Characterization of CD8+ T-cell response in acute and resolved hepatitis A virus infection.

BACKGROUND & AIMS: In contrast to the infection with other hepatotropic viruses, hepatitis A virus (HAV) always causes acute self-limited hepatitis, although the role for virus-specific CD8 T cells in viral containment is unclear. Herein, we analyzed the T cell response in patients with acute hepatitis by utilizing a set of overlapping peptides and predicted HLA-A2 binders from the polyprotein. METHODS: A set of 11 predicted peptides from the HAV polyprotein, identified as potential binders, were synthesized. Peripheral blood mononuclear cells (PBMCs) from patients were tested for IFNγ secretion after stimulation with these peptides and ex vivo with HLA-A2 tetramers. Phenotyping was carried out by staining with the activation marker CD38 and the memory marker CD127. RESULTS: Eight out of 11 predicted HLA-A2 binders showed a high binding affinity and five of them were recognized by CD8+ T cells from patients with hepatitis A. There were significant differences in the magnitude of the responses to these five peptides. One was reproducibly immunodominant and the only one detectable ex vivo by tetramer staining of CD8+ T cells. These cells have an activated phenotype (CD38hi CD127lo) during acute infection. Three additional epitopes were identified in HLA-A2 negative patients, most likely representing epitopes restricted by other HLA-class I-alleles (HLA-A11, B35, B40). CONCLUSIONS: Patients with acute hepatitis A have a strong multi-specific T cell response detected by ICS. With the tetramer carrying the dominant HLA-A2 epitope, HAV-specific and activated CD8+ T cells could be detected ex vivo. This first description of the HAV specific CTL-epitopes will allow future studies on strength, breadth, and kinetics of the T-cell response in hepatitis A.

The dental practitioner and child protection in Scotland.

OBJECTIVES: To identify from general dental practitioners: undergraduate and postgraduate training experience in child protection; numbers of suspected cases of child physical abuse; reasons for failing to report suspicious cases of child physical abuse; knowledge of local child protection protocols and procedures for referral. MATERIALS AND METHODS: Postal questionnaires were sent to 500 randomly selected general dental practitioners in Scotland, with a further 200 sent to a random sample of the original 500 to increase response rate. RESULTS: Sixty-one per cent (306) of the original 500 questionnaires, and 35% (69) of the second random mail shot of 200 questionnaires were returned. Only 19% could remember any undergraduate training and 16% had been to a postgraduate lecture or seminar in child protection. Twenty-nine per cent of dentists had seen at least one suspicious case in their career. Only 8% of suspicious cases were referred on to the appropriate authorities. Reasons for failure to refer revealed that 11% were concerned about a negative impact on their practice, 34% feared family violence towards the child, 31% feared violence directed against them, and 48% feared litigation. Only 10% of dentists had been sent a copy of the local child protection guidelines on commencing work and only 15% had seen their Area Child Protection Committee (ACPC) Guidelines via any route. CONCLUSIONS: Due to lack of training or clear guidelines for dentists in Scotland, most practitioners were unsure what to do in the event of a suspicion of child abuse. Twenty-one per cent of dentists had encountered suspicious cases but failed to take any action. Dentists overwhelmingly requested appropriate training. This training should address dental competence in assessment of suspicious indicators and involve dentists in inter-agency child protection training.

Increased expression of the CD45RO (memory) antigen on T cells in HIV-infected children.

Expression of the CD45RO putative memory cell antigen on CD4 (helper) and CD8 (cytotoxic/suppressor) lymphocytes of children born to HIV-infected women was investigated using the UCHL1 antibody. Significantly raised numbers of CD45RO+ CD8 lymphocytes were found in all nine of the infected children compared with uninfected and control children. Expression of CD45RO on CD4 lymphocytes was variable; absolute numbers were not increased, although the percentage was increased in four out of nine infected children. All the infected children except two (who had comparatively low numbers of CD45RO+ CD8 cells) were clinically well, which suggests that an increase in CD45RO+ CD8 cells may be indicative of a functionally active immune response against HIV.

Cytotoxic T lymphocyte activity in children infected with HIV.

