Influenza virus genetic sequences in the blood of children with congenital pathology of the CNS

Summary Influenza A virus genetic sequences revealed by dot hybridization were detected in peripheral blood cells, serum and liquor of three children with congenital pathology of the CNS. The children were born to mothers who contacted influenza during pregnancy. The virus-specific sequences were found for a long period of time (83 days in one case). The serum of the child did not contain antibodies against M protein suggesting that viral nucleocapsids but not the virus particles persist in the organism of the sick child.     

Induction by an inactivated influenza virus of congenital pathology and pregnancy pathology in mice

Intravenous inoculation of pregnant mice with inactivated (noninfectious) influenza virus reduces by one-third their fertility owing to the death of the fetuses. Among the progeny of such females, there are specimens with signs of progressive pathology clinically similar to that which develops in the progeny born to the females intranasally inoculated during pregnancy with a live (infectious) influenza virus. The frequency of such pathology depends both on the virus strain and on genetic characteristics of mice. The role of influenza virus surface structures in the development of pathology of pregnancy and pathology in the progeny is discussed.     

CNS pathology in hereditary syndromes of congenital developmental defects

Analysis of the incidence and diagnostic importance of the congenital central nervous system (CNS) defects in 334 children with multiple congenital developmental defects (MCDD) dying under 1 year allowed the author to distinguish 4 groups of defects according to their informative value for establishing the nosological diagnosis: defects of a high, moderate, small informative value and noninformative ones. Special microscopic study of the CNS performed in 116 stillborns and children of the first year of life with various MCDD showed the disturbance of main morphogenetic processes (mitotic cell activity, cell migration, differentiation and maturation) as a basis of the observed pathological conditions. General rules of the CNS developmental defects in chromosomal and non-chromosomal syndromes may point to the common routes of the genetic material realization.     

The pathomorphological changes in the organs and tissues of mice with congenital pathology induced by the inactivated influenza virus]

The structural and functional changes in organs and tissues of 30 young mice born from mothers treated intravenously with irradiation-inactivated influenza virus were studied. A detailed morphological analysis showed that a single inoculation of pregnant females with inactivated influenza virus resulted in the progeny in morphological lesions in organs and tissues typical of slow influenza infection.     

NK cells exacerbate the pathology of influenza virus infection in mice

NK cells offer a first line of defense against viruses and are considered beneficial to the host during infection. Nevertheless, little is understood regarding the phenotype and function of NK cells in the lung during influenza virus infection. We found that the frequency of NK cells in mouse lung increased during influenza infection, with the majority of a mature phenotype. Cell surface CD107a and intracellular IFN‐γ were detected in cells expressing multiple NK‐cell receptors in infected lung, suggesting that NK cells were activated during infection. The activating receptor NKp46 was predominantly negative on such cells, possibly as a result of encountering influenza HA. Depletion of NK cells in vivo with anti‐asialo GM1 or anti‐NK1.1 reduced mortality from influenza infection and surviving mice recovered their body weight. Pathology induced by NK cells was only observed with high, not medium or low‐dose influenza infection, indicating that the severity of infection influences NK‐cell‐mediated pathology. Furthermore, adoptive transfer of NK cells from influenza‐infected lung, but not uninfected lung, resulted in more rapid weight loss and increased mortality of influenza‐infected mice. Our results indicate that during severe influenza infection of the lung, NK cells have a deleterious impact on the host, promoting mortality.     

Persistence of cell-mediated immunity to influenza A virus in mice.

Cytotoxic T-cell (Tc) immunity to influenza A virus in mice persists for at least 2 years. Both T-helper (Th) and Tc cells are present and fully functional in old mice; however, the frequency of memory Tc-cell precursors declines with age.     

