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Allergy, immunity, and infection

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G219 T CELL RECEPTOR OLIGOCLONALITY IN THE PRESENCE AND ABSENCE OF RECOMBINASE ACTIVATING GENE DEFECTS IN OMENN SYNDROME (OS)

A. R. Gennery1, A. P. Williams2, E. Hodges2, A. Villa3, J. J. M. van Dongan4, A. J. Cant1, J. L. Smith2. 1Department of Paediatrics, Newcastle General Hospital, Newcastle upon Tyne, NE4 6BE; 2Wessex Immunology Service, Southampton University Hospitals, Southampton SO16 6YD; 3ITBA, CNR, Cervi 93, Italy; 4Erasmus University, Rotterdam, 3000 DR Rotterdam, The Netherlands

Introduction: OS, a form of severe combined immunodeficiency syndrome characterised by hepatosplenomegaly, lymphadenopathy, an erythematous rash, eosinophilia, and elevated IgE, is characterised by oligoclonal T cell expansions and defects in the recombinase genes RAG1 and RAG2. We describe nine cases of OS with typical clinical and immunological features but with a RAG defect being identified in only two cases.

Method: Two colour flow cytometry using monoclonal antibodies against CD3 and TCRVβ families was used to map TCRVβ usage. T and B clonal cell populations were examined in peripheral blood lymphocytes (PBLs) by PCR and sequencing of TCRβ/TCRγ T cell and IgH FR2/FR3 B cell products. Nine OS patients were investigated and their RAG, RAG2, and Artemis genes were sequenced and compared with results from age matched controls.

Results: All nine OS patients showed absent TCRVβ families; four had predominant TCRVβ families. Six patients had oligoclonal TCR gene rearrangements, including one with oligoclonal TCRGD rearrangements. One child had a functional IGH rearrangement, an observation not previously reported. A RAG gene mutation was identified in only two patients.

Conclusion: In a clinically homogeneous population of OS patients, oligoclonal T cell expansions were seen in six of eight individuals and clonal B cells were found in another. Molecular characterisation identified only two individuals with a deficiency in the recombinase gene RAG1 and none with a deficiency in artemis. This suggests that OS is a genetically heterogeneous condition not only characterised by defects in the RAG1/2 recombinase genes.

G220 LEUCOPENIA IS ASSOCIATED WITH BACTERAEMIA AND DEATH—BUT ONLY IN CHILDREN WITHOUT MALARIA

S. Ladhani, A. O. Cole, B. Lowe, K. Kowuondo, C. R. J. C. Newton. Centre for Geographical Medicine Research (Coast), Kenya Medical Research Institute, Kilifi, Kenya

Aim: To determine the association between leucopenia, bacteraemia, and death in children with malaria and other medical conditions who were admitted to a large rural Kenyan hospital over a 12 month period.

Methods: The case records of all children admitted to Kilifi District Hospital, Kenya, between January and December 2000 were analysed retrospectively. Leucopenia was defined as a white cell count of less than 6.1×109/l, based on screening 126 healthy children from the local population.

Results: Leucopenia was identified in 9.3% of 2830 children. Malaria accounted for 53% of leucopenia cases but only 10.2% of children with malaria had leucopenia. In this group, leucopenia was not associated with severity (13/139 v 150/1230, p 0.33), bacteraemia (2/139 v 30/1230, p 0.46), or death (1/139 v 26/1230, p 0.26) compared with children with normal or high white count. In contrast, of the 125 leucopenic children without malaria, 20% had significant bacteraemia and 23% died compared with 6.7% (p<0.001) and 11% (p<0.001) of 1336 children with normal or high white count, respectively. In particular, of the 146 children with significant bacteraemia, 52% of 27 leucopenic children died compared with 24% of 119 children with normal or high white count (OR 3.3, 95% CI 1.4 to 8.1, p 0.005). This occurred despite 87% of leucopenic children who died receiving antibiotics on admission.

Conclusions: Leucopenia is not associated with severity, bacteraemia, or death in children with malaria. In contrast, leucopenia in children without malaria is associated with a 3.5-fold (95% CI 2.1 to 5.7) and 2.4-fold (95% CI 1.6 to 3.8) increase in the risk of significant bacteraemia and death, respectively. In particular, over half the leucopenic children with significant bacteraemia died despite most receiving antibiotics.

