDF): tablet: 150, 200, 250, 300 mg; powder: 40 mg1 g powder Truvada: combination of FTC, TDF (200, 300 mg) Truvada Low Strength: combinations of FTCTDF (100, 150 mg); (133, 200 mg); (167, 250 mg) Cimduo: combination of 3TC, TDF (300 mg, 300 mg) Atripla: combination of FTC, TDF, EFV (200, 300, 600 mg) Complera: combination of FTC, TDF, RPV (200, 300, 25 mg) Delstrigo: combination of 3TC, TDF, DOR (300, 300, 100 mg) Stribild: combination of FTC, TDF, EVG, COBI (200, 300, 150, 150 mg) Symfi: combination of 3TC, TDF, EFV (300, 300, 600 mg) Symfi Lo: combination of 3TC, TDF, EFV (300, 300, 400 mg) Temixys: combination of 3TC, TDF (300, 300 mg) 2 yr to 12 yr and 10 kg: 8 mg kgdose qd Weight probands for 2 yr and 17 kg: 17 to 22 kg: 150 mg qd 22 to 28 kg: 200 mg qd 28 to 35 kg: 250 mg qd 35 kg: 300 mg qd (max dose) Atripla (40 kg): 1 tablet qd Cimduo (35 kg): 1 tablet qd Complera (35 kg): 1 tablet qd Symfi (40 kg), Symfi Lo 12 yr (35 kg and SMR 4 or 5): 1 tablet qd on empty stomach Stribild (35 kg, SMR 4 or 5): 1 tablet qd Temixys (35 kg): 1 tablet qd Delstrigo: Child and adolescent 35 kg and virologically suppressed: 1 tablet qd SMR Sexual maturity rating Common: nausea, vomiting, diarrhea, asthenia, flatulence Less common: lactic acidosis with hepatic steatosis, hepatomegaly, decreased bone density, renal toxicity (glomerular and proximal tubule dysfunction) Baseline creatinine, urinalysis for protein and glucose should be obtained before starting. Screen for HBV before TDF is given, because exacerbation of hepatitis may occur when TDF is discontinued. Cautious use in SMR 1 and 2 patients with regard to bone mineral density. Zidovudine (Retrovir, AZT, ZDV): capsule: 100 mg; tablet: 300 mg; syrup: 10 mgmL; intravenous injection: 10 mgmL (all available generic) Combivir: combination of ZDV, lamivudine (300, 150 mg) Low Risk Prophylaxis: 35 wk gestation at birth: Birth to age 4 wk: 4 mgkgdose PO bid (or 3 mgkgdose IV q12h) 30 to 35 wk gestation at birth: Birth to age 2 wk: 2 mgkgdose PO bid (or 1.5 mgkgdose IV q12h) THEN Age 2 wk to 6 wk: 3 mgkgdose PO bid (or 2.3 mg kgdose IV q12h) 30 wk gestation at birth Birth to age 4 wk: 2 mgkgdose PO bid (or 1.5 mgkgdose IV q12h) THEN Age 4 wk to 6 wk: 3 mgkgdose bid (or 2.3 mgkg dose IV q12h) (See text and Table 322.7 for recommended duration for low risk prophylaxis.) Common: bone marrow suppression (e.g., anemia, neutropenia), headache, nausea, vomiting, asthenia Less common: liver toxicity, lactic acidosis with hepatic steatosis, myopathy, fat redistribution, myopathymyositis No food restrictions Drug interactions: should not be |
7,967 | given with d4T or doxorubicin. Only antiretroviral with an IV formulation. Presumptive HIV therapy for high risk exposed infants and treatment: 35 wk gestation at birth: Birth to age 4 wk: 4 mgkgdose PO bid THEN Age 4 wk: 12 mgkgdose PO bid 30 to 35 wk gestation at birth: Birth to age 2 wk: 2 mgkgdose PO bid THEN Age 2 wk to 6 wk: 3 mgkgdose PO bid THEN Age 6 wk: 12 mgkgdose PO bid 30 wk gestation at birth: Birth to age 4 wk: 2 mgkgdose PO bid THEN Age 4 wk to 8 wk: 3 mgkgdose PO bid THEN Age 8 wk: 12 mgkgdose PO bid Infants 4 kg, 35 wk post conception and 4 wk post delivery and children: 4 kg to 9 kg: 12 mgkgdose PO bid 9 kg to 30 kg: 9 mgkgdose PO bid 30 kg: 300 mg bid (max dose) Alternative body surface area dosing: 180 240 mgm2dose PO bid Combivir (30 kg): 1 tablet bid IV dose is 75 of PO dose, same interval 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2101 Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Class adverse effects: rash is mild to severe, usually within first 6 wk. Discontinue the drug if severe rash (with blistering, desquamation, muscle involvement, or fever) Doravirine (Pifeltro, DOR) Tablet: 100 mg Delstrigo: combination of 3TC, TDF, DOR (300, 300, 100 mg) Child and adolescent 35 kg and virologically suppressed: Doravirine: 1 tablet qd Delstrigo: 1 tablet qd Common: nausea, abdominal pain, diarrhea, vivid dreams, insomnia Not approved for use in 18 yr Can have multiple drug interactions; metabolized by cytochrome P450 3A. If co administered with rifabutin, dose DOR bid Efavirenz (Sustiva, EFV): capsule: 50, 200 mg; tablet: 600 mg Atripla: combination of EFV, FTC, TDF (600, 200, 300 mg) Symfi Lo: combination of 3TC, TDF, EFV (300, 300, 400 mg) Symfi: combination of 3TC, TDF, EFV (300, 300, 600 mg) Children 3 yr: Consult with expert; not recommended for children 3 yr Children 3 yr: 10 to 15 kg: 200 mg qd 15 to 20 kg: 250 mg qd 20 to 25 kg: 300 mg qd 25 to 32.5 kg: 350 mg qd 32.5 to 40 kg: 400 mg qd 40 kg: 600 mg qd or 367 mgm2 body surface area (max: dose 600 mg) Atripla (40 kg): 1 tablet qd on empty stomach Symfi Lo (35 kg and SMR 4 or 5): 1 tablet qd on empty stomach SMR Sexual maturity rating For Symfi Lo consider use of therapeutic drug monitoring for pediatric patients 40 kg Symfi (40 kg): 1 tablet qd Common: transient skin rashes, CNS symptoms (e.g., vivid dreams, impaired concentration, insomnia, depression, hallucinations, |
7,968 | depression, suicidal ideation esp. in adolescents and young adults), gynecomastia Less common: increased liver enzymes; potentially teratogenic, QTc prolongation (be careful with other QT prolonging medications), false positives on some cannabinoid and benzodiazepine tests Capsules can be opened for mixing in food. Administer at bedtime on empty stomach to minimize CNS side effects. Taking with food, especially fatty meal, can increase absorption and worsen CNS side effects. Drug interactions: Efavirenz inducesinhibits CYP3A4 enzymes. For some individuals with certain CYP450 polymorphisms, Symfi Lo is appropriate (lower EFV dose). Increased clearance of drugs metabolized by this pathway (e.g., antihistamines, sedatives and hypnotics, cisapride, ergot derivatives, warfarin, ethinyl estradiol) and several other ARVs (i.e., protease inhibitors). Drugs that induce CYP3A4 (e.g., phenobarbital, rifampin, rifabutin) decrease efavirenz levels. Clarithromycin levels decrease with EFV, and azithromycin should be considered. Avoid using in individuals with a history of past or active psychiatric issues and use with caution in adolescents and young adults owing to possible affective side effects, including increased suicidality. Etravirine (ETR, Intelence): tablet: 25, 100, 200 mg Not approved for 2 yr 10 to 20 kg: 100 mg bid 20 to 25 kg: 125 mg bid 25 to 30 kg: 150 mg bid 30 kg: 200 mg bid Common: nausea, rash, diarrhea Less common: hypersensitivity reactions with rash, including Stevens Johnson syndrome, multiorgan dysfunction including hepatic failure Always administer with a meal for absorption; taking on empty stomach decreases absorption by 50. Tablets can be dispersed in water but swallowing is preferred because consumption of dispersed tablets results in lower levels. Inducer of CYP3A4 enzymes and inhibitor of CYP2C9 and CYP2C19, causing multiple interactions that should be checked before initiating ETR. Cobicistat boosted PIs, nonnucleoside reverse transcriptase inhibitors, bictegravir, and elvitegravir cobicistat should not be used with ETR. Raltegravir and dolutegravir should only be used with ETR with ritonavir (RTV) boosted atazanavir, darunavir, or lopinavir. Continued 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. 2102 Part XV u Infectious Diseases Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS Nevirapine (Viramune, NVP): tablet: 200 mg; extended release (XR) tablet: 100, 400 mg; suspension: 10 mgmL Presumptive HIV therapy for highrisk exposed infants and treatment: 32 to 34 wk gestation at birth: Birth to age 2 wk: 2 mgkgdose bid 2 wk to 4 wk: 4 mgkgdose bid 4 wk to 6 wk: 6 mgkg bid 6 wk with confirmed infection: NVP 200 mgm2dose bid 34 wk to 37 wk gestation at birth: Birth to 1 wk: 4 mgkgdose bid 1 wk to 4 wk: 6 mgkgdose bid 4 wk and confirmed infection: 200 mgm2dose bid 37 wk gestation at birth: Birth to age 4 wk: 6 mgkgdose bid Age 4 wk and confirmed infection: 200 mgm2dose bid 1 mo to 8 yr: 200 mgm2 once daily for 14 days; then |
7,969 | same dose bid (max: 200 mgdose for immediaterelease tablets) 8 yr: 120 150 mgm2 once daily for 14 days; then bid (max: 200 mgdose for immediaterelease tablets) Adolescents and adults: 200 mg once daily for 14 days; then 200 mg bid Or XR 400 mg qd (after 14 day lead in) Extended release tablets: 6 yr by BSA: 0.58 m2 to 0.83 m2: 200 mg 0.84 m2 to 1.16 m2: 300 mg 1.17 m2: 400 mg Patients already on immediate release formulation can transition to qd XR dosing without lead in Note doses are never adjusted down if patient is tolerating. 3 dose series for high risk infants (less commonly used) 32 wk gestation at birth: NOTE: DOSES ARE A FLAT DOSE, NOT PER KG Dosing intervals: Within 48 hr of birth, 48 hr after first dose, 96 hr after second dose Birth weight 1.5 2 kg: 8 mgdose PO Birth weight 2 kg: 12 mgdose PO Common: skin rash (usually in first 6 wk of therapy), headache, fever, nausea, abnormal liver function tests Less common: hepatotoxicity (rarely life threatening hepatic necrosis), hypersensitivity reactions, Stevens Johnson syndrome (1.47.1 of pediatric patients in large series) that can have multiorgan involvement No food restrictions Drug interactions: induces hepatic CYP450A enzymes (including CYP3A and CYP2B6) activity and decreases protease inhibitor concentrations. Rifampin decreases nevirapine serum levels. Anticonvulsants and psychotropic drugs using same metabolic pathways as NVP should be monitored. Oral contraceptives also may be affected. XR formulation must be swallowed whole. For children 2 yr, some experts start with bid dosing without the 14 day lead in of qd dosing. Lead in dosing decreases occurrence of rash by allowing induction of cytochrome p450 metabolizing enzymes. If rash develops during initial 14 days of therapy, do not increase dose until rash resolves. If therapy is interrupted for 14 days, restart using lead in dosing. Nevirapine should never be used for postexposure prophylaxis (PEP). 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2103 Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS Rilpivirine (Edurant, RPV): tablet: 25 mg Complera: combination of RPV, FTC, TDF (25, 200, 300 mg) Odefsey: combination of FTC, TAF, RPV (25, 200, 25 mg) Juluca: combination of RPV, Dolutegravir (DTG) (25, 50 mg) Co packaged formulation (Cabenuva): combinations injectable of RPV, cabotegravir: (900, 600 mg); (600, 400 mg) 12 yr and 35 kg: 25 mg PO qd Complera or Odefsey: 1 tablet qd Juluca (18 yr): 1 tablet qd; only for use in adults with 6 mo virologic suppression with no resistance to replace current regimen 12 years and 35 kg with virologic suppression and no history of treatment failure starting on last day of 28 day oral lead in therapy: Cabenuva (900, 600 mg) IM, then |
7,970 | Cabenuva (600, 400 mg) IM monthly Alternate every 2 mo dosing also available Headache, insomnia, rash, depression, mood changes Less common: hepatotoxicity Given with food only, 500 kcal meal (not just liquid). Do not use with proton pump inhibitors; antacids have to be spaced from dose by 2 hr before or 4 hr after. H2 antagonists should be administered 12 hr before or 4 hr after RPV. Should not be used if viral load 100,000 copiesL or drugs that induce CYP3A. Injectables can give local site reaction, soreness. Administration window is 7 days for injectable regimens. It is critical that injectable regimens are received on schedule, as prolonged subtherapeutic drug levels will lead to emergence of resistance. PROTEASE INHIBITORS Class adverse effects: GI side effects, hyperglycemia, hyperlipidemia (except atazanavir and darunavir), lipodystrophy, increased transaminases, increased bleeding disorders in hemophiliacs. Can induce metabolism of ethinyl estradiol; use alternative contraception (other than estrogen containing oral contraceptives). All of these drugs undergo hepatic metabolism, mostly by CYP3A4, with many drug interactions. Treatment note: always administer with boosting agent (RTV or COBI). Atazanavir (Reyataz, ATV): powder packet: 50 mgpacket; capsule: 150, 200, 300 mg (Note: capsules and packets are not interchangeable) Evotaz: combination of ATV, COBI (300, 150 mg) Infants and children 3 mo and 5 kg: 5 to 15 kg: ATV 200 mg (4 packets) RTV 80 mg qd 15 to 25 kg: ATV 250 mg (5 packets) RTV 80 mg qd Note: Capsules are not approved for 6 yr or 15 kg Children 6 yr and 15 kg capsule dosing: 15 to 35 kg: 200 mg RTV qd 100 mg 35 kg: 300 mg RTV 100 mg qd OR Evotaz: 1 tablet qd Common: elevation of indirect bilirubin; headache, arthralgia, depression, insomnia, nausea, vomiting, diarrhea, paresthesias Less common: prolongation of PR interval on electrocardiogram (ECG); rash, rarely Stevens Johnson syndrome, diabetes mellitus, nephrolithiasis Administer ATV with food to increase absorption and decrease GI side effects. Do not open capsules. Review drug interactions before initiating because ATV inhibits CYP3A4, CYP1A2, CYP2C9, and UGT1A1 enzymes. Use with caution with cardiac conduction disease or liver impairment. TDF, antacids, H2 receptor antagonists, and proton pump inhibitors decrease ATV concentrations. PPIs should be taken 12 hr before boosted ATV and not coadministered. COBI is a pharmacokinetic enhancer (boosting agent) used to optimize drug levels; it is not interchangeable with ritonavir. It can alter renal tubular secretion of Cr, resulting in elevated Cr with normal GFR. Continued 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. 2104 Part XV u Infectious Diseases Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS Darunavir (Prezista, DRV): tablets: 75, 150, 600, 800 mg; suspension: 100 mgmL Prezcobix: combination DRV, COBI (800, 150 mg) Symtuza: combination DRV, TAF, FTC, COBI (800, 10, 200, 150 mg) 3 yr or 10 |