Of the Edinburgh cohort of approximately 130 children born to HIV-infected women, 9 are infected and alive. This article describes results from the first 18 months of a natural history study of seven of these, and two adopted children, studying the CD8 T cell-mediated cytotoxicity against HIV proteins (Gag, Tat, Pol, and Env), over time, and relating it to clinical progression and viral activity. Autologous EBV cell lines infected with vaccinia-HIV constructs were used as target cells, and bulk-cultured peripheral blood mononuclear cells as effector cells. The children ranged in age from 0 to 93 months, with six of the nine showing CTL activity to one or more HIV proteins. The specificity of the response was directed against Tat in the younger children, switching to Pol, then Gag or Env. Preliminary analysis of virological data showed no association between CTL and virus activity. The children with CTLs tended to be well clinically, but the cohort needs to be studied longer before conclusions can be made about CTL activity and HIV disease progression. Cytotoxic T lymphocyte activity has also been observed in two children diagnosed as HIV uninfected. These results show the importance of looking at CTL specificity, and may have implications in vaccine design.

HLA antigen frequencies in children born to HIV-infected mothers.

Tissue-typing for HLA-A, B, and DR antigens was carried out on 53 babies, 47 of them unrelated, born to mothers known to be HIV-infected from intravenous drug usage or sexual contact with drug users. These babies were followed up to assess whether HLA phenotype was associated with vertical transmission of HIV infection or disease progression. Of the 47 unrelated babies, eight became infected with HIV. The frequency of HLA-DR3 was three times higher in the HIV-positive infants compared to the HIV-negative infants (43 per cent vs 15 per cent) in our study population. Conversely, HLA-A3 was three times less common in the HIV-positive infants (12.5 per cent vs 42 per cent). A comparison of HLA antigens between our study group babies and babies born to healthy mothers unselected for HIV status revealed higher proportions of HLA-B18, B7, and DR2 in the study group. Moreover, the combination, A3, B7, DR2 was four times commoner in our study population relative to controls (RR = 3.9; p less than 0.003), but was found only in babies who were not HIV infected. The combination A1, B8, DR3, in contrast, was found less often than expected in our study group (RR = 0.39) and was disproportionately represented amongst the infected babies. We have observed an unexpectedly low (6 per cent) mother-to-infant transmission rate of HIV among prospectively studied intravenous drug users. We speculate that the unusually high ratio of the common antigen combinations (often halotypes), A3, B7, DR2 to A1, B8, DR3 in this population may be contributory.

Virus infections of the respiratory tract in HIV-infected children.

In order to determine whether the rates of respiratory viral infection and the severity of respiratory symptoms in HIV-infected children were higher than those in noninfected children, nose and throat swabs for viral isolation were taken at 3-month intervals during the first 2 years of life from 50 children born to HIV-infected women. Similar samples were obtained during the first year of life from 19 control children born to HIV seronegative mothers. Of the 50 children, five proved to be HIV-infected while 45 were presumed to be uninfected. HIV-infected children had significantly more respiratory symptoms and a higher proportion of samples from which viruses were isolated than the non-HIV-infected children. Also, more infected episodes required admission to hospital in the HIV-infected group. There was no such difference between the non-HIV-infected and the control children. Three HIV-infected children received intravenous immunoglobulin therapy. Among these the proportion of positive samples for viral isolation was greater before than after treatment began. These results suggest that HIV-infected children are more susceptible to recurrent viral infection and that passive immunotherapy may be of benefit to such children.

Measles, mumps and rubella immunisation in children at risk of infection with human immunodeficiency virus.

A retrospective serological study of 81 children at risk of HIV (II HIV-infected, 70 HIV-negative) was performed to assess susceptibility to measles, mumps and rubella and response to measles, mumps and rubella (MMR) immunisation. There was no difference in the initial serological response between the HIV-infected and HIV-negative children. Repeat serology should be performed on HIV-infected children as during follow-up antibodies may be lost. Reimmunisation should be considered for the seronegative.

Cardiac dysfunction in paediatric HIV infection.