G221 A PROSPECTIVE STUDY ON THE REVACCINATION OF CHILDREN RECEIVING HAEMOPOIETUC PROGENITOR CELLS TRANSPLANT (HPCT) AGAINST Haemophilus Influenzae b and tetanus

S. R. Patel, P. T. Heath, M. Ortin. The Royal Marsden Hospital, Sutton, and Department of Child Health and Vaccine Institute, St George’s Hospital Medical School, London

Introduction: There are controversial data on the need and the ideal timing for the revaccination of children receiving HPCT. The aim of this ongoing study is to explore the effects of HPCT on immunity against tetanus and H Influenzae (Hib) and the response to post-HPCT vaccination given according to the RCPCH 2002 guidelines.

Method: Thirty nine children who had received routine vaccines prior to undergoing a HPCT (13 autologous, 26 allogeneic) at The Royal Marsden Hospital were included. Pre-immunisation serology was taken at the time of administering vaccines (three doses, starting 12–18 months after transplant). Post-immunisation serology was taken at an average of 4 weeks later.

Results: Pre and post-immunisation serology were available in 20 and 14 cases respectively. Pre-immunisation, five had non-protective titres against Hib (<0.15 μg/ml) and four optimal (>1.0 μg/ml). Antibody levels had no relationship with the indication for HPCT. There were no significant differences in the pre-immunisation titres between autologous and allogeneic HPCT or between conditioning schedules. Post-immunisation, optimal protective levels were achieved in 13/14 cases. Responses were significantly (p<0.009) higher in allografts. Prior to tetanus vaccination, two had non-protective (<0.01 IU/ml), and five optimal titres (>1.0 IU/ml). Again, no differences were seen between graft type or conditioning schedules. Vaccination produced protective levels in all cases with 13/14 optimal responses. A non significant tendency for better responses in allografts was seen.

Conclusion: The current guidelines for re-vaccination result in protective titres against Hib and tetanus in nearly all cases. Post-HPCT immunity against both is similarly depressed in autologous and allogeneic grafts and response to vaccination after allografts appears better. The suppressive effect of autografts on the immune system is more relevant than expected and needs to be further assessed.

G222 USE OF A KILLED WHOLE CELL GROUP B NEISSERIA MENINGITIDIS VACCINE IN AN ANIMAL MODEL

S. B. Welch1, C. P. Sandiford2, D. Litt1, J. B. Stephens2, J. S. Kroll1, C. A. Ison2, M. Levin1. Departments of 1Paediatrics and 2Medical Microbiology, Faculty of Medicine, Imperial College London

Background: Development of a serogroup B meningococcal vaccine is an urgent healthcare priority. Previous attempts at a killed whole cell vaccine have been largely abandoned because of local and systemic side effects, and because of the absence of adequate measures of immunity. The requirements of a suitable vaccine are safety and protection against multiple strains of serogroup B N meningitidis.

Methods: We injected young adult rabbits intradermally with whole heat killed serogroup B N meningitidis. The development of immunity was measured using a whole blood bacterial killing assay (WBA). Local reactions were assessed by measuring the size of skin lesions. We injected further animals with bacteria pretreated with recombinant bactericidal/permeability increasing protein (rBPI) to bind and inactivate endotoxin, and compared the extent of local skin reactions and immunity measured by WBA.

Results: Rabbits injected with untreated heat killed bacteria developed killing of multiple strains of N meningitidis in the whole blood assay, whereas bacterial survival did not change in controls. However, injected rabbits did develop significant local skin reactions. Rabbits injected with BPI treated bacteria developed a similar degree of bacterial killing and cross-protection, but with significantly reduced skin reactions.

Conclusions: BPI treated whole killed bacteria are a potentially useful vaccine in this animal model. Further experiments to validate the effectiveness and determine the applicability of this to humans are required.

G223 WHO NEEDS PAEDIATRIC ALLERGY, IMMUNITY, AND INFECTION SPECIALISTS?