7,971 | kg: Do not use 3 yr to 12 yr: 10 to 11 kg: DRV 200 mg RTV 32 mg bid 11 to 12 kg: DRV 220 mg RTV 32 mg bid 12 to 13 kg: DRV 240 mg RTV 40 mg bid 13 to 14 kg: DRV 260 mg RTV 40 mg bid 14 to 15 kg: DRV 280 mg RTV 48 mg bid 15 to 30 kg: DRV 375 mg RTV 48 mg bid 30 to 40 kg: DRV 450 mg RTV 100 mg bid 12 yr and 30 to 40 kg: DRV 450 mg RTV 100 mg bid 40 kg: DRV 600 mg RTV 100 mg bid 12 yr and 40 kg and no DRV mutations: DRV 800 mg RTV 100 mg qd OR Prezcobix: 1 tablet qd 40 kg with DRV mutation(s): DRV 600 mg RTV 100 mg bid 40 kg with no DRV or TDFTAF resistance: Symtuza: 1 tablet qd Common: diarrhea, nausea, vomiting, abdominal pain, fatigue, headache Less common: skin rashes (including Stevens Johnson syndrome), lipid and liver enzyme elevations and hepatotoxicity, hyperglycemia, fat maldistribution DRV should always be given with food for absorption and to decrease GI side effects. Contraindicated for concurrent therapy with cisapride, ergot alkaloids, benzodiazepines, pimozide, or any major CYP3A4 substrates. Use with caution in patients taking strong CYP3A4 inhibitors, or moderatestrong CYP3A4 inducers. Contains sulfa moiety: potential for cross sensitivity with sulfonamide class DRV should not be administered once daily to individuals 12 yr or 40 kg. COBI is a pharmacokinetic enhancer (boosting agent) used to optimize drug levels; it is not interchangeable with ritonavir. It can alter renal tubular secretion of Cr, resulting in elevated Cr with normal GFR. LopinavirRitonavir (Kaletra, LPVr): tablet: 10025 mg, 20050 mg; solution: 8020 mg permL (contains 42 alcohol, 15 propylene glycol) 14 days: Not approved 14 days to 18 yr: LPV 300 mgm2 dose RTV 75 mgm2dose bid In treatment nave children 1 yr a dose of 230 mgm2dose bid can be used. 18 yr: LPV 400 mg RTV 100 mg bid Or 800 mg LPV 200 mg RTV qd 45 kg: If taken with NVP, EFV, fosamprenavir, or nelfinavir: LPV 600 mg RTV 150 mg bid Common: diarrhea, headache, nausea and vomiting, lipid elevation, alteration of taste, hyperlipidemia (hypertriglyceridemia) Less common: fat redistribution, hyperglycemia, diabetes mellitus, pancreatitis, hepatitis, PR interval prolongation, QT interval prolongation and torsades de pointes. Life threatening cardiotoxicity risk in neonates. Do not administer before postmenstrual age of 42 wk and postnatal age of 14 days due to potential severe toxicities. If patient on concomitant NVP or EFV, dosing must be adjusted and it must be given bid. No food restrictions for tablets but has better GI tolerability when given with or after a meal. Oral solution should be administered with high fat meal to increase absorption. Pills must be swallowed whole. Poor palatability of oral solution is difficult to mask with flavorings or foods. Once daily dosing is poorly tolerated in most children, and plasma concentration variability makes |
7,972 | qd dosing contraindicated in children and adolescents. Interacts with drugs using CYP3A4, which can cause multiple drug interactions. Ritonavir (Norvir, RTV): capsule: 100 mg; tablet: 100 mg; solution: 80 mg mL (contains 43 alcohol) Only use is to enhance other PIs; dose varies (see information for specific PI) Common: nausea, headache, vomiting, abdominal pain, diarrhea, taste aversion, lipid abnormalities, perioral paresthesias Less common: fat redistribution, hyperglycemia, diabetes mellitus, pancreatitis, hepatitis, PR interval prolongation, allergic reactions Administration with food enhances bioavailability and reduces gastrointestinal symptoms. RTV solution should not be refrigerated (store at 2025C). RTV is potent inhibitor of CYP3A4 and CYP2D6 and inducer of CYP3A4 and CYP1A2 that leads to many drug interactions (e.g., protease inhibitors, antiarrhythmics, antidepressants, cisapride). Use cautiously with inhaled steroids (Cushing syndrome has been reported specifically with coadministration with fluticasone). 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2105 Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS ENTRY AND FUSION INHIBITORS Fostemsavir (Rukobia, FTR): Extended release tablet 600 mg Safety and efficacy data not established for 18 yr Adults 18 yr: 1 tablet twice daily QTc prolongation with higher than recommended doses, increased transaminases in Hep B or Hep C co infection Reserved for treatment in experienced patients with significant resistance. Tablet must be swallowed whole. Do not co administer with strong P450 CYP 3A4 inducers. Potential drug interactions. Ibalizumab (Trogarzo, IBA) IV: single dose vial 200 mg1.33 mL Safety and efficacy data for 18 yr olds not established Adults 18 yr: Loading dose 2000 mg IV, maintenance dose 800 mg q2 wk Diarrhea, nausea, rash, dizziness, IRIS, possible development of anti IBA antibodies Reserved for treatment in experienced patients with significant resistance. Used in combination with optimized cART regimen. Maraviroc (Selzentry, MVC): oral solution: 20 mgmL; tablet: 25, 75, 150, 300 mg Given with potent CYP3A inhibitors (all PIs): 2 to 10 kg: Not recommended 10 to 20 kg: 50 mg bid 20 to 30 kg: 75 80 mg bid 30 to 40 kg: 100 mg bid 40 kg: 150 mg bid Given with noninteracting drugs such as NRTIs, T 20, NVP, RAL, or other drugs not affecting CYP3A: 2 to 4 kg: 30 mg bid 4 to 6 kg: 40 mg bid 6 to 10 kg: 100 mg bid 10 to 14 kg: 150 mg bid 14 to 30 kg: 200 mg bid 30 to 40 kg: 300 mg bid 40 kg: 300 mg bid Insufficient data for all children and adolescents for dosing with potent CYP3A inducer, including EFV, ETR Adults: Given with noninteracting medications: 300 mg bid Given with potent CYP3A inhibitors (including all PIs): 150 mg bid Given with potent CYP3A inducers including EFV and ETR 600 mg bid Common: fever, upper respiratory infectionlike symptoms including |
7,973 | cough, nausea, vomiting, rash, abdominal pain, musculoskeletal symptoms, dizziness Testing for CCR 5 tropic virus required; virus must not have mixed tropism (i.e., CCR 5 CXC4) to have efficacy. No food restrictions. MVC is a CYP3A4 and P glycoprotein (Pgp) substrate, which may cause many drug interactions. Caution should be used when given to patients with hepatic impairment or cardiac disease or receiving CYP3A4 or P glycoprotein modulating drugs. INTEGRASE INHIBITORS (INSTI) Class side effects: headache, mild GI symptoms, potential significant weight gain for some INSTIs Bictegravir (BIC) Only available as Biktarvy: combinations of BIC, TAF, FTC (50, 25, 200 mg); (30, 15, 120 mg) 2 y and 14 kg to 25 kg: 1 tablet (30, 15, 120 mg) qd 25 kg: 1 tablet (50, 25, 200 mg) qd Diarrhea, nausea, headache, No food restrictions. Metabolized by UGT1A1 and CYP450 (CYP) 3A. For children unable to swallow tablet whole, tablet can be split and all parts swallowed separately within 10 min. All patients should be screened for HBV before using FTC or TAF. Avoid in severe hepatic impairment. Continued 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. Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS Cabotegravir (Vocabria, CAB): Tablet: 30 mg Single dose vial for IM injection (Apretude): 600 mg (PrEP only) Co packaged formulation (Cabenuva): combinations injectable of RPV, CAB: (900, 600 mg); (600, 400 mg) PrEP (CAB only) Adolescents and adults 35 kg confirmed HIV negative who meet criteria: Optional oral lead in for 1 mo (dosing below) then on last day oral lead in, patient receives IM 600 mg CAB monthly for 2 mo then every 2 mo For treatment of HIV (CABRPV): 12 y and 35 kg and adults with suppressed viral load and no history of treatment failure: Optional oral lead in with oral RPV and CAB for 1 mo: CAB 30 mg, RPV 25 mg PO qd Monthly administration: Starting on last day of oral lead in IM CABRPV (600900 mg) first month then CABRPV (400600 mg) monthly Every 2 mo administration: Starting on last day of oral lead in IM CABRPV (600900 mg) monthly for 2 mo then CABRPV (600900 mg) every 2 mo. Injection site reactions, depression, insomnia, headache, rash (can be severe with systemic symptoms), hepatotoxicity, weight gain, CPK elevation, ACTH stimulation test alteration of unclear significance Close monitoring and strong engagement in care needed for injectable therapies as missing doses with prolonged subtherapeutic levels can lead to emergence of resistance and for PrEP acquisition of resistant HIV infection. There is a 7 day dose administration window for the monthly dose. CAB and RPV are injected separately into separate ventrogluteal sites. Dolutegravir (Tivicay, DTG): film coated tablet: 10, 25, 50 mg Dispersible tablets for oral suspension (Tivicay PD): 5 mg Triumeq: combination of ABC, 3TC, DTG |
7,974 | (600, 300, 50 mg) Juluca: combination of RPV, DTG (25, 50 mg) Dovato: combination of DTG, 3TC (50, 300 mg) Triumeq PD: combination of ABC, lamivudine, dolutegravir (60, 30, 5 mg) Neonates: not approved 4 wk, 3 kg, dispersible tablets: 3 kg to 6 kg: 5 mg qd 6 kg to 10 kg: 15 mg qd 10 kg to 14 kg: 20 mg qd 14 to 20 kg: 25 mg qd 20 kg 30 mg qd 14 kg film coated tablets: 14 kg to 20 kg: 40 mg qd 20 kg: 50 mg qd 25 kg: Triumeq: 1 tablet qd Juluca: 1 tablet qd; only for use in patients with 6 mo virologic suppression with no resistance to replace current regimen. Can be used in adolescents meeting weight requirements for treatment simplification Dovato: 1 tablet qd; can be used in adolescents meeting weight requirements for treatment simplification Triumeq PD (10 kg to 25 kg): Must be dispersed, not swallowed whole, cut or chewed 10 kg to 14 kg: 4 tablets 14 kg to 20 kg: 5 tablets 20 kg to 25 kg: 6 tablets Insomnia, headache, neuropsychiatric illness Rare: rash, hepatotoxicity, hypersensitivity reactions Film coated tablets and dispersible tablets are not bioequivalent and are not interchangeable. Film coated tablets should not be used in 14 kg patients. Juluca and Dovato are not recommended as first line regimens for children and adolescents but if child meets weight criteria and viral load criteria could be used to reduce pill burden). Elvitegravir (EVG): only found in 2 co formulated fixed dose combination (FDC) tablets Stribild: combination of EVG, FTC, TDF, COBI (150, 200, 300, 150 mg) Genvoya: combination of FTC, TAF, EVG, COBI (200, 10, 150, 150 mg) 25 kg: Genvoya 1 tablet qd 35 kg and SMR 4 or 5: Stribild 1 tablet qd SMR Sexual Maturity Rating Nausea, diarrhea, headache, fatigue Administer with food. EVG is metabolized by CYP3A4 and modestly induces CYP2D6 that can cause multiple drug interactions. Use cautiously with nephrotoxic drugs. Administer 4 hr before or after antacids, multivitamins or supplements that contain iron, calcium, aluminum, or magnesium. COBI is a pharmacokinetic enhancer (boosting agent) used to optimize drug levels; it is not interchangeable with ritonavir. It can alter renal tubular secretion of Cr, resulting in elevated Cr with normal GFR. 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2107 Table 322.3 Summary of Antiretroviral Therapies Available in 2023contd DRUG (TRADE NAMES, FORMULATIONS) DOSING SIDE EFFECTS COMMENTS Raltegravir (Isentress, RAL): film coated tablet: 400 mg; film coated high dose (HD) tablet: 600 mg; chewable tablet: 25, 100 mg (scored); granules for oral suspension: 100 mg suspended in 10 mL of water for final concentration of 10 mgmL Presumptive therapy for highrisk exposed neonates and treatment: 37 wk gestation at birth and 2 |
7,975 | kg (oral suspension): Birth to age 1 wk: approximately 1.5 mgkgdose qd 2 to 3 kg: 4 mg qd 3 to 4 kg: 5 mg qd 4 to 5 kg: 7 mg qd If parent on raltegravir in 2 24 hr before delivery, delay first dose 24 48 hr after birth. Start other ART ASAP. Age 1 4 wk: approximately 3 mg kgdose bid 2 to 3 kg: 8 mg bid 3 to 4 kg: 10 mg bid 4 to 5 kg: 15 mg bid Infant and Pediatrics dosing Oral suspension: Children age 4 wk and 3 kg to 20 kg: approximately 6 mgkg dose bid 3 to 4 kg: 25 mg bid 4 to 6 kg: 30 mg bid 6 to 8 kg: 40 mg bid 8 to 10 kg: 60 mg bid 10 to 14 kg: 80 mg bid 14 to 20 kg: 100 mg bid Chewable tablet: 3 kg to 6 kg: 25 mg bid 6 to 10 kg: 50 mg bid 10 to 14 kg: 75 mg bid 14 to 20 kg: 100 mg bid 20 to 28 kg: 150 mg bid 28 to 40 kg: 200 mg bid 40 kg: 300 mg bid Film coated tablet: 25 kg: 400 mg bid HD tablet: 40 kg HD tablet: 1200 mg qd for treatment nave patients or patients virologically suppressed on RAL 400 mg bid Common: nausea, headache, dizziness, diarrhea, fatigue Less common: itching, creatine phosphokinase elevation, myopathy, rhabdomyolysis, depression, hypersensitivity, insomnia, fever Rare: rash including Stevens Johnson, TEN, hypersensitivity reaction Oral suspension, film coated tablet and chewable tablet are not interchangeable; chewable tablets and suspension have better oral bioavailability than film coated tablet; hence, higher dose for film coated tablets. The chewable tablet can be crushed. Place tablet in small clean cup, add 5 mL (1 tsp ) of liquid (water, breast milk, juice) and let stand for 2 min while pill absorbs liquid. Use spoon to crush remaining intact pill. Administer immediately. Add 5 mL of liquid to cup, swirl, and administer that liquid as well to ensure full dose consumed. Film coated tablets must be swallowed whole. RAL is metabolized by UGT1A1 glucuronidation, and inducers of this system (e.g., rifampin) will reduce RAL levels, whereas inhibitors of this system (e.g., ATV) will increase RAL levels. Do not administer rifampin, ETR, or calcium carbonate with once daily raltegravir (HD). Aluminum and magnesium containing antacids should not be taken while on RAL. UGT1A1 metabolism is low at birth and increases rapidly over first 4 6 wk of life. No data for preterm infants. Antiretroviral drugs often have significant drug drug interactions, with each other and with other classes of medicines, which should be reviewed before initiating any new medication. The information in this table is not all inclusive. Updated and additional information on dosages, drug drug interactions, and toxicities is available and regularly updated on the AIDSinfo website at https:www.nih.govresearch traininghivaids info center Modified from the Guidelines for use of antiretroviral agents in pediatric HIV infection. |
