Central nervous system abnormalities in pediatric human immunodeficiency virus infection

With the recent improvements in treatment of HIV, the disease has become a chronic one. The mean survival time of HIV-infected children is now 9-10 years, which is more than 4 times the mean age of such children who died in 1990. Yet, the prevalence of HIV encephalopathy has not decreased despite use of HAART. Rather, it is expected that as patients live longer, the prevalence of CNS manifestations will actually increase. Thus, more children can be expected to manifest encephalopathy, cerebral aneurysms and CNS lymphoma. As AIDS patients live longer, newer and more effective drugs to combat the neurological effects of HIV infection will be required. There is little evidence that HIV damages neurons directly; rather, the damage appears to occur indirectly via viral proteins or neurotoxic factors causing excessive stimulation by excitatory amino acids such as glutamate and quinolinate. This common pathway is similar to that seen in acute neuronal injury and CNS degenerative diseases and may make HIV encephalopathy amenable to pharmacotherapy. The very complexity of HIV CNS entry mechanisms and neuropathogenesis provides a host of sites for potential therapeutic interventions and hope for the future.     

Neurologic and neurodevelopmental manifestations of pediatric HIV/AIDS: a global perspective.

Neurodevelopmental abnormalities associated with HIV infection have been described since the first reports of pediatric AIDS in the 1980s. Before antiretroviral therapy (ART) became widely available, progressive HIV-1 encephalopathy (PHE) was reported in the US in 13-35% of children with HIV-1 infection and in 35-50% of children with AIDS. Introduction of ART can prevent PHE and reverse PHE present at ART initiation, but a high prevalence of residual problems has been described. Even though 90% of HIV-infected children live in the developing world, few children have access to ART and little is known regarding the neurological manifestations of perinatal HIV infection in those regions. Mechanisms of pediatric HIV-1 neuropathogenesis and factors associated with neurodevelopmental abnormalities in perinatally infected children are not yet fully understood. Studies have demonstrated that HIV-1 enters the CNS soon after infection and may persist in this compartment over the entire course of HIV-1 infection. The CNS is a distinct viral reservoir, differing from peripheral compartments in target cells and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique environment. We reviewed the literature on pediatric neuroAIDS and identified gaps in the current knowledge.     

Vertical human immunodeficiency virus-1 infection: Involvement of the central nervous system and treatment

Involvement of the central nervous system (CNS) contributes substantially to morbidity and mortality of vertical infection with the human immunodeficiency virus (HIV)-1. The clinical spectrum ranges from minor developmental disabilities to severe and progressive encephalopathy. Progression of the disease varies considerably. Both direct viral and indirect host-related pathogenic mechanisms have been proposed. The diagnosis depends on neurological and neurodevelopmental assessments. So far, HIV-1-specific antiviral treatment has shown limited effects on neurological manifestations in symptomatic children. Thus, efforts are needed to improve prevention and treatment of CNS involvement. It is still unclear whether early use of antiretroviral agents is of benefit. Conclusion Since experience of treatment of HIV-1 infections in adults cannot easily be translated to children, paediatric clinical trials are needed to answer questions specific to the unique characteristics of children. Received: 10 March 1996ƒAccepted: 10 May 1996     

Viral loads in dual infection with HIV-1 and cytomegalovirus

OBJECTIVE—A one year study of the relation between cytomegalovirus (CMV) and human immunodeficiency virus (HIV) viral loads in a cohort of children with vertically acquired HIV-1 infection.DESIGN—Comparative analysis of viral load measurements for CMV and HIV-1 in peripheral blood leucocytes (PBLs) of individual children in relation to age and clinical staging.METHODS—Nested polymerase chain reaction (PCR) was used to measure HIV-1 proviral DNA and CMV genomic DNA in PBLs of 56children.RESULTS—The CMV load was highest in 0-2 year old HIV positive children with stage C disease (range, 1-7143 copies/100 ng DNA; median, 125) and was significantly lower in older children. Although higher in young children, HIV-1 viral load did not show the same marked reduction with age that is seen with CMV. Over a one year period, testing of serial samples for both viruses in a subgroup of children revealed a discordant relation between viral loads for CMV and HIV-1.CONCLUSIONS—CMV viral load falls much faster than HIV viral load in dually infected children. Screening for clinical CMV disease is most likely to be of benefit in children under 2 years of age with stage C disease. In the few children studied, levels of CMV and HIV replication appear to be independent.     