F. A. I. Riordan. Department of Child Health, Birmingham Heartlands Hospital, Birmingham

The distribution of specialists in paediatric allergy, immunity, and infection (PAII) is extremely uneven in the UK. Few regions have tertiary specialists from whom advice on PAII can be sought. Other sources may be used instead.

Aim: To define frequently asked questions about PAII, who asks them, and where the answers are found.

Method: In a region with no tertiary specialist, a general paediatrician with an interest in PAII recorded every request for advice between Aug 2001 and Aug 2003. Information on who requested advice, advice given, and where answers were found was recorded.

Results: There were 200 requests for advice (169 phone calls, 13 letters, 11 emails). Questions came from 157 hospital doctors (118 consultants), 24 GPs, 8 nurses, 5 parents. The hospital doctors worked in 22 hospitals, 144 were paediatricians (29 subspecialists), 14 adult specialists. 122 questions were about infection (HIV 47, TB 28), 35 vaccination, 27 immunology, and 16 allergy. Answers to 140 questions could be found in available resources (books 95, guidelines 34). 106 answers were found in just three books or five guidelines (Red book, Green book and Blue book, TB/HIV, pregnancy, malaria, PENTA, splenectomy guidelines). For 60 questions advice was based on personal experience or discussion with other colleagues. On review at least three answers given were incorrect.

Conclusions: Requests for PAII advice came from a variety of healthcare professionals and others throughout a region. Most requests were by phone, but email requests are likely to increase. Almost 25% of questions were about HIV, reflecting the recent increase in cases and antenatal detection. Answers for 53% of questions could be found in a small number of books/guidelines. These need to be available in all paediatric units, and incorporated into general and subspeciality training. The establishment of clinical service networks should improve access for the 30% of questions that need “expert opinion”.

G224 WITHDRAWN

G225 A PROSPECTIVE STUDY ON THE INFLUENCE OF ANTI-NEOPLASTIC TREATMENT ON THE IMMUNISATION STATUS AGAINST HAEMOPHILUS INFLUENZAE B AND TETANUS IN CHILDREN RECEIVING TREATMENT FOR ACUTE LEUKAEMIA

S. R. Patel1, P. T. Heath2, M. Ortin1. 1The Royal Marsden Hospital, Sutton; 2Department of Child Health and Vaccine Institute, St George’s Hospital Medical School, London

Introduction: New trends for the treatment of childhood acute myeloblastic and lymphoblastic leukaemia (AML, ALL) include more aggressive schedules whose effects on the immunisation status remain unknown.

Method: As part of an ongoing study, patients between the ages of 1 and 16 years receiving treatment for AML or ALL as per national standard protocols at The Royal Marsden Hospital were enrolled in this study. All children (n 29) received one dose of H Influenzae (Hib) and tetanus vaccines at least 6 months after completion of anti-leukaemia treatment, as per RCPCH 2002 guidelines. Antibody concentrations were measured before and 4 weeks after vaccination using standard ELISA methods.

Results: Pre- and post-immunisation serology were available in 22 and 21 cases, respectively. Pre-immunisation Hib titres were as follows: 6<0.15 μg/ml and 8>1.0 μg/ml. Patients with AML had significantly (p<0.02) lower titres than patients with ALL (mean (SD) 0.39 (0.32) v 2.43 (3.28) μg/ml). All patients responded to vaccination with optimum (>1.0 μg/ml) protective levels regardless of their diagnosis, although higher responses were seen in ALL patients (7.85 (2.70) v 5.33 (4.24)). Pre-immunisation tetanus titres were protective (>0.01 IU/ml) in all cases. Patients with ALL had significantly (p<0.03) higher titres than those with AML (0.25 (0.2) IU/ml v 0.13 (0.02) IU/ml). All but one patient acquired optimal protective levels (>0.1 IU/ml). Patients with ALL responded better to vaccination than those with AML (p<0.0001).

Conclusion: Vaccination of children with leukaemia (ALL and AML) according to current guidelines provides excellent protection against Hib and tetanus.