7,976 | http:aidsinfo.nih.govcontentfilespediatricguidelines.pdf. improve their pharmacokinetic profile. This strategy provides more effective drug levels with less toxicity and less frequent dosing. Cobi cistat provides an alternative to ritonavir as a pharmacokinetic booster but does not have antiviral activity against HIV. Although cobicistat is a potent inhibitor of cytochrome P450 3A, it is a weak inhibitor of CYP2D6 and other CYP isoforms (e.g., CYP1A2), making pharmaco logic interactions with many drugs more predictable than for ritona vir, which is also active against these isoforms. Studies with cobicistat show a good tolerability profile and less effect on adipocytes (resulting in lesser accumulations of lipid and a milder response to insulin). The better solubility of cobicistat compared with ritonavir has helped the development of more single tablet combination regimens with cobi cistat. Cobicistat is used for boosting both PIs and INSTIs. However, cobicistat is currently approved only for children 25 kg; it is not rec ommended for use in pregnancy because of a paucity of data and con cern for pharmacokinetics. Adherence Adherence to the medication schedules and dosages is fundamental to cART success. Therefore assessment of the likelihood of adherence to treatment is an important factor in initiating therapy and choice of regimen. Numerous studies show that compliance of 90 results in less successful suppression of the viral load. In addition, several stud ies document that almost half of the pediatric patients surveyed were nonadherent to their regimen. Poor adherence to prescribed medication regimens results in subtherapeutic drug concentrations and enhances the development of resistant viruses, leading to limited treatment options. Several barriers to adherence are unique to children with HIV infection. Combination antiretroviral regimens in liquid form are often unpalatable and require extreme dedication on the part of the caregiver and child; a reluctance to disclose the childs disease to others reduces social support; there may be a tendency to skip doses if the caregiver is not around or when the child is in school. Adolescents have other issues 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. 2108 Part XV u Infectious Diseases that reduce adherence. Denial of the diagnosis, an unstructured lifestyle, feelings of invincibility, desires for normalcy, adherence fatigue to life long medications, affective disorders, and substance use are just a few of the many factors that may interfere with long term adherence in this growing population. These and other barriers make involving the family in optimizing adherence essential when possible. Intensive education on the relationship of drug adherence to viral suppression, training on drug administration, frequent follow up visits, peer support, ongoing sup port including text messaging and other platforms from medical team and case managers, and commitment of the caregiver and the patient are critical for successful antiviral treatment. Multiple methods such as the viral load response, self reporting of missed doses during the last 3 7 days, and pharmacypill counting should be |
7,977 | used to assess adherence. Assessing for emergence of resistant virus on sequencing (genotype) can also be a helpful tool in patients not achieving virologic suppression as expected. For older children and adults, long acting injectable regimens also now exist and have the potential for enormous benefit for adher ence, though currently are only FDA approved for individuals with viro logic suppression and no history of treatment failure. Initiation of Therapy The decision of when to initiate cART has evolved significantly over the years in both adults and children. When cART was first introduced, medication regimens had significant side effects, leading to decisions to delay therapy until it was thought to be most beneficial, usually after advanced immunologic suppression had developed. The Strategic Tim ing of Antiretroviral Treatment (START) trial demonstrated a strong benefit in starting therapy earlier in adults, even before CD4 counts fell into an immunosuppressed range; this became more feasible with the development of safer, better tolerated medications. In adults, it has also been found that receiving suppressive cART eliminates the risk of the sexual transmission of HIV to others. Current adult guidelines recom mend the initiation of cART in all adults with HIV. In line with the adult guidelines, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV now also recommends starting treatment for all children with HIV as soon as possible. For children 1 year of age, the Children with HIV Early Antiretroviral Therapy (CHER) trial has clearly demonstrated the benefit of early immediate ART. Children younger than 1 year of age are at high risk for disease progression, and immunologic and virologic tests to iden tify those likely to develop rapidly progressive disease are less predic tive than in older children. Therefore all HIV infected infants younger than 1 year of age should be treated with cART as soon as the diagno sis of HIV infection has been confirmed, regardless of their clinical or immunologic status or viral load. Data suggest that HIV infected infants who are treated before the age of 3 months control their HIV infection better than infants whose cART started later than 3 months of age. Among older children, mortality rates are lower and growth is more normal in children who are started on immediate cART. Ini tiation of cART therapy should be deferred in children with active cryptococcal meningitis, tuberculosis infection, or disseminated MAC infection in collaboration with an HIV expert. The pediatric HIV guidelines are updated twice yearly, and care providers should check for revisions regularly at https:www.nih.gov research traininghivaids info center. Dosages Children are usually treated with higher doses (per kilogram weight) than adults because of reduced absorption or increased drug metabo lism. Data on ART drug dosages for neonates, especially premature infants, are often limited. Because of the immaturity of the neonatal liver, there often must be an increase in the dosing interval of drugs primarily cleared through hepatic glucuronidation. For some medications in older children, ART dosagesselections need to factor in sexual |
7,978 | maturity rating (SMR) (formerly known as Tanner staging). Fortunately thanks to evolving pediatric pharmaco kinetic data, many simpler regimens are now available to children 25 kg, including once daily, single pill (fixed dose combination) regimens (see Table 322.3 for comprehensive dosing information for current HIV drugs used in children as of February 2023). Because some ART agents may alter the metabolism of some hormonal contraceptives and decrease their effectiveness, interactions should be considered when choosing contraceptive agents for adolescents. A comprehensive table of interactions of HIV medications with hormonal contraceptives can be found in the perinatal HIV guidelines that are updated twice yearly at https:www.nih.govresearch traininghivaids info center. Medroxyprogesterone (DMPA) is a reasonable choice for most cART regimens. Alternative long acting contraception options, such as use of an intrauterine device, should also be considered. Changing Antiretroviral Therapy A change in therapy should be strongly considered when the current regimen is judged ineffective as evidenced by an increase in viral load, deterioration of the CD4 cell count, or clinical progression. Develop ment of toxicity or intolerance to drugs is another reason to consider a change in therapy. When a change is considered, the patient and family should be reassessed for adherence concerns. Because adherence is a major issue in this population, resistance testing (while the patient is taking antiretroviral medications) is important in identifying adher ence issues (e.g., detectable virus sensitive to current drug regimen is consistent with a lack of adherence) or the development of resistance (e.g., evidence of resistance mutations to current drug regimen). In both situations, other contributing factors, such as poor absorption, an incorrect dose, or drug drug interactions, should be carefully reviewed. While considering possible new drug choices, the potential for cross resistance should be addressed. In starting a new regimen in a patient with virologic failure, the new regimen should include at least two, but preferably three, fully active antiretroviral medications, with assess ment of the anticipated activity based on the treatment history and resistance testing (genotype or less commonly phenotype). The goal is to achieve and maintain virologic suppression. If virologic suppression cannot be achieved, the goals of therapy should focus on preserving immunologic function and preventing further disease progression, as well as preventing the emergence of additional drug resistance (which could limit future treatment options). Monitoring Antiretroviral Therapy To ensure proper monitoring, the CD4 cell count, viral load, com plete blood count, chemistries, urinalysis, and serum lipids should be obtained before an initiation of or change in cART to have a baseline for comparisons during treatment. At entry into care, genotypic resis tance testing should be done as well. Children must be seen within 1 4 weeks after initiation of new cART to reinforce and counsel regarding adherence and to screen for potential side effects. Ideally, telephone or text follow up by the medical team for adherence and side effects also occurs in the interval between cART start and the follow up visit. Virologic and immunologic surveillance (using the quantitative HIV RNA PCR |
7,979 | and CD4 lymphocyte count), as well as clinical assessment, should be performed regularly while on cART. The initial virologic response (i.e., at least a fivefold 0.7 log10 reduction in viral load) should be achieved within 4 8 weeks of initiating ART. The maximum response to therapy usually occurs within 12 16 weeks but may be later (24 weeks) in very young infants. Thus HIV RNA levels should be measured at 4 8 weeks and 12 24 weeks after therapy initiation. Once an optimal response has occurred, the viral load should then be measured at least every 3 6 months. If the response is unsatisfac tory, another viral load should be determined as soon as possible to verify the results before a change in therapy is considered. Virologic failure is defined as a repeated plasma viral load 200 copiesmL after 6 months of therapy. The CD4 cells respond more slowly to success ful treatment, particularly in patients with long standing infection and CD4 suppression. CD4 counts should be monitored every 3 4 months and potentially can be done less frequently in adolescents and adults with documented virologic suppression. Potential toxicity should be monitored closely for the first 8 weeks (including complete blood count, serum chemistries), and if no clinical or laboratory toxicity is documented, follow up visits are recommended every 1 2 months for children 18 months to allow increases in medication doses in 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2109 association with weight gain) and every 3 4 months for older children and adolescents. Monitoring for potential toxicity should be tailored to the patients medication regimen. Toxicities include but are not limited to hematologic complications (e.g., zidovudine); hypersensitivity rash (e.g., efavirenz); lipodystrophy (e.g., redistribution of body fat seen with NRTIs and PIs, which can take several years to emerge); hyper lipidemia (elevation of cholesterol and triglyceride concentrations); hyperglycemia and insulin resistance (e.g., PIs); mitochondrial toxicity leading to severe lactic acidosis; electrocardiogram abnormalities (e.g., atazanavir, lopinavir); abnormal bone mineral metabolism (e.g., teno fovir disoproxil fumarate but not tenofovir alafenamide); and hepatic toxicity, including severe hepatomegaly with steatosis. After a patient is on a stable regimen, labs outside of CD4 count and viral load can be done every 6 12 months. An important part of every visit is ongo ing adherence counseling given the need for excellent adherence to cART to avoid the emergence of resistance. Detailed current guidelines for monitoring HIV infected children during therapy can be found at https:www.nih.govresearch traininghivaids info center. Resistance to Antiretroviral Therapy Young children usually are at greater risk than adults for develop ing resistance because they have higher viral loads and fewer ART options than adults (reflecting the fact that only some agents are available in a liquid formulation and have pharmacokinetic dos ing data for children). |