Detection of infection with human immunodeficiency virus (HIV) type 1 in infants by an anti-HIV immunoglobulin A assay using recombinant proteins.

To diagnose infection with the human immunodeficiency virus (HIV) soon after birth in infants born to HIV type 1-infected women, we developed antiviral IgA Western blot and dot blot assays with recombinant HIV-1 proteins. Thirty-three infants born to HIV-1-seropositive mothers and nine infants born to HIV-1-seronegative intravenous drug-abusing mothers were followed prospectively. Infection was documented by positive virus culture. Results with the polymerase chain reaction were used for comparison. Twelve infants were found infected with HIV-1; the earliest age at which cultures became positive ranged from birth to 31 weeks of age. Of the 12 culture-positive infants, 10 had anti-HIV IgA antibodies detectable initially between birth (cord blood) and 27 weeks of age. Anti-HIV IgA was not present in the uninfected infants or in the control subjects, either by Western blot or dot blot assays. Testing for anti-HIV IgA antibodies with recombinant HIV-1 proteins is an effective method for detecting viral infection in newborn and young infants.     

Viral loads in dual infection with HIV-1 and cytomegalovirus.

OBJECTIVE: A one year study of the relation between cytomegalovirus (CMV) and human immunodeficiency virus (HIV) viral loads in a cohort of children with vertically acquired HIV-1 infection. DESIGN: Comparative analysis of viral load measurements for CMV and HIV-1 in peripheral blood leucocytes (PBLs) of individual children in relation to age and clinical staging. METHODS: Nested polymerase chain reaction (PCR) was used to measure HIV-1 proviral DNA and CMV genomic DNA in PBLs of 56 children. RESULTS: The CMV load was highest in 0-2 year old HIV positive children with stage C disease (range, 1-7143 copies/100 ng DNA; median, 125) and was significantly lower in older children. Although higher in young children, HIV-1 viral load did not show the same marked reduction with age that is seen with CMV. Over a one year period, testing of serial samples for both viruses in a subgroup of children revealed a discordant relation between viral loads for CMV and HIV-1. CONCLUSIONS: CMV viral load falls much faster than HIV viral load in dually infected children. Screening for clinical CMV disease is most likely to be of benefit in children under 2 years of age with stage C disease. In the few children studied, levels of CMV and HIV replication appear to be independent.     

Inflammatory mediators and neonatal brain damage

Inflammatory mediators are multifunctional cytokines that play important roles both in normal central nervous system (CNS) development and in the response of the brain to diverse forms of injury. Interleukin (IL)-1beta, tumor necrosis factor-alpha and IL-6 are among the best-characterized early-response cytokines. Recent data suggest that they may be synthesized and secreted by several CNS cell types, including microglia, astrocytes and neurons. Biological effects of these cytokines that could influence the progression of injury in the brain include stimulating the synthesis of other cytokines and neuronal injury mediators such as nitric oxide synthase, inducing leukocyte infiltration and the expression of adhesion molecules, influencing glial gene expression and damaging oligodendrocytes. In the immature brain, proinflammatory cytokines might lead to white matter damage during prenatal intrauterine infection and contribute to progressive neuronal damage in acute brain injury evoked by cerebral hypoxia-ischemia. Interrupting the proinflammatory cascade might limit the extent of irreversible injury.     