G226 RESPONSE OF DEXAMETHASONE TREATED FORMER PRETERM INFANTS TO A SINGLE DOSE OF MENINGOCOCCAL C CONJUGATE VACCINE

I. Ahmad1, P. Clarke1, P. J. Powell2, J. E. Connell3, A. R. Bedford-Russell4, R. Borrow5, P. T. Heath4, J. Southern6, N. Andrews6, E. Miller6, M. J. Robinson1. 1Hope Hospital, Salford; 2Royal Bolton Hospital; 3St Mary’s Hospital, Manchester; 4St George’s Hospital, London; 5PHLS Meningococcal Reference Unit, Manchester; 6HPA Immunisation Division, CDSC, London

Background: Attenuated antibody responses have been reported in premature infants who received neonatal dexamethasone treatment. The duration of immunosuppression may extend into later infancy.

Aim: To assess the immune response of former preterm infants who received dexamethasone, to a single MCC immunisation given after infancy.

Methods: In a cohort study, 49 previously unimmunised toddlers born at <33 weeks’ gestation were given a single MCC-CRM197 vaccine at the age of 13 months. Sera obtained 4 weeks post immunisation were analysed for serum bactericidal antibody (SBA) and serogroup C specific IgG antibody. Immune responses of the subgroup who received dexamethasone in the management of neonatal chronic lung disease were compared with those of the non-steroid treated subgroup, and with an historical cohort of term infants who were given a single dose of the same vaccine at the age of 13 months. An SBA titer of ⩾8 was taken to indicate a protective response.

Results: Following a single MCC dose, the IgG antibody geometric mean concentration (GMC) for the cohort was 11.8 (95% CI 8.9 to 15.6) μg/mL and the SBA geometric mean titre (GMT) for responding infants was 898 (524 to 1540). For the steroid treated subgroup the IgG antibody GMC was 16.0 (10.0 to 25.7) μg/mL and SBA GMT in responders was 2195 (843 to 5716). Corresponding values for the non steroid treated subgroup were 10.8 (7.8 to 15.0) μg/mL and 645 (350 to 1187), respectively. Proportions of infants achieving the protective titre did not differ significantly between subgroups (p 0.42). The proportion of steroid treated former preterm infants attaining the protective titre after the single dose (10/11: 91%) was the same as that in a term cohort (64/70: 91%).

Conclusion: Prior dexamethasone treatment given in early infancy does not adversely affect immunogenicity, nor reduce the likelihood of a protective SBA titre following a single MCC dose at the age of 13 months.

G227 THE USE OF AN IN VITRO IFNγ PRODUCTION ASSAY TO DIAGNOSE PAEDIATRIC MYCOBACTERIAL LYMPHADENOPATHY

N. A. Davidson1, J. Clark1, A. J. Cant1, R. Freeman2, D. Moss3, A. R. Gennery1. 1School of Clinical and Medical Sciences, University of Newcastle upon Tyne; 2Health Protection Agency, Newcastle General Hospital; 3Launch Diagnostics Ltd, Longfield, Kent

Introduction: Mycobacterial lymphadenitis (ML) caused by M tuberculosis requires 6 months chemotherapy; more commonly it is caused by environmental mycobacteria (M avium, M malmoense) when the best treatment is complete excision of the infected node. Diagnosis is difficult; mycobacterial culture takes months and is often negative. Skin prick testing (SPT) with mycobacterial antigens is painful, requires two clinic visits, and false positive results due to antigen cross reactivity occur. Using a commercial assay, previously piloted in children with a positive heaf test,1 we measured in vitro IFNγ production against mycobacterial antigens to assess its use as a diagnostic aid in ML.

Methods: Five millilitres of blood were taken from 10 children with ML and 9 controls. Whole blood samples were incubated overnight with M tuberculosis, M avium, and M malmoense antigens and IFNγ levels in the supernatant measured by ELISA.

Results: Ten children with MCL were tested, with 9 controls. Five of 10 ML were identified as infected with M malmoense by the assay (three culture proven), one with M avium (culture proven), and three with M tuberculosis (one M tuberculosis, two M malmoense on culture). One was negative (M malmoense on SPT). Six controls were identified as negative, one as infected with M tuberculosis, one as infected with M malmoense, one indeterminate.