7,980 | The high mutation rate of HIV (mainly as a result of the absence of error correcting mechanisms in the reverse transcriptase enzyme) results in the generation of viruses with mul tiple mutations every day in the absence of cART. Failure to reduce the viral load to 50 copiesmL on cART because of nonadherence resulting in subtherapeutic drug levels increases the risk for devel oping resistance by selecting those mutant viruses with a competi tive advantage (i.e., drug resistance mutations). Even effectively treated patients do not completely suppress all viral replication, and persistence of HIV transcription and evolution of envelope sequences continues in the latent cellular reservoirs, though data show that this evolution does not appear to affect the emergence of resistance to cART in virologically suppressed patients. Accumula tion of resistance mutations, particularly in nonadherent patients, progressively diminishes the potency of the cART and challenges the physician to find new regimens. For some drugs (e.g., nevirap ine, lamivudine), a single mutation is associated with resistance, whereas for other drugs (e.g., zidovudine, lopinavir, darunavir, etravirine, etc. ), several mutations are needed before significant resistance develops. Testing for drug resistance, especially when devising a new regimen, is standard of care. Two types of tests are available; genotype is most commonly used, but the phenotype may be helpful in select patients with complex viral resistance as a result of exposure to multiple cART regimens. The phenotype measures the virus susceptibility in various concen trations of the drug. This allows calculation of the drug concentration that will inhibit the viral replication by 50 (IC50). The ratio of the IC50 and a reference virus IC50 is reported as the fold resistance change. Note that this test is usually combined with a genotype when used but is largely reserved for patients with extremely complex mutations. The genotype predicts the virus susceptibility from mutations identified in the HIV genome isolated from the patient and is the more commonly used test. Several online sites (e.g., http:hivdb.stanford.edu) can assist in interpreting the tests results. Several studies show that the treatment success is higher in patients whose cART was guided by genotype or phenotype testing. Neither method may detect drug resistance if the amount of the resistant virus is 10 of the circulating population or if it is present only in the latent reservoir. Note that if a patient has not been tak ing cART for several weeks, the absence of selective drug pressure will make the dominant population of circulating viruses revert to the wild type, and resistance mutations can be missed. It is recommended to test for drug resistance before initiating ther apy and before changing treatment because of virologic failure. When changing therapy, the resistance test results should be considered in the context of previous resistance tests results, if done, and drugs used in previous regimens. Supportive Care Even before cART drugs were available, a significant impact on the quality of life and survival of HIV infected children was achieved when supportive care was given. A multidisciplinary |
7,981 | team approach is desir able for successful management. After the initiation or change of cART, more frequent visits or contacts with the patientcaregivers for sup port and education will help in their acceptance and adjustment to the new regimen and will contribute to a better adherence. Close attention should be paid to the nutritional status, which is often delicately bal anced and may require aggressive supplementation, especially in chil dren with advanced disease. Painful oropharyngeal lesions and dental caries may interfere with eating, and thus routine dental evaluations and careful attention to oral hygiene are important. Paradoxically, an increasing number of adolescents with perinatally acquired or behav ioral riskacquired disease are obese. Some teens experience cART related central lipoaccumulation (usually related to older agents), but others have poor dietary habits and inactivity as the cause of their obe sity, just as others do who are obese in epidemic numbers in the United States. Their development should be evaluated regularly, with the provision of necessary physical, occupational, andor speech therapy. Recognition of pain in the young child may be difficult, and effective nonpharmacologic and pharmacologic protocols for pain management should be instituted when indicated. All HIV exposed and HIV infected children should receive standard pediatric immunizations (Table 322.4). Live oral polio vaccine should not be given because of poor immunologic response in HIV infected children and concern for live vaccination in potentially immuno compromised children. The risk and benefits of rotavirus vaccination should be considered in HIV exposed infants. Because 1 of these infants in resource rich settings will develop HIV infection, the vac cine should be given in infants with negative testing at 2 3 weeks and 6 8 weeks of age. In other situations, the considerable attenuation of the vaccines strains should be considered, and unless the infant has clinical symptoms of AIDS or a CD4 count 750, vaccination is likely appro priate; consultation with an HIV expert is recommended. Other live bacterial vaccines (e.g., bacillus Calmette Gurin) should be avoided because of the high incidence of bacillus Calmette Gurinrelated disease in HIV infected infants. Varicella and measles mumps rubella vaccines are recommended for children who are not severely immuno suppressed (i.e., CD4 cell percentage 15, absolute CD4 count 500 cellsL for ages 1 5 years), but these vaccines should not be given to severely immunocompromised children (i.e., CD4 cell percentage 15, absolute CD4 count 500 cellsL for age 1 5 year). Of note, prior immunizations do not always provide protection, as evidenced by outbreaks of measles and pertussis in immunized HIV infected chil dren. The durability of vaccine induced titers is often short, especially if vaccines are administered when the childs CD4 cell count is low, and reimmunization when the CD4 count has increased may be indicated. It is recommended that children with HIV receive quadrivalent menin gococcal conjugate vaccine at a younger age than the routine schedule. Adolescent vaccines are also important, including the Tdap booster and HPV vaccine. The current recommended annotated vaccine schedule for HIV |
7,982 | infected children is found here (updated annually): https:ww w.cdc.govvaccinesscheduleshcpimzchild adolescent.html. Prophylactic regimens are integral for the care of HIV infected children. All infants 4 6 weeks to 1 year of age who are proved to be HIV infected should receive prophylaxis to prevent P. jiroveci pneu monia regardless of the CD4 count or percentage (Tables 322.5 and 322.6). Infants exposed to HIV infected individuals should receive the same prophylaxis until they are proved to be noninfected; how ever, prophylaxis does not have to be initiated if there is strong pre sumptive evidence of noninfection (i.e., nonbreastfed infant with two negative HIV PCR tests at 14 days and 4 weeks of age, respectively). When the HIV infected child is 1 year of age, prophylaxis should be given according to the CD4 lymphocyte count (see Table 322.5). The best prophylactic regimen is 150 mgm2day of TMP and 750 mg 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. 2110 Part XV u Infectious Diseases m2day of SMX (maximum: 3201,600 mg) given as 1 2 daily doses 3 days (consecutively or every other day) per week or daily if preferred for ease of adherence. For severe adverse reactions to TMP SMX, alternative therapies include dapsone, atovaquone, and aerosolized pentamidine. Prophylaxis against MAC should be offered to HIV infected chil dren with advanced immunosuppression (i.e., CD4 lymphocyte count 750 cellsL in children 1 year of age, 500 cellsL in children 1 2 year of age, 75 cellsL in children 2 5 years of age, and 50 cellsL in children 6 years of age) (see Table 322.6). The drugs of choice are azithromycin (20 mgkg maximum: 1,200 mg once a week orally or 5 mgkg maximum: 250 mg once daily orally) or clarithromycin (7.5 mgkg twice daily orally). In rare situations, rifabutin 300 mg daily can be an alternative for children 6 years of age, though efficacy data in children is very limited. Based on data for adults, primary prophylaxis against most opportu nistic infections may be discontinued if patients have experienced sus tained (6 months duration) immune reconstitution with cART, even if they had previous opportunistic infections such as Pneumocystis pneumonia or disseminated MAC. HIV infected children are at higher risk for TB and thus should have tuberculin skin testing (5 tuberculin units purified protein derivation PPD) or IFN release assay (IGRA) testing for TB annually; an induration of 5 mm should be considered positive for the PPD. IGRA is preferred in children with history of BCG Table 322.4 Routine Childhood Immunization Schedule for HIV Infected Children VACCINE BIRTH 1 MO 2 MO 4 MO 6 MO 1215 MO 2 YR 4 6 YR 11 12 YR Hepatitis B HepB HepB HepB Measles, mumps, and rubella Varicella vaccines MMR Varicella If CD4 500 MMR Varicella If CD4 200 Influenza Annual COVID 19 Regular schedule Pneumococcal conjugate vaccine PCV PCV |
7,983 | PCV PCV Pneumococcal polysaccharide vaccine PPSV23 Haemophilus influenzae B vaccine Hib Hib Hib Hib Diphtheria, tetanus and pertussis DTaP DTaP DTaP DTaP DTaP Tdap Inactivated polio vaccine IPV IPV IPV IPV Hepatitis A vaccine HepA HepA Meningococcal conjugate vaccine MCV4 (2 shot series) HPV vaccine HPV (3 shot series) Rotavirus vaccine RV (2 to 3 shot series) Dengue Dengue (3 shot series) If CD4 200 Note some combination vaccines may allow for fewer doses to be administered (such as for combination vaccines containing DTaP and Hib; followed recommended schedule of product) MMR vaccine and varicella vaccine should only be administered to children age 1 5 yr with absolute CD4 count 500 sustained for 6 mo and children 5 yr with CD4 count 200 sustained for 6 mo (or CD4 15 if absolute count unavailable). MMRV is contraindicated in HIV infected children. For immune reconstituted children can consider giving second MMR and varicella vaccines 1 3 mo after first dose as long as criteria are met. Inactivated influenza vaccine should be used in ages 6 mo. COVID 19 vaccination is recommended for HIV infected children and should be given per the pediatric recommendations, including boosters starting at 6 mo of age. PCV15 or PCV20 can be used. PPSV23 is given and boosted at 5 years; If PCV20 is given, PPSV23 optional. PPSV23 must be given 8 weeks after PCV given. MCV4 (quadrivalent conjugate vaccine) should be administered starting 24 mo with 2 dose series 8 wk apart. Must be given at least 4 wk after completion of PCV13 series. Booster recommended at 5 years. Meningococcal B conjugate vaccine also should be considered. HPV vaccine should be given in a 3 shot series at 0, 1 2 mo, 6 mo (minimum intervals 4 wk from dose 1 to 2, 12 wk from dose 2 to 3 with minimum of 5 mo between doses 1 and 3). HIV patients require 3 shots regardless of age series is started. Rotavirus vaccine has not been well studied in infants with HIV infection. It should be given to low risk exposed infants. For infected infants, use caution particularly in those with significant immunosuppression. If given, series must be started before 15 wk of age and completed by 8 mo of age. Dengue vaccination is recommended for children 9 16 yr living in endemic areas of dengue who have laboratory confirmed dengue at 0, 6 mo, 12 mo. It should not be given if CD4 200. It is not recommended for children traveling to dengue endemic areas. Current vaccine schedule with recommendations for immunocompromised populations can be found here (updated annually): https:www.cdc.govvaccinesschedulesdownloads child0 18yrs child combined schedule.pdf. 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2111 Table 322.5 Recommendations for Pneumocystis jiroveci Pneumonia Prophylaxis and CD4 Monitoring for HIV Exposed Infants |