Safety and efficacy of enfuvirtide for 48 weeks as part of an optimized antiretroviral regimen in pediatric human immunodeficiency virus 1-infected patients

BACKGROUND: Enfuvirtide is the only entry inhibitor approved for the treatment of human immunodeficiency virus (HIV)-1 infection. It is approved for use in adults and dosage recommendations exist for children aged 6 years or older. METHODS: T20-310 was a multicenter, open-label, nonrandomized, noncomparative study of the safety and efficacy of 2.0 mg/kg (maximum 90 mg) twice-daily subcutaneous enfuvirtide for 48 weeks in 52 treatment-experienced, HIV-1-infected pediatric patients (3-16 years) receiving optimized background therapy. RESULTS: Enfuvirtide was generally well tolerated, and no new patterns of adverse events compared with adults were observed. Mild-to-moderate injection-site reactions were the most common adverse event. Of those participants on treatment for 48 weeks, the median change from baseline in HIV-1 RNA was -1.17 log10 copies/mL (n = 32), and there was a median CD4 change of +106 (n = 25) cells/mm3 and +4.7 CD4%. Seventeen (32.7%) patients achieved a viral load decrease of > or =1 log10 copies/mL and 11 (21.2%) achieved HIV-1 RNA <400 copies/mL. Virologic and immunologic treatment responses were substantially better for children (<11 years) than adolescents. Steady-state mean enfuvirtide C(trough) levels were stable during 24 weeks with no differences between children and adolescents. CONCLUSIONS: Enfuvirtide is an effective treatment for HIV-1 infection in children and adolescents receiving optimized background therapy and has a favorable safety profile. Efficacy in adolescents was inferior; probably related to unique adherence challenges. The long-term safety and efficacy of enfuvirtide in pediatric patients is comparable to that observed in adults.     

小儿中枢神经系统单纯疱疹病毒感染的临床横断面研究

目的了解小儿中枢神经系统单纯疱疹病毒(HSV)感染的患病情况,并对其临床特点进行分析。方法收集2001年6月~2002年6月住院的中枢神经系统病毒感染患儿150例的脑脊液(cerebrospinal fluid,CSF)标本,应用套式PCR检测脑脊液中HSV-DNA及酶联免疫吸附法检测脑脊液中特异性HSV-IgM抗体。结果6例患儿脑脊液中HSV1-DNA( ),另1例HSV1-IgM( ),单纯疱疹病毒占中枢神经系统病毒感染的4.67%;呈散发性起病,无明显季节、年龄、性别分布特点,与其他病毒感染相比,惊厥持续状态、精神症状发生率高(P<0.01),意识障碍、病死率差异无显著性。结论①单纯疱疹病毒感染占儿童中枢神经系统感染的4.67%,不是儿童病毒性脑炎的常见病原,呈散发性起病,无明显季节、性别、年龄分布特点;②儿童中枢神经系统单纯疱疹病毒感染多为HSV1的原发感染,可导致脑炎、脑干脑炎、急性播散性脊髓膜炎;③单纯疱疹病毒脑炎(herpes si mplexvirus encephalitis,HSE)起病较危重,出现精神症状较多,及时有效的抗病毒治疗能明显改善病情,降低病死率。     

新生儿中枢神经系统单纯疱疹病毒感染的临床横断面研究

目的通过分子生物学方法了解新生儿中枢神经系统单纯疱疹病毒(HSV)感染情况,并对其临床特点进行分析。方法收集考虑中枢神经系统病毒感染新生儿40例的脑脊液(CSF)标本,通过套式PCR检测CSF中HSV-DNA及酶联免疫吸附法检测CSF中特异性HSV-IgM抗体。结果2例患儿检测CSF中HSV-1 DNA( ),其母亲妊娠期均体健,无生殖器疱疹史,无皮损;1例提示为播散性感染,另1例局限为中枢神经系统感染。40例CSF检测HSV-2 DNA均阴性。结论HSV感染占新生儿中枢神经系统病毒感染的5%,不是常见病原;1型可能为新生儿HSV中枢感染的常见类型,可能与我国孕母HSV-2血清感染率较低有关。     

The biology of erythropoietin in the central nervous system and its neurotrophic and neuroprotective potential