Conclusion: This new assay appears to differentiate between M avium and M tuberculosis infection. Apparent cross reactivity of M tuberculosis with the M malmoense antigens may be reduced by the addition of M tuberculosis specific antigens to the assay.

1

G228 CONFOCAL VISUALISATION OF GREEN FLUORESCENT PROTEIN EXPRESSING S PNEUMONIAE IN RAT BRAIN FOLLOWING EXPERIMENTAL MENINGITIS

R. A. Hirst, B. Patel, C. D. Ockleford, P. W. Andrew, C. O’Callaghan. Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE2 7LX

Introduction: Despite antimicrobial therapy and modern intensive care S pneumoniae meningitis has a high mortality and morbidity rate. The mechanism by which S pneumoniae attach and invade the brain during meningitis is unclear. In this study we demonstrate, in a rat model of experimental meningitis, that expression of green fluorescent protein in pneumococci greatly aids determination of the location of the bacteria inside the brain. We present evidence that the pneumococci attach and invade brain regions including the pia membrane, the lateral ventricle wall, and the outer cerebrocortex.

Aim: To use a rat model of meningitis in order to locate D39 pneumococci expressing GFP (pGFP1) in the brain using fluorescent confocal microscopy.

Methods: Male Wistar rats were administered 104colony forming units (cfu) S pneumoniae: pGFP1 into their cerebrospinal fluid (CSF) via a cisternal catheter. The controls were cisternally injected with sterile phosphate buffered saline. When the infected rats reached the lethargic stage of the disease, they were euthanased and their brains perfused with PBS to remove the blood. This was followed by fixation with 4% v/v para-formaldehyde. The brain was then removed and coronal cryo-sections made prior to imaging using confocal microscopy.

Results:S pneumoniae: pGFP1 caused clinical symptoms of meningitis in the rats at 27 h. At this time the control rats were healthy. The levels of the bacteria within the CSF ranged between 105 and 109 cfu/ml in the infected group and the CSF from PBS injected rats was clear of bacteria. Examination of the brain sections by confocal microscopy revealed that the fluorescent bacteria were associated with the pia membrane surrounding the cerebrocortex. The bacteria were also located within the brain parenchyma, such as the outer cerebrocortex and the wall of the lateral ventricle. The parenchymal bacteria were observed in diploids, whereas CSF and membrane associated bacteria formed chains containing multiple bacteria.

Conclusion: Our data demonstrate GFP fluorescent pneumococci cause the same meningitis as wild type bacteria and the bacteria attach to the pia membrane and penetrate the brain parenchyma in vivo.

G229 LIPODYSTROPHY IN HIV-1 INFECTED CHILDREN IN THE ERA OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART)

A. Dzwonek1, T. Cole1, V. Novelli2, M. Lawson1. 1Institute of Child Health, London, UK; 2Great Ormond Street Hospital for Children, London, UK

Background: HAART slows the progression of HIV disease and lowers mortality and morbidity in children. Coincident with these advances, an increasing number of reports have identified the emergence of body composition changes described as lipodystrophy syndrome.

Objective: To determine the prevalence of lipodystrophy in HIV-1 infected children.

Patients and Methods: A cross sectional study evaluating HIV infected children aged 3–17 years attending an HIV family clinic (Nov 02–03). Subjects following routine assessment underwent further physical examination to obtain anthropometry, weight, height, skinfold thickness (biceps, triceps, subscapular, suprailiac), and circumferences (waist, arm, thigh, calf). BMI was calculated and the measurements converted to z scores using the British 1990 reference for height, weight, BMI, and waist circumference, and the Dutch Reference Manual (1996) for mid upper arm, thigh, and calf circumferences, and the skinfold thicknesses.

Results: 95 patients (48 females) of Sub-Saharan African origin with vertically acquired HIV-1 infection were enrolled. CDC category of HIV was as follows: clinical category A 26%, B 49%, and C 24%; and immune category:1 60%, 2 38%, and 3 2%. At enrolment 68% of children were receiving HAART. Of these, 63% had a protease inhibitor (PI). D4T as a part of backbone NRTI regimen was used in 68%. The table summarises the anthropometry z scores. Subscapular, biceps, and triceps skin fold thicknesses were significantly different from the controls.