7,984 | and HIV Infected Children, by Age and HIV Infection Status AGEHIV INFECTION STATUS PJP PROPHYLAXIS CD4 MONITORING Birth to 4 6 wk, HIV exposed No prophylaxis None HIV infection reasonably excluded No prophylaxis None 1 yr, HIV infected or HIV indeterminate Prophylaxis regardless of CD4 count or percentage According to local practice for initiation or follow up of cART 1 5 yr, HIV infected Prophylaxis if CD4 500 cellsL or 15 According to local practice for initiation or follow up of cART 6 yr, HIV infected Prophylaxis if CD4 200 cellsL or 15, According to local practice for initiation or follow up of cART The National Perinatal HIV Hotline (1 888 448 8765) provides consultation on all aspects of perinatal HIV care. See text. More frequent monitoring (e.g., monthly) is recommended for children whose CD4 counts or percentages are approaching the threshold at which prophylaxis is recommended. Prophylaxis should be considered on a case by case basis for children who might otherwise be at risk for PJP, such as children with rapidly declining CD4 counts or percentages or children with category C conditions. Children who have had PJP should receive PJP prophylaxis until their CD4 count is 200 cellsmm3 for patients age 6 yr, CD4 percentage is 15 or CD4 count is 500 cellsmm3 for patients age 1 to 6 yr for 3 consecutive mo after receiving cART for 6 mo. cART, Combined antiretroviral therapy; PJP, Pneumocystis jiroveci pneumonia. Table 322.6 Prophylaxis to Prevent First Episode of Opportunistic Infections Among HIV Exposed and HIV Infected Infants and Children, United States PATHOGEN PREVENTIVE REGIMEN INDICATION FIRST CHOICE ALTERNATIVE STRONGLY RECOMMENDED AS STANDARD OF CARE Pneumocystis pneumonia HIV infected or HIV indeterminate infants age 1 12 mo; HIV infected children age 1 5 yr with CD4 count of 500 cellsL or CD4 percentage of 15; HIV infected children age 6 12 yr with CD4 count of 200 cellsL or CD4 percentage of 15; 13 yr with CD4 count 200 or 15 TMP SMX, 150750 mgm2 body surface area per day or 5 10 mg kgday (TMP)25 50 mgkgday (SMX) (max: 3201,600 mg) orally qd or bid 3 times weekly on consecutive days Or qd or bid orally 3 times weekly on alternate days Dapsone: age 1 mo: 2 mgkg (max: 100 mg) orally qd; or 4 mgkg (max: 200 mg) orally once a week Atovaquone: age 1 3 mo and 24 mo 12 yr: 30 mgkg orally qd with food Age 4 24 mo: 45 mgkg orally qd with food; 13 yr 1,500 mg orally qd with food Aerosolized pentamidine: age 5 yr: 300 mg once a month by Respirgard II (Marquest, Englewood, CO) nebulizer Malaria Living or traveling to area in which malaria is endemic Same for HIV infected and HIV uninfected children. Refer to http:www.cdc.govmalaria for the most recent recommendations. Mefloquine, 5 mgkg orally 1 time weekly (max: 250 mg) Atovaquoneproguanil (Malarone) qd 11 20 kg: 62.5 mg25 mg (1 pediatric tablet) 21 30 kg: 2 pediatric tablets 31 40 |
7,985 | kg: 3 pediatric tablets 40 kg: 1 adult tablet (250 mg100 mg) Doxycycline, 2.2 mgkg body weight (maximum 100 mg) orally qd for children 8 yr Chloroquine, 5 mgkg base (equal 7.5 mgkg chloroquine phosphate) orally up to 300 mg weekly (only for regions where the parasite is sensitive) Continued 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. 2112 Part XV u Infectious Diseases Table 322.6 Prophylaxis to Prevent First Episode of Opportunistic Infections Among HIV Exposed and HIV Infected Infants and Children, United Statescontd PATHOGEN PREVENTIVE REGIMEN INDICATION FIRST CHOICE ALTERNATIVE Mycobacterium tuberculosis Isoniazid sensitive TST reaction 5 mm Or Prior positive TST result without treatment Or Positive interferon release assay (IGRA) result Or Close contact with any person who has contagious TB. TB disease must be excluded before start of prophylaxis Age 12 yr: 12 doses of weekly isoniazid (15 mgkg rounded up to the nearest 50 or 100 mg; max 900 mg) and rifapentine: 1014.0 kg: 300 mg 14.125.0 kg: 450 mg 25.132.0 kg: 600 mg 32.149.9 kg: 750 mg 50.0 kg: max 900 mg 12 weekly doses of isoniazid (25 mgkg for children age 212 yr) and rifapentine: 1014.0 kg: 300 mg 14.125.0 kg: 450 mg 25.132.0 kg: 600 mg 32.149.9 kg: 750 mg 50.0 kg: max 900 mg Or 20 30 mgkg body weight (max: 900 mg) orally 2 times weekly for 9 mo; DOT highly recommended Rifampin, 15 20 mgkg body weight (max: 600 mg) orally daily for 4 mo Isoniazid 1015 mgkg (max 300 mg) daily and rifampin 1020 mgkg (max 300 mgday) for 3 mo Isoniazid 1015 mgkg body weight (max 300 mg) daily for 69 mo Isoniazid resistant Same as previous pathogen; increased probability of exposure to isoniazid resistant TB Rifampin, 10 20 mgkg body weight (max: 600 mg) orally daily for 4 mo Consult TB expert Multidrug resistant (isoniazid and rifampin) Same as previous pathogen; increased probability of exposure to multidrug resistant TB Choice of drugs requires consultation with public health authorities and depends on susceptibility of isolate from source patient Mycobacterium avium complex For children age 6 yr with CD4 count of 50 cellsL; age 2 to 6 yr with CD4 count of 75 cellsL; age 1 to 2 yr with CD4 count of 500 cellsL; age 1 yr with CD4 count of 750 cellsL Clarithromycin, 7.5 mgkg (max: 500 mg) orally bid Or Azithromycin, 20 mgkg (max: 1,200 mg) orally once a week Azithromycin, 5 mgkg body weight (max: 250 mg) orally qd Or Children age 5 yr Rifabutin, 300 mg orally qd Varicella zoster virus Exposure to varicella or shingles with no history of varicella Or Zoster or seronegative status for VZV Or Lack of evidence for age appropriate vaccination Varicella zoster immunoglobulin (VariZIG), 125 IU10 kg (max: 625 IU) IM, administered ideally within 96 hr after exposure; potential benefit up |
7,986 | to 10 days after exposure If VariZIG is not available and 96 hr from exposure, acyclovir 20 mg kg (max: 800 mg) 4 times a day for 7 days starting 710 days postexposure Or IVIG, 400 mgkg, administered once Vaccine preventable pathogens Standard recommendations for HIV exposed and HIV infected children Routine vaccinations (see Table 322.4) USUALLY RECOMMENDED Toxoplasma gondii Seropositive IgG to Toxoplasma and severe immunosuppression: age 6 yr with CD4 percentage 15; age 6 yr with CD4 count 100 cellsL TMP SMX, 150750 mgm2 orally qd or divided bid Dapsone, age 1 mo: 2 mgkg or 15 mgm2 (max: 25 mg) orally qd Plus Pyrimethamine, 1 mgkg (max: 25 mg) orally qd Plus Leucovorin, 5 mg orally every 3 days Or Atovaquone per PJP dosing Invasive bacterial infections Hypogammaglobulinemia (i.e., IgG 400 mgdL) IVIG 400 mgkg body weight every 2 4 wk 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2113 PATHOGEN PREVENTIVE REGIMEN INDICATION FIRST CHOICE ALTERNATIVE Cytomegalovirus CMV antibody positivity and severe immunosuppression (CD4 count 50 cellsL for 6 yr; CD4 percentage 5 for 6 yr) Valganciclovir, 900 mg orally qd with food for older children who can receive adult dosing For children age 4 mo to 16 yr, valganciclovir oral solution 50 mgmL at dose in milligrams 7 BSA CrCl (up to maximum CrCl of 150 mLmin1.73 m2) orally qd with food (maximum dose 900 mgday) NA Information in these guidelines might not represent FDA approval or FDA approved labeling for products or indications. Specifically, the terms safe and effective might not be synonymous with the FDA defined legal standards for product approval. Daily trimethoprim sulfamethoxazole (TMP SMX) reduces the frequency of certain bacterial infections. Compared with weekly dapsone, daily dapsone is associated with a lower incidence of PCP but higher hematologic toxicity and mortality rates. Patients receiving therapy for toxoplasmosis with sulfadiazine pyrimethamine are protected against PCP and do not need TMP SMX. TMP SMX, dapsone pyrimethamine, and possibly atovaquone (with or without pyrimethamine), protect against toxoplasmosis; however, data have not been prospectively collected. Substantial drug interactions can occur between rifamycins (i.e., rifampin and rifabutin) and protease inhibitors and nonnucleoside reverse transcriptase inhibitors. A specialist should be consulted. Children routinely being administered intravenous immunoglobulin (IVIG) should receive VariZIG if the last dose of IVIG was administered more than 21 days before exposure. Protection against toxoplasmosis is provided by the preferred anti Pneumocystis regimens and likely by atovaquone. CMV, Cytomegalovirus; FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency virus; IgG, immunoglobulin G; IM, intramuscularly; IVIG, intravenous immunoglobulin; PCP, Pneumocystis pneumonia; TB, tuberculosis; TMP SMX, trimethoprim sulfamethoxazole; TST, tuberculin skin test; VZV, varicella zoster virus. From Panel on Opportunistic Infections in Children with and Exposed to HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Children with |
7,987 | and Exposed to HIV. Department of Health and Human Services. Available at https:clinicalinfo.hiv.govenguidelinespediatricopportunisticinfection. Table 1: Primary Prophylaxis. Accessed 11523. Table 322.6 Prophylaxis to Prevent First Episode of Opportunistic Infections Among HIV Exposed and HIV Infected Infants and Children, United Statescontd vaccination. If the child is living in close contact with a person with TB, the child should be tested more frequently. Of note, the sensitiv ity of PPD and IGRA are reduced in severely immunocompromised patients. The Guidelines for Prevention and Treatment of Opportu nistic Infections Among HIV Exposed and HIV Infected Children (https:www.nih.govresearch traininghivaids info center) should be consulted for these and other opportunistic infections that may occur in these populations. To reduce the incidence of opportunistic infections, parents should be counseled about (1) the importance of good handwashing; (2) avoiding raw or undercooked food (Salmo nella); (3) avoiding drinking or swimming in lake or river water or being in contact with young farm animals (Cryptosporidium); and (4) the risk of playing with or having certain pets (Toxoplasma and Barton ella from cats, Salmonella from reptiles). PROGNOSIS The improved understanding of the pathogenesis of HIV infection in children and the availability of more effective antiretroviral drugs has changed the prognosis considerably for children with HIV infec tion. The earlier cART is started, the better the prognosis. In settings with ready access to early diagnosis and ART, progression of the dis ease to AIDS has significantly diminished. Since the advent of cART in the mid 1990s, mortality rates in perinatally infected children have declined more than 90 and most children in highincome settings survive to adolescence and adulthood. Even with only partial reduction of the viral load, children may have significant immunologic and clini cal benefits. In general, the best prognostic indicators are the sustained suppression of the plasma viral load and the restoration of a normal CD4 lymphocyte count. If determinations of the viral load and CD4 lymphocytes are available, the results can be used to evaluate progno sis. It is unusual to see rapid progression in an infant with a viral load 100,000 copiesmL. In contrast, a high viral load (100,000 copies mL) over time is associated with a greater risk for disease progression and death. CD4 count is also another prognostic indicator with mor tality rate significantly higher in profoundly immunosuppressed indi viduals. To define the prognosis more accurately, the use of changes in both markers (CD4 lymphocyte percentage and plasma viral load) is recommended. Even in resource limited settings where cART and molecular diag nostic tests are less available, the use of cART has had a substantial benefit on the survival of HIV infected children and has reduced the likelihood of mortality by 75. Children with opportunistic infections (e.g., Pneumocystis pneumonia, MAC), encephalopathy and regressing developmental milestones, or wasting syndrome, which are all AIDS defining conditions, have the worst prognosis, with 75 dying before 3 years of age. A higher risk of death was documented in children who did not receive TMP SMX preventive therapy. Persistent |