This review summarizes published as well as preliminary data on the biology of erythropoietin (Epo) in the developing and mature human central nervous system (CNS). Both Epo receptor (Epo-R) and Epo gene expression underlie developmental changes and a brain-specific regulation. These features suggest a different role of Epo in normal brain development than in neuroprotection and neuronal tissue repair after brain injury. Epo concentrations in the cerebrospinal fluid may have primary paracrine effects. While the transport of Epo across the intact blood brain barrier (BBB) is generally limited in humans, systemically produced or administrated Epo may cross during BBB dysfunction. Summarized data of the in vivo and in vitro effects of Epo in the CNS show significant neuroprotective and neurotrophic effects of this molecule. These effects are mediated by several mechanisms, including the activation of a variety of genes and their consecutive protein production. Therapeutic strategies involving activation of the CNS Epo-R are discussed, including the potential use of Epo mimetic peptides.     

Tight Junctional Damage in Experimental Mumps-Associated Hydrocephalus

Tight junctions in the central nervous system (CNS) are a major component of brain barriers including the blood-brain barrier (BBB) and blood-CSF barrier, which regulate solute entry and protect against invasion by microorganisms. In this study, we examined the breach of tight junctions in mumps virus-induced hydrocephalic brain in hamsters using antibodies to Laminin B1 chain and zonula occludentes (ZO-1) immuno-histochemistry, and evaluated the role of tight junctions in the pathogenesis of hydrocephalus after mumps virus infection.
In suckling hamsters intracerebrally inoculated with mumps virus, severe periventricular edema, ependymal cell loss, and ventricular dilation were observed. ZO-1-immunoreactive tight junctions in the hydrocephalic brains were severely damaged in the choroid plexus and ependyma, and in white matter capillaries as early as 3 days after inoculation. These changes were suspected to increase the permeability in blood-brain and blood-CSF barriers, leading to periventricular edema. We concluded that the pathologic features of mumps virus-induced hydrocephalus are intimately related to the breach of tight junctions.     

Neurologic complications of HIV infection in children.

Neurologic abnormalities occur frequently in children with symptomatic HIV-1 infection (class P2) and include cognitive, language and motor deficits, as well as acquired microcephaly. Neurologic abnormalities can be seen as early as the first 3 months of age and can precede signs of immune deficiency and systemic illness. Hypotonia, delayed or poor head control and decreased vocalizations are some of the early neurologic manifestations of HIV-1 infection. In the majority of cases CNS impairment appears to be related to HIV-1 brain infection although at this time the exact timing of CNS invasion by the virus and the pathogenesis of CNS dysfunction are unknown. Treatment with antiretroviral agents can at least temporarily improve neurologic functioning in some children with HIV-1-related encephalopathy.     

Increased burden of respiratory viral associated severe lower respiratory tract infections in children infected with human immunodeficiency virus type-1

OBJECTIVES: To determine the burden of viral associated severe lower respiratory tract infections (SLRTI) in human immunodeficiency virus-infected (HIV+) and HIV-uninfected (HIV-) urban black South African children. METHODS: Children with SLRTI aged 2 to 60 months were enrolled between March 1997 and March 1998. Monoclonal antibody immunofluorescent testing was performed on nasopharyngeal aspirates to detect respiratory syncytial virus (RSV), influenza A and B, parainfluenza 1-3, and adenovirus-specific antigens. RESULTS: Of the 990 children studied, 44.6% were HIV+. The estimated burden of disease of viral associated SLRTI in children under 2 years was increased for RSV, influenza A/B viruses, parainfluenza 1-3 viruses, and adenovirus in children who were HIV+ compared with children who were HIV- (P <.001). Viral pathogens, however, were identified less frequently (15.7% vs 34.8%, P < 10(-5)) and bacterial pathogens more frequently (12.5% vs 5.8%, P <.0001) in children who were HIV+ than in children who were HIV- and had SLRTI. The seasonal peak for RSV in late summer-early autumn observed in children who were HIV- was less evident in children who were HIV+ (P =.02). Children who were HIV+ and had virus-associated SLRTI had a higher mortality rate (7. 5%) than did children who were HIV- (0%, P < 10(-3)). CONCLUSIONS: The contribution of viral associated SLRTI differs between HIV+ and HIV- children. In HIV+ children in South Africa, RSV isolation is not limited by season.     