A child under long term surveillance for vertically acquired HIV-I infection developed respiratory symptoms. Dilated cardiomyopathy was diagnosed. Clinical and echocardiographic assessment of six other children with symptomatic HIV disease showed no evidence of cardiac dysfunction. The exact prevalence of this complication in paediatric HIV infection is unknown, but the potential diagnostic difficulties are highlighted.

The management of children born to human immunodeficiency virus seropositive women.

Increasing numbers of children born to human immunodeficiency virus (HIV) antibody-positive women are being identified, but guidelines as to their management are lacking. We have therefore established a paediatric counselling and screening clinic for managing such children in Edinburgh. During a period of 3 years, 49 infants and children of 43 HIV seropositive women have been seen. After a median follow-up period of 23 months, four children were found to have clinical evidence of HIV disease which was non-specific and could have been missed had they not been regularly monitored. Thus, close surveillance of infants born to seropositive women is important. Identifying a single clinic where this is done has allowed experience to accumulate on issues beyond the medical management of these infants as well as contributing to the clinical care of infants with symptoms. Based on this experience, we have developed guidelines for managing children born to HIV antibody-positive women.

Maternal factors in HIV transmission.

In order to identify features associated with an increased risk of transmission of HIV from seropositive women to their offspring, 70 children of 58 HIV seropositive mothers were studied. Fifty-six children were followed prospectively from pregnancy; in 14 identified after the puerperium, obstetric notes were reviewed and stored serum was tested. Twelve infants of 10 mothers were HIV infected. Risk of transmission was increased in the first year after seroconversion; 5/9 infants born at this time were infected compared with 7/61 born subsequently (P < 0.001). Progression to stage IV in transmitters was more likely, occurring in the mothers of 9 infected children at a median of 3 years (range 0.5-6.5) and in mothers of 19 non-infected children at a median of 5 years (range 1-7) (P = 0.032). Maternal CD4+ counts < 400 x 10(6)/l were found in 7/12 transmitting and 7/49 non-transmitting pregnancies (P < 0.01). Differences in HIV antigenaemia did not reach significance. These factors may influence the counselling of mothers regarding their child's and their own prognosis.

HIV testing and prevalence in pregnancy in Edinburgh.

The objective was to study the changes in pregnancy HIV prevalence with time. Data were collected from multiple sources to provide a comprehensive record of all HIV seropositive pregnant women identified in the Edinburgh area (Scotland) until December 1992. There were 177 pregnancies in 108 HIV seropositive identified women. Risk factors were injection drug use (79% of pregnancies) and a known HIV seropositive injection drug-using partner (16%). Prevalence has decreased for Edinburgh City women from 0.5% of all pregnancies in 1986 to 0.1% in 1992; It was higher for induced abortion (0.6%) than for delivery (0.2%). HIV testing in pregnancy has declined. Comparison with unlinked anonymized testing showed that in 1990-1991, 20/22 seropositive women were known. In 1992, only 3 of 10 seropositive pregnancies were identified. The cohort initially infected by exposure to a 'drug related' risk factor between 1983 and 1985 may have increasingly finished childbearing, deliberately decided against pregnancy because of HIV status, and declined because of death, illness and emigration from the area, There may not have been major early tertiary heterosexual spread; however, data from 1992 suggest that this could now be impacting on pregnancy prevalence. Local testing policies have not adapted to this possible change.

Lack of agreement on colour description between clinicians examining childhood bruising.

INTRODUCTION: In child protection cases clinicians are often asked to describe and age bruises. This paper looks at both intra- and inter-observer variability in the description of childhood bruising. METHODS: Fifty-eight bruises on 44 children were described by three observers, the bruises were then photographed and the same observers described the bruises at a later date. The descriptions were compared and classified in terms of complete, partial, or no agreement, both between observers and between the in vivo and photographic descriptions. RESULTS: Complete agreement on colour description between two observers in vivo occurred in 27% of descriptions in vivo and 24% of photographs. Only 31% of descriptions completely agreed with the later description of a photograph of the same bruise. CONCLUSIONS: This marked variability in colour description, severely questions the practice of estimating the age of bruises especially from clinical photographs as evidence in child protection proceedings.

Zidovudine therapy in combination with intravenous immunoglobulin in HIV infected children.