7,988 | fever andor oral thrush, serious bacterial infections (meningitis, pneumonia, sep sis), hepatitis, persistent anemia (8 gdL), andor thrombocytopenia (100,000L) also suggest a poor outcome, with 30 of such chil dren dying before 3 years of age. In contrast, lymphadenopathy, spleno megaly, hepatomegaly, lymphoid interstitial pneumonitis, and parotitis are associated with a slower progression of disease and a better progno sis. With sustained virologic suppression and maintained immunologic function, life expectancy is quite good. Unfortunately, access to cART for children in resource limited settings lags greatly behind access for adults even today. For adults and adolescents acquiring HIV, effective cART can restore life expectancy to near normal. PREVENTION Parental Treatment and Infant Prophylaxis Use of ART for interruption of perinatal transmission has been one of the greatest achievements of HIV research. cART is documented to decrease the rate of perinatal HIV 1 transmission to 2, and to 1 if the person with HIV has a viral RNA level 1,000 copiesmL at delivery. Therefore it is recommended that all pregnant individuals be tested for HIV, and if they are positive, be treated with a cART regimen, irrespective of the viral load or CD4 count during pregnancy. All infants born to HIV infected individuals should receive zidovudine prophylaxis; duration is determined by risk status, with 2 4 weeks for low risk infants and 6 weeks for high risk infants (Table 322.7). Additional antiretroviral drugs should be added to zidovudine if the risk of acquiring HIV by the newborn is high. High risk scenarios include infants born to individuals who received neither antepartum nor intrapartum antiretroviral drugs or only intrapartum antiretroviral drugs, who do not achieve a suppressed viral load near delivery despite cART (defined as at least two consecutive tests with HIV RNA 50 cop iesmL obtained at least 4 weeks apart), who have acute or primary HIV infection during the pregnancy, who have unknown HIV status who test positive at delivery or postpartum, or infants who have a positive 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. 2114 Part XV u Infectious Diseases Table 322.7 Intrapartum and Neonatal Management for HIV Exposed Infants by Risk Category RISK OF PERINATAL HIV TRANSMISSION DEFINITION INTRAPARTUM AND NEONATAL ART MANAGEMENT Low risk (3 defined groups) Infants 37 weeks gestation who are born to a person with HIV who meets ALL of the following criteria: Is currently receiving and has received at least 10 consecutive weeks of ART during pregnancy Has achieved and maintained or maintained viral suppression for the remainder of the pregnancy Has a viral load 50 copiesmL at or after 36 wk Did not have acute HIV infection during pregnancy Has reported good ART adherence, and adherence concerns have not been identified No IV AZT required in labor Vaginal delivery Prophylaxis with zidovudine 2 wk Infants born to a person with HIV who do not meet the |
7,989 | criteria above but who have a HIV RNA 50 copiesmL at or after 36 wk gestation No IV AZT required in labor Vaginal delivery ZDV for 4 6 wk Premature infants (37 wk gestation) who are not at high risk of perinatal acquisition of HIV No IV AZT required in labor Vaginal delivery ZDV for 4 6 wk High risk Infants who are born to a person with HIV who meet ANY of the following criteria: Did not receive cART antepartum or received only intrapartum therapy Did not achieve viral suppression within 4 wk before delivery Had acute or primary HIV infection during the pregnancy or breastfeeding (in the case of the latter, breastfeeding should be immediately discontinued see text) Parent should get IV AZT in labor if viral load 1000 or unknown C section if viral load 1000 or unknown Presumptive HIV therapy regimen 6 wk with either Zidovudine, lamivudine, and nevirapine Zidovudine, lamivudine and raltegravir for up to 6 wk Alternate regimen: Zidovudine 6 wk 3 dose nevirapine protocol In all cases, duration of zidovudine should be for 6 wk if other 2 medications are discontinued before that time point. Presumed newborn HIV exposure Infants born to a person with HIV who: Have unconfirmed HIV status with at least one positive HIV test in labor or during deliverypostpartum period Have a newborn with positive HIV antibody test at delivery Same as for high risk If supplemental testing confirms person giving birth does not have HIV, infant ARV drugs should be discontinued immediately. Due to resistance of HIV 2 to NNRTIs, raltegravir regimen should be considered for high risk infants born to individuals with HIV 2. See Table 322.3 for dosing. Adapted from Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV transmission in the United States. http:aidsinfo.nih. govcontentfileslvguidelinesPerinatalGL.pdf. HIV antibody test on screening after delivery. In these scenarios, three regimen options can be considered: (1) a presumptive HIV therapy regimen of zidovudine, lamivudine, and nevirapine at treatment doses; (2) a presumptive HIV therapy regimen of zidovudine, lamivudine, and raltegravir at treatment doses; or (3) zidovudine plus the addition of three doses of nevirapine (at birth, 48 hours, and 144 hours of life) (see Table 322.7). Note that treatment doses of raltegravir for neonates are different than for older children, with an escalating dose over the 6 weeks of therapy because of evolving liver metabolism in neonates. For infants at high risk, options 1 and 2 are now preferred, though option 3 has excellent data supporting it for select patient scenarios. Enthusiasm and support for treatment regimens (particularly option 1) have been driven by a case of an apparent functional cure in an infant in 2013 who went 2 years without cART with virologic suppression before rebound of the infection occurred (the Mississippi baby), as well as a large cohort of high risk, exposed infants in Canada. For neonates, experi ence is greatest with zidovudine, which can cause transient anemia or neutropenia in |
7,990 | exposed infants. There is also a strong pool of data sup porting the safety of lamivudine in neonates, including neonates born as early as 32 weeks gestational age (GA). For the remaining drugs for treatment of infants at high risk, data are most robust for nevirapine, with dosing recommendations down to 32 weeks GA. Data for ralte gravir are more limited, supporting use only in newborns 37 weeks GA and up. In infants at high risk, consultation with an experienced HIV specialist is highly recommended. The National Perinatal HIV Hotline (1 888 448 8765) provides 247 support from experienced HIV special ists to help in managing high risk infants. Guidelines and current recom mended doses for prophylaxis in newborns are updated at least yearly and can be accessed at https:www.nih.govresearch traininghivaids info center. A complete blood count, differential leukocyte count, and platelet count should be performed at 4 8 weeks of age to monitor zidovudine toxicity. If the child is found to be HIV infected, baseline laboratory assessment (e.g., CD4 count, HIV RNA, complete blood count, chemistries, lipids, and genotype) should be obtained and cART should be started as soon as possible. Cesarean section as a preven tion strategy was examined in a multinational meta analysis, which showed that the combination of elective C section and parental zid ovudine treatment reduced transmission by 87. However, these data were obtained before the advent of cART, and the additional benefit of elective C section to the cART treated individual whose viral load is 1,000 copiesmL is negligible. Thus elective C section at 38 weeks of gestation should be considered only for pregnant individuals whose viral load is 1,000 copiesmL in late gestation, to further reduce the risk of vertical transmission. Because perinatal transmission can be reduced dramatically by treating pregnant individuals, prenatal testing and identification of HIV 1 infection as early as possible is extremely important. The benefit of therapy both for the individuals health and to prevent transmission 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 322 u Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 2115 to the infant cannot be overemphasized. The recommended universal prenatal HIV counseling and testing for all pregnant individuals has reduced the number of new infections dramatically in many areas of the United States and Europe. For those not tested during pregnancy, the use of rapid HIV antibody testing during labor or shortly after the infants birth is a way to provide perinatal prophylaxis to an additional group of at risk infants. Perinatal recommendations also now endorse the testing of pregnant individuals partners to identify partners with HIV who may transmit HIV infection to them, leading to acute HIV infection, which carries an extremely high risk of vertical transmission both intrapartum and postpartum if the individual is breastfeeding and seroconverts. Feeding of the HIV Exposed Infant: Breastfeeding Recommendations and |
7,991 | Prophylaxis It is universally recommended that all pregnant individuals receive a cART regimen appropriate for their own health, which should be con tinued for the remainder of their lives. This approach improves paren tal survival, lowers the transmission risk to sexual partners, promotes simplified universal treatment regimens, and reduces transmission during breastfeeding and future pregnancies. Breastfeeding has been recommended for infants born to individuals with HIV in resource limited settings by the WHO and other authori ties for nearly 2 decades. This recommendation was based on strong evidence that early weaning is not safe in resource limited settings because of the high risk of death from malnutrition and diarrhea in formula fed infants without a consistent source of clean water and for mula. Furthermore, exclusive breastfeeding (no additional solids or flu ids other than water) resulted in less transmission than mixed feeding. Guidelines evolved to recommend that HIV infected persons living in resource limited settings should breastfeed their infants until at least 12 months of age, with exclusive breastfeeding for the first 6 months, and cART should continue to be provided to the breastfeeding parent. Data from multiple large studies of this practice in low and middle income countries have shown suppressive parental cART is extremely effective in preventing transmission of HIV via breastfeeding to 1. Additionally, there have been a series of smaller case series in resource rich settings with individuals on suppressive cART breast feeding with no transmission documented. However, it is important to stress that the rate of transmission even for fully suppressed HIV infected breastfeeding individuals is not zero. Because of this data, in January 2023, the guidelines in the U.S. for recommended infant feed ing have significantly changed for feeding of the HIV exposed infant. These recommendations were made for several reasons: Recognition of the very low risk of transmission from virologically suppressed individuals. Recognition of the benefits of breastfeeding to both the infant (im proved immune status, lower risk of developing asthma, obesity, type 1 diabetes, severe lower respiratory disease, otitis media, sud den infant death syndrome, gastrointestinal infections, and necrotiz ing enterocolitis) and breastfeeding parent (decreased risk of hyper tension; type 2 diabetes; breast, endometrial, and ovarian cancers; bonding with infant; decreased monetary costs of feeding). Recognition that pregnant individuals living with HIV in the United States are disproportionately Black, a group that has significantly higher prevalence of many of these negative health outcomes as well and that prohibiting breastfeeding in this group denies them potential benefit. Recognition of important cultural pressures that may affect the de sire to breastfeed and fear that by not breastfeeding, HIV status may be inadvertently disclosed to family and friends. Recognition that some individuals living with HIV in the past who were prohibited from breastfeeding did so surreptitiously without support that could have decreased risk to infant. It is now recommended that expectant individuals with HIV should receive evidence based, patient centered counseling regarding infant feeding starting early, ideally before conception or in early pregnancy. The provider |
7,992 | should engage in open minded shared decision mak ing in discussing the decision to breastfeed or formula feed the infant throughout the pregnancy. Key points of counseling should include: Achieving and maintaining viral suppression through ART during pregnancy and postpartum decreases breastfeeding transmission risk to less than 1, but not zero. Replacement feeding with properly prepared formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. This is the recommended feeding choice for individuals living with HIV who do not have suppressed viral load through the third trimester and at delivery given the sig nificantly increased risk of HIV transmission to the infant. Individuals with HIV who are on cART with a sustained undetect able viral load and who choose to breastfeed will be supported in this decision. Individuals with HIV who choose to formula feed should also be supported in their decision, and potential barriers should be ad dressed. It is important to stress that engaging Child Protective Services or similar agencies is not an appropriate response to infant feeding choices of an individual living with HIV. This puts an important thera peutic relationship at risk for both the individual and the infant, can result in harm to families, and can further exacerbate the stigma and discrimination that individuals living with HIV face. The risk of HIV transmission via breastmilk for individuals on sup pressive cART (50) is 1. There are ways to make risk of transmis sion as low as possible in this scenario, including providing excellent parental support such as addressing resource needs, mental health, and helping promote cART adherence. The postpartum period is a time of high risk for developing nonadherence to cART because of the stress of child raising, lack of sleep, potential postpartum depression (PPD) and other factors. Individuals living with HIV who give birth have significantly higher rates of PPD that is associated with signifi cant rise in cART nonadherence, so early screening and treatment of PPD is critical. Support of a lactation specialist is also important to help establish and maintain good milk supply so that mixed feeding can be minimized and to promote good breast health and avoidance of milk stasis, bleeding nipples, and mastitis. In the pre cART era, mixed feeding (i.e., introduction of breast milk plus other liquid or solid foods, including formula) was associated with increased risk of transmission of HIV, particularly in the first 2 months of life; no data are available in this area (including just formula supplementa tion) in the context of cART and virologic suppression. Because of this historical data, the goal is exclusive breastfeeding for 6 months to minimize risk. It is recommended that individuals with HIV who are breastfeed ingchestfeeding have HIV RNA testing every 1 2 months to moni tor virologic suppression closely. For the breastfed infant, the initial testing schedule is dictated by risk of infant at birth. Additionally, the breastfed infant should receive testing at 1 2 months and |