Persistence of Coxsackie A13 virus in the families of children ill with rheumocarditis

Virological and clinico-instrumental examinations were carried out three times during one year in 13 patients with rheumatic carditis and 34 of their relatives from 13 families. Besides, probands from 5 families had been examined 1-3 years before this study during treatment for rheumocarditis. Among 62 virus strains isolated from feces, blood, and nasopharyngeal washings in the family foci 40 were Coxsackie A13, 12: Coxsackie B1, B2, B5; 10 viruses were not identified. Coxsackie A13 virus was isolated from probands, siblings and parents in 11 out of 13 families. Virus-neutralizing antibodies to it were demonstrated in the great majority of probands and relatives, including those families where no virus had been isolated. Coxsackie A13 virus and antibodies to it were shown to persist throughout the observation period in most families.     

Antibody to lymphocytic choriomeningitis virus in children with congenital hydrocephalus.

Antibody to lymphocytic choriomeningitis (LCM) virus was found by the indirect immunofluorescence (IF) technique in high titres in 9 out of 28 children with congenital hydrocephalus and in moderate titres in 6 mothers of these seropositive children. It is suggested that LCM virus or a closely related virus infecting the foetus in utero may play a role in the aetiopathogenesis of some cases of congenital hydrocephalus.     

CNS Persistence of HIV-1 in Children: the Untapped Reservoir

Purpose of Review

The central nervous system (CNS) represents a potential HIV-1 reservoir that may need to be specifically targeted by remission strategies. Perinatally HIV-1-infected children and youth are exposed to HIV-1 at a critical period of brain development. This review summarizes the current literature regarding HIV-1 and the CNS in perinatal infection.

Recent Findings

HIV-1-associated encephalopathy is prevalent with perinatal infection and neurocognitive impairment persists even following antiretroviral treatment (ART)-mediated suppression of viremia. Compartmentalization of HIV-1 between plasma and CSF of ART-naïve, perinatally infected children suggests the presence of a CNS reservoir; however, similar studies have not yet been conducted with ART suppression. CSF viral escape where CSF and plasma virus concentrations are discordant has been reported in this population, but larger studies with well-defined virologic and immunologic parameters are needed.

Summary

A better understanding of HIV-1 persistence in the CNS with perinatal infection is essential for improving long-term neurocognitive outcomes and for designing strategies to induce HIV-1 remission in this population.

     

The course of fever following influenza virus infection in children treated with oseltamivir

Although the effectiveness of oseltamivir against influenza virus infection is well known, there has been no report analyzing the detailed time course of fever following the drug treatment in children. Oseltamivir was prescribed for 4 days to every child with a positive result for rapid immunological test for influenza virus during 2002--2003, 2003--2004, and 2004--2005 epidemics. Only those who were 1-12 years of age and prescribed oseltamivir within 24 hr after the onset of fever were included in the analysis. The numbers of children with type A/H3N2 disease for the three seasons were 64, 77, and 33, and those with type B disease were 102, 4, and 86, for the respective seasons. The period until normalization of temperature was obtained from six-hourly recordings of body temperature. By multiple regression analysis, temperature periods were longer in type B than in type A/H3N2 disease, negatively associated with age, and positively with maximal body temperature (all: P < 0.001). The effectiveness of oseltamivir on body temperature in type B disease was less apparent in the 2004--2005 than in the 2002--2003 season, irrespective of age. No such between-season difference was observed for Type A/H3N2 disease. Frequencies of ineffective cases with biphasic fever (19.6% and 43.0% during 2002--2003 and 2004--2005 seasons) were significantly higher in type B than in type A/H3N disease (12.0% and 11.8%, respectively). The effectiveness of oseltamivir depends on a child's age, maximal body temperature and the virus type. This study confirmed recent reports indicating decreased effectiveness of oseltamivir against type B disease.     

Liver biopsies in the diagnosis of congenital and acquired pathology of the hepatobiliary system in children

Analysis was made of the biopsy material from children with hepatobiliary pathology and the results are presented. Structural basis of fibrocholangiocystosis and mucoviscidosis is described. Specific hepatic lesion in lymphogranulomatosis was found to be very rare. The authors provide as with new information concerning liver morphometry for chronic hepatitis and cirrhosis, i. e. estimation of portal tract area and the proportional content of collagenous tissue in them.     