Abstract G229

Conclusions: The fat pattern for these patients is clearly different from Dutch and British controls, suggesting the presence of lipodystrophy.

G230 STETHOSCOPES MAY CAUSE CROSS CONTAMINATION OF MULTIRESISTANT BACTERIA BUT REGULAR CONVENTIONAL CLEANING METHODS DECONTAMINATE EFFECTIVELY

S. Eisen1, S. Phillips2, D. Keady2, A. Bateman2, S. N. Faust1. 1Department of Paediatrics, Imperial College Faculty of Medicine; 2St Mary’s NHS Trust

Background and Aims: Following a cluster of cases of multiresistant bacteria on our neonatal and paediatric intensive care units, and the identification of vancomycin resistant enterococcus (VRE) on a stethoscope on the NICU, we investigated the role of stethoscopes in mediating cross contamination, and the efficacy of currently used cleaning methods. ICU bed spaces and ward cubicles have their own individual stethoscopes.

Methods: We plated directly onto blood agar and MSA selective media 29 stethoscope heads from paediatric (n 7) and neonatal (n 6) intensive care units, special care baby unit (n 4), paediatric infection ward (IDW) cubicles (n 7), and medical staff (MS) (n 5). Staff were then asked to clean the stethoscopes with the methods they usually employed and the stethoscopes were reswabbed. Colonies were counted and identified after 48 h.

Results: No vancomycin resistant enterococci (VRE) or methicillin resistant Staphylococcus aureus (MRSA) were identified before or after cleaning. However, 56% of stethoscopes were contaminated with coagulase negative staphylococci (CNS), bacilli, or other organisms before cleaning. The personal stethoscopes of staff members and PICU beds were more contaminated (70% and 68% dirty, respectively) than the instruments allocated to individual patients on NICU (46%), SCBU (38%), and IDW (57%). After cleaning, there was an 80% reduction in colony growth. There was no significant difference in efficacy between alcohol wipes (72% reduction) or detergent and water methods (82%) used for cleaning (p 0.51).

Conclusions: The high prevalence of contaminated stethoscopes was effectively reduced by conventional cleaning methods. The efficacy of decontamination appears limited by the frequency rather than method of cleaning. Our study demonstrates that easily available stethoscope cleaning methods are effective at reducing colony growth. The use of staff members’ own stethoscopes should be discouraged unless meticulous cleaning takes place between patients in any clinical area.

G231 HAEMOPHILUS INFLUENZAE TYPE B (HIB) ANTIBODY RESPONSE FOLLOWING PRAGMATIC UK IMMUNISATION WITH MIXED REGIMES OF ACELLULAR AND/OR WHOLE CELL DTPHIB COMBINATION VACCINES

J. E. Berrington, A. C. Fenton, G. P. Spickett, J. N. S. Matthews, M. O’Keeffe, A. J. Cant. Royal Victoria Infirmary, Newcastle upon Tyne, UK

Introduction: Between 1999 and 2002 in the UK there were two combination DTPHib vaccines: one whole cell (DTPwHib) and one acellular pertussis (DTPaHib). DTPaHib reduces Hib response if given for all three primary immunisations. We measured Hib antibody response after pragmatic primary vaccination in relation to the number of whole cell vaccines received.

Methods: IgG against Hib was measured by EIA in 166 preterm infants and 45 term infants completed (the binding site). The probability of achieving an anti-Hib titre >1.0 μg/ml after three immunisations in relation to the total number of whole cell immunisations administered was modelled using logistic regression, controlling for gestation. The effect on the logged titres was analysed using censored linear regression.

Results: See table.

Abstract G231

Conclusion: DTPaHib was associated with reduced anti-Hib levels and anti-Hib responses of <1.0 μg/ml (p<0·0005). The use of this vaccine in the UK coincided with an increase in Hib disease, and the reduced responses seen may help to explain this increase in disease.