7,993 | 4 6 months to avoid an interval of 3 months between tests, and every 3 months after the 4 to 6 month test for as long as breastfeeding continues. It is recommended to avoid rapid weaning, with a goal of weaning over 2 4 weeks because of pre cART data associating rapid weaning with increased risk of HIV transmission to the infant. Infants should be tested 4 6 weeks, 3 months, and 6 months after weaning is complete (see Fig. 322.4). Several studies demonstrate the efficacy of ART prophylaxis of the breastfed infant in preventing transmission of HIV during breastfeed ing in the era before cART being recommended for all pregnant indi viduals and in some studies in which pregnant individuals received cART but did not have viral load routinely monitored. Successful regimens have included daily single dose nevirapine (NVP), lamivu dine (3TC), lopinavirritonavir (LPVr), and a combined NVP ADV regimen. For infants at low risk, it is not clear whether additional pro phylaxis during breastfeeding after the initial prophylaxis of 2 6 weeks adds additional benefit; that said, some experts choose to provide pro phylaxis for infants at low risk. In the scenario in which an individual with HIV who is not virologically suppressed elects to breastfeed after counseling despite recommendations not to do so because of increased risk, it is recommended that the infant receive 6 weeks of three drug presumptive HIV therapy (high risk), and then daily NVP throughout 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. 2116 Part XV u Infectious Diseases breastfeeding and for 1 4 weeks after weaning to further mitigate risk of HIV transmission (Table 322.8). HIV negative breastfeeding individuals with a sexual partner with HIV should also be monitored closely for developing HIV infection, because acute infection during breastfeeding carries a high risk of transmission to the infant (2953). It is recommended that these individuals consider preexposure prevention (PrEP) (see later) and practice barrier protection consistently to decrease risk of acute HIV infection during the breastfeeding period and educated on the signs and symptoms of acute HIV infection. They should also be tested every 1 2 months for seroconversion; if they become positive, breast feeding should cease, and the infant should be placed on a high risk three drug presumptive HIV therapy regimen for 28 days and tested per the high risk schedule with start point at time of cessation of breastfeeding. Risk of transmission of HIV goes up considerably if virologic sup pression in the breastfeeding parent is compromised. Therefore fre quent HIV RNA (viral load) monitoring is recommended so that if there is virologic rebound, risk can be mitigated. In the scenario that viral load becomes detectable in the breastfeeding parent, it is recom mended that the parent stop breastfeeding the infant immediately; milk can be pumped and discarded to maintain supply. The indi |
7,994 | vidual should be provided counseling regarding adherence, support, and resources, and discussion of whether to cease breastfeeding alto gether or continue given the risk of HIV transmission to the infant should occur. Other scenarios that would require either modifying or stopping breastfeeding (in some cases temporarily) include cracked or bleeding nipples and mastitis. In these conditions, breastfeed ing can continue on the unaffected side, and milk from the affected side should be pumped and discarded until the breast is fully healed and recovered. Again, having an experienced lactation consultant involved in the care of these individuals is critical. Clinicians are strongly encouraged to consult the national Perinatal HIVAIDS hot line (1 888 448 8765) with questions about infant feeding by indi viduals with HIV; the hotline provides 247 support from experienced HIV specialists to help in managing infants at high risk. U.S. guide lines for prevention of vertical transmission are regularly updated at https:www.nih.govresearch traininghivaids info center and the international guidelines are regularly updated at the WHO website (https:www.who.inthealth topicshiv aidstabtab1). Prevention of Sexual Transmission: Preexposure Prophylaxis and Postexposure Prevention Prevention of sexual transmission involves avoiding the exchange of bodily fluids. In sexually active adolescents, barrier protection (male and female condoms) should be an integral part of programs to reduce sexu ally transmitted diseases, including HIV 1. Unprotected sex with older partners, multiple partners, transactional sex, and the use of recreational drugs can be associated with acquisition of HIV 1 infection in adoles cents and young adults. Educational efforts about avoidance of risk fac tors and safer sex practices are essential for older school age children and adolescents and should begin well before the onset of sexual activity. In addition, promising research for sexually active adults may translate to increased prevention for adolescents. Three African trials demonstrated that male circumcision was associated with a 5060 reduction in the risk of HIV acquisition in young men. For females, use of a 1 vaginal gel formulation of tenofovir during intercourse was found to reduce HIV acquisition by nearly 40 in one study, though subsequent trials have had variable efficacy; other topical microbicides are being investigated. An increasingly important tool for HIV prevention is PrEP using once daily dosing of co formulated tenofovir and emtricitabine, approved for adolescents and adults weighing at least 35 kg (77 lb). The efficacy of PrEP in preventing sexual acquisition of HIV in MSM, heterosexual couples, and individuals in noncommitted relationships ranges from 7092. A depo injectable PrEP option (cabotegravir) dosed every 8 weeks is now approved for adults and adolescents 12 years weighing at least 35 kg (77 lb). large randomized multinational clinical trials of HIV serodiscordant adults have demonstrated that effective cART therapy in the HIV infected partner essentially eliminates secondary sexual transmission to an unin fected sexual partner, creating the catchphrase U U or undetectable untransmittable. The data from these trials can likely be extrapolated for youth with long standing virologic suppression. Postexposure prevention (PEP) is another important tool in HIV prevention and has been |
7,995 | used in healthcare workers after needlesticks and body substance exposures. It can also be effective after a single high risk event (including unprotected sexual activity, high risk sex ual assault, and intravenous drug useneedle sharing). PEP should be given as soon as possible after the high risk exposure, ideally within 24 hours and at the latest within 72 hours of the exposure to have effi cacy. Efficacy is higher the sooner it is given. Baseline testing should be performed at the time PEP is started, but initial doses should not be delayed for laboratory test results. Baseline testing includes HIV antigenantibody testing (fourth generation HIV ELISA), hepati tis B and C testing (because most high risk exposures have risk of transmission of these as well), serum creatinine, and alanine ami notransferase (ALT). If a patient is hepatitis B immune (including having completed a full hepatitis B vaccine series), hepatitis B test ing does not need to be performed. For sexual exposures, gonorrhea, chlamydia, and syphilis, testing should be done. After completion of a PEP course, follow up testing should be done at 4 6 weeks and 3 months after exposure. If hepatitis C was transmitted, HIV testing should be repeated at 6 months as well, because HIV seroconver sion can be delayed in patients with co infection with hepatitis C. PEP regimens are three drug treatment regimens for 28 days. For Table 322.8 Infant Antiretroviral Prophylaxis for Newborns of Individuals Who Breastfeed NEWBORNS AT LOW RISK OF HIV ACQUISITION DURING BREASTFEEDING RECOMMENDED REGIMEN DURATION ZDV 2 wk EXTENDED POSTNATAL PROPHYLAXIS FOR NEWBORNS AT HIGH RISK OF HIV TRANSMISSION DURING BREASTFEEDING RECOMMENDED REGIMEN DURATION ZDV 4 6 wk NVP SIMPLIFIED AGE BASED DOSING FOR NEWBORNS 32 WK GESTATION RECEIVING EXTENDED NVP PROPHYLAXIS DURING BREASTFEEDING AGE VOLUME NVP MGML ORAL SYRUP DAILY 6 wk to 6 mo 2 mL 6 mo to 9 mo 3 mL 9 mo to 1 4 wk post weaning 4 mL This extended neonatal prophylaxis regimen is optional for low risk infants, though recommended by some experts. For high risk breastfed infants (parent not virologically suppressed), 6 wk of ZDV (plus additional agents as recommended in Table 322.7) followed by extended neonatal NVP prophylaxis is recommended. For breastfeeding parents with viral resistance to NVP, alternative regimens for infant prophylaxis after completion of the 4 6 wk of presumptive HIV therapy include daily 3TC or LPVr; see Table 322.3 Antiretroviral Drug Dosing Recommendations for Newborns for dosing information. Extended NVP prophylaxis during breastfeeding recommendations are adapted from the Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a Public Health Approach. If prescribed, these simplified doses should start following confirmation of a negative infant NAT test and completion of a presumptive HIV therapy regimen in infants at high risk of HIV acquisition. For infants at low risk of transmission, these doses can be given from birth. World Health Organization. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public |
7,996 | health approach. Geneva: World Health Organization, 2021. Table A1.7. Available at https: www.who.intpublicationsiitem9789240031593. (Accessed 5 Nov 2023) 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 323 u Human T Cell Leukemia Viruses (1 and 2) 2117 individuals 12 years old, generally the preferred regimen consists of tenofovir DF emtricitabine with either dolutegravir or raltegravir (note that dolutegravir allows for a once daily regimen). For indi viduals 2 years old to 12 years old, the preferred regimen is tenofovir DF emtricitabine raltegravir. For those 2 years old the preferred regimen is zidovudine lamivudine raltegravir. In the rare cases in which the source patient is known to have HIV infection and is in care, selection can be guided by the source patients genotype andor treatment history. Abacavir and nevirapine are both contraindicated for use in PEP. SUMMARY The course and prognosis of HIV infection has improved dramatically as a consequence of cART for all ages, particularly with newer agents with fewer side effects. With good adherence, patients can achieve prolonged virologic suppression and immune function can be preserved or recon stituted. However, lifelong adherence and side effects of medications are important challenges to recognize that can prevent patients from achiev ing good outcomes. Globally, great strides have been made in prevent ing vertical transmission and increasing access to cART for children and adults, which is important for maintaining health as well as driving down sexual and vertical transmission with virologic suppression. However, there is still much work to be done to ensure the end of the global HIV epidemic, including continued advancement of our understanding of the immunology of HIV latency and reservoirs, HIV vaccines, and contin ued increases in access to cART worldwide, particularly in children. Visit Elsevier Ebooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 323 Human T Cell Leukemia Viruses (1 and 2) Paul Spearman and Lee Ratner ETIOLOGY Human T cell leukemia viruses 1 (HTLV 1) and 2 (HTLV 2) are mem bers of the Deltaretrovirus genus of the Retroviridae family, which are single stranded RNA viruses that encode reverse transcriptase, an RNA dependent DNA polymerase that transcribes the single stranded viral RNA into a double stranded DNA copy. HTLV 1 was the first human retrovirus discovered, isolated in 1979 from a cutaneous T cell lymphoma. The closely related virus HTLV 2 was subsequently iden tified in 1981. HTLV 1 is associated with adult T cell leukemialym phoma (ATL) and HTLV 1associated myelopathytropical spastic paraparesis (HAMTSP), whereas HTLV 2 is less pathogenic and rarely is associated with neurologic diseases. HTLV 1 and 2 share a genome homology of approximately 65. The genome contains gag, pr, pol, and env genes and several nonstructural genes. The nonstructural proteins include the Tax and Rex regulatory proteins, the novel proteins essential for virus spread (p30, p12, and p13), and the antisense encoded HTLV 1 basic leucine zipper |