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目的观察中枢神经系统感染患儿血清和脑脊液(CSF)中基质金属蛋白酶(MMP-2、MMP-9)水平,并结合CSF白蛋白指数(AQ),探讨MMP-2、MMP-9在中枢神经系统感染血脑屏障(blood-brainbarrier,BBB)破坏中的作用。方法2004-09—2005-10河北医大附属二院采用ELISA法检测18例化脓性脑膜炎患儿急性期、恢复期及22例病毒性脑炎患儿急性期血清和CSF中MMP-2、MMP-9水平,并与非中枢神经系统感染对照组比较。结果化脓性脑膜炎(化脑)、病毒性脑炎(病脑)患儿急性期血清和CSF中MMP-2、MMP-9水平显著高于正常对照组(P<0·001),且化脑组显著高于病脑组(P<0·001)。化脑组恢复期患儿血清和CSF中MMP-2、MMP-9水平与对照组无明显差异(P>0·05)。结论中枢神经系统感染患儿血清和CSF中MMP-2、MMP-9水平显著增高,提示MMP-2、MMP-9可能参与了中枢神经系统感染的病理过程。     

脑缺氧缺血后血脑屏障通透性改变及其机制研究进展

血脑屏障(blood brain barrier,BBB)是存在于血液和脑组织之间的屏障系统,可保持中枢神经系统内环境的相对稳定.脑缺氧缺血可导致BBB通透性发生变化.该文综述了BBB结构基础、功能以及脑缺氧缺血损伤时BBB结构和功能改变的范围、时间及其机制.利用这一理论对BBB调控可能在治疗缺氧缺血性脑损伤及中枢神经...     

Detection of HIV RNA by in situ hybridization in peripheral blood mononuclear cells of seronegative children born to HIV-infected mothers

Of 44 children born to human immunodeficiency virus (type 1) (HIV)-infected mothers, 11 have become seronegative. After the loss of maternal antibodies all children were analysed for several immunological functions and virological parameters in order to determine their HIV status. All children to date are clinically healthy and have normal immune functions. HIV-1 was detected by p24 antigen in one child, by in situ hybridization in nine children while viral cultures were all negative. These data suggest that the rate of vertical transmission of HIV-1 may be underestimated if seronegative children are considered to be not infected. They also suggest that molecular biological techniques are more sensitive than HIV antigen assay or viral cultures.     

Evaluation and treatment of the human immunodeficiency virus-1-exposed infant

In developed countries, care and treatment are available for pregnant women and infants that can decrease the rate of perinatal human immunodeficiency virus type 1 (HIV-1) infection to 2% or less. The paediatrician has a key role in the prevention of mother-to-child transmission of HIV-1 by identifying HIV-exposed infants whose mothers’ HIV infection was not diagnosed before delivery, prescribing antiretroviral prophylaxis for these infants to decrease the risk of acquiring HIV-1 infection, and promoting avoidance of HIV-1 transmission through human milk. In addition, the paediatrician can provide care for HIV-exposed infants by monitoring them for early determination of HIV-1 infection status and for possible short- and long-term toxicities of antiretroviral exposure, providing chemoprophylaxis for Pneumocystis pneumonia, and supporting families living with HIV-1 infection by providing counselling to parents or caregivers.     

Thrombocytosis in pediatric HIV infection

Thrombocytopenia has been extensively reported in association with HIV infection. Twenty-four children (6%) from a cohort of 400 children with platelet counts >500,000/mm(3) were reviewed. All had symptomatic disease and 10 (42%) patients died. In 4 children the platelet count exceeded 700,000/mm(3) and in 1 patient the platelet count was 1.5 million/mm(3). There were no thrombotic complications, and no specific therapy was required for the thrombocytosis. Thus HIV-1 infection, a chronic viral infection, is another etiologic agent for thrombocytosis and is associated with severe disease.