There is little published data on concomitant use of zidovudine and intravenous immunoglobulin (IV IgG). In this paper we review our experience of four HIV-1 infected children treated with zidovudine for periods of 19-33 months (mean 26.5 months) subsequent to starting IV IgG for period of 18-20 months (mean 19 months). In these children the only clear benefit we found was in one child who had developed HIV encephalopathy which resolved after starting zidovudine. The respective roles of zidovudine and intravenous immunoglobulin in HIV-1 infected children need to be clarified in larger comparative trials.

Non-accidental head injury: a consequence of deprivation?

BACKGROUND: Non-accidental head injury (NAHI) is a significant personal and public health problem, with considerable mortality and morbidity. The evidence base for risk factors specific for NAHI is limited due to difficulties with case definition and study design. The risk factors associated with NAHI in infants was evaluated in this study, and the extent to which indices of deprivation influence this health problem was addressed. METHODS: A 10-year prospective study was conducted in Scotland involving all paediatric hospitals and other general hospital departments admitting children. Subjects were children ≤2 years of age, with a diagnosis of "suspected NAHI". Socioeconomic characteristics of the index cases were compared to the general population, using the Scottish Index of Multiple Deprivation (SIMD) 2006. RESULTS: There were highly significant differences (p<0.001) between the SIMD rank scores of the NAHI cases and scores for the whole Scottish population. For the cohort, SIMD ranks ranged from 34 to 6253 (median 1210; mean 1577) compared to the population range of 1-6505 (median and mean=3253). Similar differences were found for each of the component domains of income, employment, health, education, crime and housing (p<0.001). In contrast, the scores for "geographic access" (to essential service) were higher than for the whole population (p<0.001), indicating that the deprivation was not due to lack of local services. CONCLUSION: In Scotland, children who present with suspected NAHI originate predominantly from the most deprived areas of the community. Public health and intervention strategies should be focused in these areas.

The epidemiology of oro-nasal haemorrhage and suffocation in infants admitted to hospital in Scotland over 10 years.

OBJECTIVE: To estimate the incidence of oro-nasal haemorrhage (ONH) and suffocation in infancy and to investigate their aetiology and overlap. Setting A 10-year retrospective hospital based study from Scotland, UK. METHODS: The hospital notes of all infants presenting with ONH or suffocation identified through the Information Services Division of the Scottish Health Service were reviewed by three paediatric consultants, two with child protection expertise. The hospital-based incidences of haemorrhages from different sites were calculated and the causes ascertained. When trauma was involved, a decision was made whether it was likely to have been accidental. RESULTS: 7 cases of suffocation and 88 of ONH were recorded at hospital discharge over 10 years. This gives an incidence of ONH of 1.62 (1.30 to 1.99)/10,000 live births (95% CI) which consists of haemorrhage arising from nose or mouth (N/M), n=65 (1.19/10,000 (0.92 to 1.52)); haematemesis, n=11 (0.20/10,000 (0.10 to 0.36)); haemoptysis, n=3 (0.06/10,000 (0.1 to 0.16)) and pulmonary haemorrhage, n=9 (0.17/10,000 (0.08 to 0.31)). No suffocation cases were recorded as having a coincident ONH, but five ONH cases were probably caused by airway obstruction. 40 of 65 cases of N/M were associated with trauma, which in 15 cases were thought to be probable abuse; four were associated with coagulation abnormalities. 2/3 haemoptysis cases, 2/11 haematemesis cases and 8/65 N/M cases were associated with a coincident respiratory tract infection, though in 4/8 of these cases, there was an associated apparent life-threatening event. CONCLUSIONS: Haemorrhage from the N/M is rare in infancy. Trauma is commonly involved and child protection concerns often poorly explored. Pulmonary haemorrhage and several cases of ONH were associated with probable airway obstruction. Information, in cases of ONH, is in general recorded badly, and an investigation and management plan are suggested.

Injuries to the head, face, mouth and neck in physically abused children in a community setting.