7,997 | factor, HBZ. HTLV 1 and 2 infect cells via the ubiquitous glucose transporter type or via neuropilin 1, both of which serve as virus receptors. HTLV 1 and 2 can infect a variety of cells, with HTLV 1 most often found in CD4 T cells and HTLV 2 showing preference for CD8 T cells. After viral entry, reverse transcription produces a double stranded DNA copy of the RNA genome that is transported into the nucleus and integrated into chromo somal DNA (the provirus), evading the typical mechanisms of immune surveillance and facilitating lifelong infection. EPIDEMIOLOGY AND MODES OF TRANSMISSION HTLV 1 has infected 15 20 million persons globally. It is endemic in southwestern Japan (where 10 of adults are seropositive); areas of the Caribbean, including Jamaica and Trinidad (up to 6); and in parts of sub Saharan Africa (up to 5). Lower seroprevalence rates are found in South America (up to 2) and Taiwan (0.11). There is microclustering with marked variability within geographic regions. The seroprevalence of HTLV 1 and HTLV 2 in the general popu lation in the United States is 0.010.03 for each virus, with higher rates with increasing age. The prevalence of HTLV 1 infection is high est in babies born in endemic areas or in persons who have had sexual contact with persons from endemic areas. The prevalence of HTLV 2 infection is highest in intravenous drug users, with a seroprevalence of 8.817.6 in this population. HTLV 1 and 2 are transmitted as cell associated viruses from mother to child and transmission through genital secretions, con taminated blood products, and intravenous drug use. Mother to child transmission during the intrauterine period or peripartum period is estimated to occur in less than 5 of cases but increases to approxi mately 20 with breastfeeding. Higher maternal HTLV 1 proviral load and prolonged breastfeeding are associated with greater risk of mother to child transmission. In Japan, approximately 2025 of children born to HTLV 1infected mothers became infected before recommendations that seropositive mothers should avoid breastfeed ing, with a marked reduction to 2.5 transmission after restriction of breastfeeding. HTLV 2 may also be transmitted via breastfeeding, but it has a slightly lower reported transmission rate via breast milk of approximately 14. DIAGNOSIS HTLV 1 and HTLV 2 infections are diagnosed by screening using a second generation enzyme immunoassay with confirmation by immu noblot, indirect immunofluorescence, or line immunoassays. Poly merase chain reaction can also be used to distinguish HTLV 1 from HTLV 2 infection. CLINICAL MANIFESTATIONS The lifetime risk of disease associated with HTLV 1 infection is esti mated at 510 and is highest after vertical transmission. HTLV 1 is associated with ATL and several nonmalignant conditions, including the neurodegenerative disorder HAM, also known as tropical spastic paraparesis (TSP) and sometimes termed HAMTSP. The geographic epidemiologic characteristics of ATL and HAM are similar. HTLV 1 associated arthropathy mimics rheumatoid arthritis, including a positive rheumatoid factor. Treatment is with antiinflammatory agents. HTLV 1associated uveitis may be unilateral or bilateral, is more |
7,998 | common among women, and resolves spontaneously, although it often recurs within 1 3 years. Topical corticosteroids hasten recov ery. HTLV 1associated infective dermatitis is a chronic and recur rent eczematous disease occurring during childhood and adolescence that predisposes to staphylococcal infection. HTLV 1 infection predis poses to disseminated and recurrent Strongyloides stercoralis infection, increased risk of developing tuberculosis disease after latent infection, and severe scabies. ADULT T CELL LEUKEMIALYMPHOMA The age distribution of ATL peaks at approximately 50 years, under scoring the long latent period of HTLV 1 infection. HTLV 1infected persons remain at risk for ATL even if they move to an area of low HTLV 1 prevalence, with a lifetime risk for ATL of 24. Most cases of ATL are associated with monoclonal integration of HTLV 1 pro virus into the cellular genome of CD4 T lymphocytes, resulting in unchecked proliferation of CD4 T cells. There is a spectrum of disease that is categorized into different forms: acute, lymphomatous, chronic, primary cutaneous smoldering, and primary cutaneous tumoral. The acute form of ATL comprises 5575 of all cases. Smoldering subclini cal lymphoproliferation may spontaneously resolve in approximately 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. 2118 Part XV u Infectious Diseases half of cases or progress to chronic leukemia or lymphomatous, or even acute ATL. Chronic, low grade, HTLV 1associated lymphoprolif eration (pre ATL) may persist for years with abnormal lymphocytes with or without peripheral lymphadenopathy before progressing to the acute form. Acute ATL is characterized by hypercalcemia, lytic bone lesions, lymphadenopathy that spares the mediastinum, hepa tomegaly, splenomegaly, cutaneous lymphomas, and opportunistic infections. Leukemia may develop with circulating polylobulated malignant lymphocytes, called flower cells, possessing mature T cell markers. Antiviral therapy with zidovudine and interferon is the standard therapy for leukemic type ATL in the United States and Europe. In lymphoma type ATL, response rates may be improved using the anti CCR4 monoclonal antibody mogamulizumab with chemotherapy. Allogeneic hematopoietic stem cell transplantation is sometimes employed. HUMAN T CELL LYMPHOTROPIC VIRUS 1 ASSOCIATED MYELOPATHY HAM is more common in women than in men and has a relatively short incubation period of 1 4 years after HTLV 1 infection, com pared with 40 60 years for ATL. HAM occurs in up to 4 of per sons with HTLV 1 infection, usually developing during middle age. It is characterized by infiltration of mononuclear cells into the gray and white matter of the thoracic spinal cord, leading to severe white matter degeneration and fibrosis. HTLV 1 is found near but not directly within the lesions, suggesting that reactive inflammation is a major mechanism of disease. The cerebrospinal fluid typically shows a mildly elevated protein and a modest monocytic pleocyto sis, along with antiHTLV 1 antibodies. Neuroimaging studies are normal or show periventricular lesions in the white matter. Clini cal manifestations include gradual onset of slowly progressive, |
7,999 | sym metric neurologic degeneration of the corticospinal tracts and, to a lesser extent, the sensory system that leads to lower extremity spas ticity or weakness, lower back pain, and hyperreflexia of the lower extremities with an extensor plantar response. The bladder and intestines may become dysfunctional, and men may become impo tent. Some patients develop dysesthesias of the lower extremities with diminished sensation to vibration and pain. Upper extremity function and sensation, cranial nerves, and cognitive function are usually preserved. Treatment regimens have included corticoste roids, danazol, interferon, plasmapheresis, high dose vitamin C, and antivirals, all with minimal effects. Recent studies examined the effects of mogamulizumab (anti CCR4 antibody) on HAM, but results are not yet conclusive. HUMAN T CELL LYMPHOTROPIC VIRUS 2 HTLV 2 was originally identified in patients with hairy cell leuke mia, although most patients with hairy cell leukemia are seronegative for HTLV 2 infection. HTLV 2 has been rarely isolated from patients with leukemias or with myelopathies resembling HAM, and there is limited evidence of disease specifically associated with HTLV 2 infection. PREVENTION Routine antibody testing of all blood products for HTLV 1 and 2 is performed in many developed countries and is effective in preventing blood transfusionassociated infections. Unfortunately, this testing is not always available in low and middle income countries with higher endemicity. Prenatal screening and avoidance of breastfeeding by HTLV 1infected mothers is an effective means of reducing mother to child transmission of HTLV 1. Safe sexual practices to avoid sexu ally transmitted infections, such as condom use and avoiding multiple sexual partners, may reduce transmission of both HTLV I and HTLV 2. No vaccine is available. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 324 Transmissible Spongiform Encephalopathies David M. Asher and Brian S. Appleby The transmissible spongiform encephalopathies (TSEs, prion dis eases) are slow infections of the human nervous system, consisting of at least four diseases of humans (Table 324.1): kuru; Creutzfeldt Jakob disease (CJD) with its variantssporadic CJD (sCJD), famil ial CJD (fCJDsome authorities prefer genetic CJD), iatrogenic CJD (iCJD), and new variant or variant CJD (vCJD); Gerstmann Strussler Scheinker syndrome (GSS); and fatal familial insomnia (FFI), or the even more rare sporadic fatal insomnia syndrome. sCJD can also be further subdivided based on clinical features e.g., Heidenhain variant in which early onset of occipital blindness is prominentor differences in characteristics of abnormal prion proteine.g., variably protease sensitive prionopathy (VPSPr). TSEs also affect animals. The most common and best known TSEs of ani mals are scrapie in sheep, bovine spongiform encephalopathy (BSE or mad cow disease) in cattle, and a chronic wasting disease (CWD) of deer, elk, reindeer, and moose found in parts of the United States, Canada and, more recently, in Norway, Sweden, and Finland. A TSE of camels has recently been described in North Africa, and others might be anticipated. So far, of all the TSEs of animals, only BSE has proven zoonotic (i.e., transmissible to humans). All TSEs have similar clinical manifestations and histopathology, and all are |
8,000 | slow infections with very long asymptomatic incuba tion periods (often years), durations of several months or more, and overt disease affecting only the nervous system. TSEs are relentlessly progressive after illness begins and invariably fatal. The most striking neuropathologic change that occurs in each TSE, to a greater or lesser extent, is vacuolation, sometimes leading to spongy degeneration of the cerebral cortical gray matter. ETIOLOGY The TSEs are transmissible to susceptible animals by inoculation of suspensions of brain and some other tissues from affected subjects. Although the infectious agents replicate in a few cell cultures, they do not achieve the high titers of infectivity found in brain tissues or cause recognizable cytopathic effects in cultures. Most studies of TSE agents, before discovery of the prion proteins, used in vivo bioassays, relying on the transmission of typical neurologic disease to animals as evidence that the agent was present. Inoculation of susceptible recipient animals with small amounts of infectious TSE agents results, months or years later, in the accumulation in tissues of large amounts of agent having the same physical and biologic properties as the origi nal agent. The TSE agents display a spectrum of extreme resistance to inactivation by a variety of chemical and physical treatments that is unknown among conventional pathogens. This characteristic, as well as their partial resistance to protein disrupting treatments and their consistent association with abnormal isoforms of the normal host encoded prion protein (PrP), stimulated the hypothesis that the TSE agents are probably subviral in size, composed of protein, and devoid of nucleic acid. The term prion (for proteinaceous infectious agent), coined by S. B. Prusiner, is now widely used for such agents. The prion hypothesis pro poses that the molecular mechanism by which the pathogen specific information of TSE agents is propagated involves a self replicating change in the folding of host encoded PrP associated with a transition 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 324 u Transmissible Spongiform Encephalopathies 2119 from an helix rich structure in the native protease sensitive con formation (cellular PrP or PrPC) to a sheet rich structure in the protease resistant conformation associated with infectivity. The exis tence of a second host encoded proteintermed protein Xthat par ticipates in the transformation was once postulated to explain certain otherwise puzzling findings but was never identified. The prion hypothesis is still not universally accepted; it relies on the postulated existence of a genome like coding mechanism based on differences in protein folding that have not yet been satisfactorily elucidated at a molecular level. In addition, it has yet to account con vincingly for the many biologic strains of TSE agent that have been observed, although strain specific differences in glycosylation patterns Table 324.1 Clinical and Epidemiologic Features of Human Transmissible Spongiform Encephalopathies (Prion Diseases) DISEASE CLINICAL FEATURES SOURCE OF INFECTION GEOGRAPHIC DISTRIBUTION AND PREVALENCE |
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