G232 FOLLOW UP OF CHILDREN EXPOSED TO ANTIRETROVIRAL THERAPY IN PREGNANCY (CHART)

C. D. Hankin1, P. A. Tookey1, E. G. H. Lyall2, C. S. Peckham1. 1Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London; 2Imperial College School of Medicine and St Mary’s Hospital, London

Introduction: The number of uninfected children born to diagnosed HIV infected women in the UK increased from about 100 a year in the mid 1990s to over 600 in 2002. Most of these children were exposed to antiretroviral therapy (ART) in fetal life and there is concern about possible rare adverse side effects, for example mitochondrial dysfunction and malignancy.

Methods: A protocol based on routine surveillance through the National Study of HIV in Pregnancy and Childhood (NSHPC) has been established to maintain contact with uninfected children (CHART). Prospectively collected data on ART exposure and birth outcome are available from the NSHPC. Parental consent for inclusion in CHART is requested via the paediatrician who notified the child to the NSHPC, and annual follow up information is collected by standard questionnaire. A pilot study with children born 1996–2000 in 12 hospitals was extended to include all uninfected children born in the UK since 2001. Children are eligible once laboratory confirmation of their uninfected status is reported.

Results: By November 2003, 221 (26%) of 836 eligible children had been enrolled, one had died (SIDS), 84 (10%) were lost to follow up, and 32 parents (4%) had declined. We were awaiting information for 60%. Among the 221 enrolled children, 64% were exposed to a variety of combination therapies in utero, 30% to monotherapy, and 5% were born to women who had no antenatal ART. At last follow up, 10 (5%) children were reported to have had a serious health or developmental problem, of whom at least half had a congenital defect identified perinatally.

Conclusions: The number of children eligible for enrolment in CHART will increase substantially. Developing a practical and acceptable method of follow up for these uninfected children is challenging but necessary in light of the variety of ART regimens and concern about possible side effects.

G233 NON-RESPONSIVE COMMUNITY ACQUIRED PNEUMONIA IN SOUTH AFRICAN CHILDREN

L. M. McNally1,2, P. M. Jeena2, K. Gajee2, S. A. Thula2, A. W. Sturm2, D. Goldblatt1, H. M. Coovadia2, A. M. Tomkins1. 1The Institute of Child Health, London; 2Nelson R Mandela School of Medicine, Durban

Aims: To determine whether children in an HIV endemic area respond to a modified WHO antimicrobial regimen for very severe pneumonia; the aetiology of non-responsive pneumonia; and whether a different antimicrobial regimen should now be used in HIV endemic areas either for all children or for a subgroup of children.

Methods: Children aged 1–59 months admitted with WHO defined (very) severe pneumonia were recruited. A regimen of intravenous penicillin and gentamicin was used. In addition, all infants received high dose co-trimoxazole. All children had anonymous linked HIV testing. Children who failed to respond were investigated further including either lung aspiration or non-bronchoscopic BAL.

Results: 362 children were recruited. 70% were under one year and 70% were HIV infected. 61% children responded to the antimicrobial regimen. HIV infected children, especially those with hepatosplenomegaly and oral thrush, were significantly more likely to fail to respond (58% v 73%). 117 children had further testing (97 NBBALs, 10 lung aspirate, and 7 pleural aspirates). CMV (42), Gram negative bacteria (31), PCP (30), and TB (25) were the most commonly isolated organisms in non-responders. 60% of non-responders had more than one organism isolated. Four HIV exposed but uninfected children had PCP. We proved mother to child transmission of PCP in one of these children.

Conclusions: Children in an HIV endemic area should be treated as HIV infected until proven otherwise. HIV exposed but uninfected children also appear to be at an increased risk of pneumonia. HIV infected children are more likely to fail standard treatment. 13% of all infants had PCP, therefore high dose co-trimoxazole should be included in the treatment regimen for infants in HIV endemic areas.

G234 COMPLETE ABSENCE OF PENICILLIN RESISTANCE IN 118 NASOPHARYNGEAL (NP) PNEUMOCOCCAL ISOLATES IN 234 CHILDREN ATTENDING DAY CARE

A. Roche, M. Sharland, P. T. Heath, J. Haigh, A. Breathnach, D. Strachan. Department of Community Health Sciences, St George’s Hospital Medical School; Paediatric Infectious Disease Unit and Department of Medical Microbiology, St George’s Hospital NHS Trust, London

Background: There is an association between a child’s attendance at day care and their risk of bacterial colonisation of the nasopharynx. There are also concerns that day care centres may be a focus for transmission of antibiotic resistant organisms. A large expansion of pre-school day care provision is planned in the UK. There are very limited local data on bacterial carriage and antibiotic resistance in this setting.