OBJECTIVES: The aims of the present study were to identify the incidence of orofacial injuries found within a cohort of physically abused children, and examine demographic data surrounding the alleged perpetrator, the location in which the alleged assault occurred, the mechanism of injury and the actual orofacial injury incurred. METHODS: The research took the form of a retrospective study of clinical case records of children with suspected physical abuse from 1 June 1998 to 31 May 2003. Seven hundred and fifty case records were identified and 390 (46.7%) were available for data extraction. RESULTS: Fifty-nine per cent (n = 230) of children had signs of abuse on the head, face or neck. The alleged perpetrator was the mother in 104 cases (26.7%), the father in 100 (25.6%) and mother's partner in 49 other cases (12.6%). More than half (53.3%) of the alleged abuse occurred in the child's home; in 32.3% of cases, the location was not recorded. Other locations included outside in a public place, school and at the home of the alleged abuser. Some 23.4% (n = 54) had been punched or slapped around the head, neck or face, 17.4% (n = 40) had been struck by an object, and 15.2% (n = 35) had allegedly sustained multiple modes of injury. Bruising to the head, neck or face was seen in 95.2% (n = 219) of children, and 32.6% (n = 75) had abrasions; 65.2% (n = 150) of the bruises and 22.9% (n = 53) of the abrasions were on the face. CONCLUSIONS: Fifty-nine per cent of physically abused children in the present cohort had orofacial signs of abuse which would be easily visible to a dental practitioner. The commonest injuries were bruises and abrasions. This concurs with previous reports in the literature and highlights the important role of dental practitioners in the recognition of children who have been abused.

Vertical transmission.

Since AIDS was first described in children, much has been learnt about the epidemiology, clinical presentations and natural history of perinatally acquired HIV disease. As yet, several questions remain unanswered about the pathogenesis of vertical transmission, the relative risk associated with each mode of transmission, the rate of transmission from mother to child, and the factors that might contribute to the efficiency of transmission. Data presented thus far suggest that intrauterine exposure poses the greatest risk, but more recent reports have reopened speculation that infection could occur at or around the time of delivery. The prospects for intervention, to stop transmission from mother to child, rest on the ability to identify HIV-infected women; the knowledge of how and when the virus infects the fetus; and how to identify, as early as possible, those truly infected infants. Resources should therefore be set aside for routine screening for HIV in antenatal women. There is also a need to quantify the contribution made by intrauterine versus intrapartum events. Lastly, promising new techniques designed to detect neonatal HIV infection must be properly evaluated against standard methods, and correlated with clinical outcome. Only then can the efficacy of antiretroviral therapy be tried, to prevent vertical transmission.

Dizygotic twins discordant for HIV and hepatitis C virus.

Twin girls were born at 37 weeks' gestation to a mother infected by HIV and hepatitis C virus. Twin 1 had symptomatic HIV infection by 9 months but was negative for hepatitis C virus antibody and RNA. Twin 2 became HIV antibody negative by 15 months but was positive for antihepatitis C virus and RNA.

Symptoms, atopy, and bronchial reactivity after lower respiratory infection in infancy.

We studied the prevalence of subsequent respiratory symptoms and the relation between atopic status and bronchial reactivity in 200 index children and their controls 7 years after acute lower respiratory tract infections in infancy. Index children with recurrent symptoms differed from controls in respect of social and family characteristics and atopic background. Ventilatory function was diminished and bronchial reactivity increased. Symptom free index children also came from poorer environmental backgrounds, but did not otherwise differ from controls. 'Atopic' index children differed significantly from controls in respect of subsequent symptoms and ventilatory function and similar adverse trends were observed in 'non-atopic' index children. A comparable proportion of 'atopic' and 'non-atopic' index children showed bronchial reactivity (33.5% and 38.9% respectively). Index subgroups with and without bronchial reactivity had increased cough and wheeziness compared with respective matched controls. The former included children with 'established' asthma and the latter those with 'established' bronchitis. Atopic backgrounds were similar in both subgroups, with no differences between cases and controls. These findings suggest that atopic background and bronchial reactivity are not closely related but may contribute independently to the persistence of symptoms after respiratory infections in infancy. Bronchial reactivity may be a more useful basis than atopic status on which to separate children with episodic cough or wheeze, or both, into 'asthmatic' and 'bronchitic' subgroups.