Epidemiological analysis of the influenza virus A carrier state in healthy children

Clinical and laboratory examinations in two permanently observed children's institutions were carried out in 1968--1978. Altogether, 241 children were examined virologically 759 times, of them 181 children were found to be truly healthy. In the epidemic period the latter yielded virus in 3.7%, in the interepidemic period in 1%. Unlike asymptomatic infection, transitory virus carrier state was not accompanied by antibody production, and in a number of such cases subsequently led to an overt clinical disease.     

Alpha‐mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function

Alpha‐mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty‐four patients, aged 6–35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF‐oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age‐inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau‐protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF‐biomarkers and cognitive function and CSF‐oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF‐biomarkers and CSF‐oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.     

Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children

The highly sensitive gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN-gamma ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 10(7) fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with >or=100 spot-forming cells/10(6) peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN-gamma is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children.     

Chronic congenital Coxsackie virus infection in the etiology of allergic disease in children

The authors prove the involvement of congenital Coxsackie virus infection in the etiology of allergic diseases in children: 1) indications of high risk of vertical transmission of viruses of this group from mothers with persistent infection to children are more incident in the history of mothers whose children develop allergies in comparison with healthy age-matched children (83 vs. 38.8%); 2) Coxsackie viruses are detected in sick children more often than in healthy ones (58.1-81.1 vs. 7.4%); 3) the persistence of Coxsackie A and B viruses is confirmed in the majority of patients examined over time; 4) in the mothers examined in parallel with their sick children Coxsackie viruses were detected virtually as often as in their children; and 5) reduction of endogenous chronic Coxsackie infection by energy metabolism correction in the risk group women during pregnancy prevents the development of allergic diseases in their children.     

Reassortment and gene interactions in the crossing of low-pathogenic avian influenza H5 virus with human influenza virus

The reassortants obtained via the crossing of highly productive influenza virus A/Puerto Rico/8/34 (H1N1) strain and the low pathogenic avian influenza virus A/Duck/Primorie/2621/2001 (H5N2) strain were genotyped and characterized. The H5N2 reassortant having 6 genes from A/Puerto Rico/8/34 virus has the high level of reproduction in chick embryos, while slightly more moderate than in the parent A/Puerto Rico/8/34 strain. The reproduction of the H5N1 reassortant that had 7 genes from A/Puerto Rico/8134 virus was very low. The serial passage selection allowed the investigators to obtain the H5N1 strain that was reproductively close to the H5N2 reassortant. This variant had one amino acid substitution in hemagglutinin (N244D, H3 numbering) and a lower affinity for fetuin. By the level of virulence to mice, the H5N1 and H5N2 reassortants were close to A/Puerto Rico/8/34 virus and greatly differed in this respect from low virulent A/Duck/Primorie/2621/2001 (H5N2). The results are discussed in connection with the problem of vaccination when there is a threat for H5N1 virus subtype-caused pandemic.     

Persistence of varicella-zoster virus viraemia in patients with herpes zoster

BackgroundHerpes zoster is caused by the reactivation of varicella-zoster virus from sensory neurons. The commonest complication following zoster is chronic pain termed post herpetic neuralgia.ObjectivesTo investigate the dynamics of VZV viraemia and viral load following the resolution of zoster and its relationship to PHN development.Study designBlood samples were collected at baseline, 1 month, 3 months and 6 month from a prospective study of 63 patients with active zoster. Quantification of VZV DNA in whole blood was performed using a real-time PCR assay.ResultsDuring acute zoster, all patients had detectable VZV DNA in their blood. VZV DNA remained detectable in the blood of 91% of patients at 6 months although levels declined significantly (p < 0.0001). A history of prodromal symptoms (p = 0.005) and severity of pain at baseline (p = 0.038) as well as taking antivirals (p = 0.046) and being immunocompromised (p = 0.043) were associated, with longer time to recovery from PHN. Viral DNA loads were consistently higher in patients with risk factors for PHN and higher viral DNA loads over time were associated with longer time to recovery (p = 0.058 overall and 0.038 in immunocompetent).ConclusionsBased on these observations we hypothesise that VZV replication persists following acute shingles and that higher viral DNA loads contribute to the risk factors for PHN.