Aim: To estimate the prevalence of nasopharyngeal carriage of Streptococcus pneumoniae and describe the antibiotic resistance patterns and serotypes in children attending day care in an inner London borough.

Methods: Nineteen child day care centres (CDCCs) in Wandsworth participated in the study between 24.03.03 and 12.11.03; 264 parents consented for their children to have a single NP swab and completed a questionnaire about their child’s health and attendance at day care. NP swabs were collected and transported in line with the WHO standard method for detecting pneumococcal carriage. Pneumococcal isolates were sent in batches to the Respiratory and Systemic Infection Laboratory of the Health Protection Agency for serotyping.

Results: 234 swabs were collected from children aged 6 months to 5 years. 54% were boys and 80% were white. 118 children carried pneumococcus in their nasopharynx. The prevalence of pneumococcal carriage was 50% (95% CI 44% to 56%). The rate of carriage across five age groups ranged from 44% (3–4 year olds) to 62% (1–2 year olds). 48 of the first 94 isolates tested (51%) were serotypes that would be covered by the 7-conjugate vaccine. None of the isolates were resistant to penicillin. The upper confidence limit for the prevalence of penicillin resistant pneumococci was calculated to be 3%. 21 isolates (17.7%) were resistant to erythromycin.

Conclusion: Overall the prevalence of pneumococcal NP carriage was higher than expected and consistent across age groups and over the study period. Our results are comparable with the findings of other day care carriage studies conducted around the world. However, the prevalence estimate for penicillin resistant pneumococci of less than 3% is considerably lower than that found across Europe or America, with the exception of The Netherlands. This may be related to the fall in community antibiotic prescribing seen in England in the past decade.

G235 EFFECTS OF COMBINATION ANTIRETROVIRAL THERAPY (CART) ON PAEDIATRIC METABOLITE LEVELS

M. P. Rhoads1, C. Smith2, G. Tudor-Williams1, P. Kyd3, S. Walters1, C. Sabin2, E. G. H. Lyall3. 1Imperial College London, London; 2Royal Free and University College London, London; 3St Mary’s Hospital, London

Aims: Treatment for HIV is extending survival into adulthood, which raises concerns about long term effects of metabolic changes in childhood.

Methods: This is a retrospective longitudinal study of the significance, extent, and frequency of raised metabolites in paediatric HIV patients before and on CART from Jan 2000 to June 2003. Routine non-fasting blood analyses included cholesterols (total C, HDL, LDL), triglyceride (TG), lactate (L), and glucose (G). Mixed effects regression models (SAS software) were used to analyse effects of CART on these metabolites.

Results: 146 (78 female) children aged 0.1–16 (6.9) years attended 1208 clinic visits, median 6.7 (1–23) visits each. 68% were from Africa. At baseline, 75 children were on therapy (30 on PI). Children on treatment had higher median total C (p 0.0001), HDL (p 0.0001), and LDL (p 0.0003), by 0.7, 0.21, and 0.43 mMol/L respectively. PI v non-PI recipients had higher cholesterols and lower L. 82% of follow up visits were for children on CART (42% including PI). Over time of follow up, in mixed effect regression, total C increased by 0.07 mMol/L/year of therapy (p 0.0001), and 53 patients (46.1%) had at least one high total C (>5 mMol/L) on treatment. There was no effect on L, TG, or G with time on CART but L declined with increasing age (p 0.0001). Over time the baseline effect of class of therapy on cholesterols lost significance. Africans had significantly lower total C, TG, LDL, and total C/HDL ratio than Caucasians.

Conclusions: To date, this is the largest reported longitudinal paediatric study of metabolites and CART. As no effect was seen on L with CART, we recommend measuring L only in symptomatic patients. CART raises cholesterol above normal basal levels and this increases with longer exposure. As HIV and CART may increase cardiovascular risk, monitoring lipids in children remains an important component of management. Drug developments for children should focus on reducing metabolic side effects.

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