Developmental immunology and vaccines: immune responses to vaccines in premature infants.

A comparatively small number of studies have assessed the safety, immunogenicity, efficacy and duration of immune responses in preterm infants compared with term infants for routinely recommended childhood immunizations.

The relationship between health-related quality of life, pain and coping strategies in juvenile idiopathic arthritis.

OBJECTIVES: To investigate the relationship between health-related quality of life (HRQL), experience of pain and pain coping strategies in children with juvenile idiopathic arthritis (JIA). To compare reports describing these variables obtained from children and their parents. METHODS: Participants were 59 children aged 8 to 18 yr with JIA and their parents. Parents and children completed the PedsQL generic core scales and arthritis module, the visual analogue scale of the Varni-Thompson Pediatric Pain Questionnaire, and the Waldron/Varni Pediatric Pain Coping Inventory. Parents rated children's functional disability using the Childhood Health Assessment Questionnaire. RESULTS: Parents reported significantly lower scores (indicating worse HRQL) than children on five of the eight PedsQL scales rating children's HRQL. Parents and children reported a significant negative relationship between pain levels and the PedsQL scores assessing children's physical, emotional and social functioning. They also reported a significant negative relationship between scores on several pain coping scales and scores on the PedsQL scales. However, the pattern of these relationships varied for reports from parents and children. CONCLUSIONS: Pain intensity and pain coping strategies have a significant and independent relationship with several domains that comprise the HRQL of children with JIA. However, parents and children have differing perceptions of the nature of these relationships. The differences emphasize the importance of clinicians obtaining information about children's HRQL, pain levels and pain coping strategies from both parents and children.

The Fc receptor for IgG (Fc gamma RII; CD32) on human neonatal B lymphocytes.

B cells express an Fc receptor for IgG (FcgammaRII; CD32) which is involved in feedback inhibition of antibody production. Engagement of FcgammaRII during ligation of the antigen receptor provides an inhibitory signal. FcgammaRII exists as several isoforms, with FcgammaRIIb (which carries an immunoreceptor tyrosine-based inhibition motif; ITIM) being predominant form on adult B cells. The inhibitory role of FcgammaRIIb may be unhelpful to the infant, since primary exposure to infectious agents is likely to be in the presence of maternal IgG. We hypothesized that neonatal B cells would be less susceptible to feedback inhibition by antibody, either through the expression of activation-competent FcgammaRII isoforms (FcgammaRIIa and FcgammaRIIc) or through reduced expression of the inhibitory FcgammaRIIb isoforms. Cord and adult B cells were examined for expression of FcgammaRII isoforms using monoclonal antibodies and RT-PCR. In vitro assays were performed to assess susceptibility of cord and adult cells to FcgammaRII-mediated suppression. Although there is no phenotypic difference in FcgammaRII expression (FcgammaRIIb predominating on both adult and cord B cells), FcgammaRIIb is expressed at lower levels on cord cells. This quantitative difference in FcgammaRIIb expression may explain the reduced susceptibility of cord B cells to antibody-mediated inhibition observed in these experiments.

Storage at -3 degrees C for 24 h alters the immunogenicity of pertussis vaccines.

The immunogenicity of pertussis antigens in an acellular and a whole-cell triple antigen vaccine used for childhood immunisation was assessed in murine models after storage of vaccines below 0 degree C. Swiss outbred and Balb/c mice received DTPa or DTPw vaccine or placebo. Vaccines were stored at 2-8 degrees C (ideal), or at -3 degrees C for 24 h. Pre and post immunisation IgG responses to pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) were measured using enzyme immunoassays (EIA). In Balb/c mice, responses to pertactin after receiving adversely stored DTPa were significantly reduced (P = 0.005, difference in GMCs 145.9% [24.6-385.4%]). A reduction in GMC to pertactin was also seen in response to adversely stored DTPw (P = 0.190,224.1% [83.8-599.2%]). Outbred mice receiving adversely stored DTPa had lower IgG antibody responses to FHA than those receiving correctly stored vaccine (P = 0.002,522.2% [26.1-2155.6%]). Outbred mice also had a significantly lower response to FHA after administration of DTPw (P = 0.009,14.0% [3.8-51.9%]). Responses to DTPa in both strains generally were greater than those to DTPw. Storage of pertussis vaccines below 0 degree C appears to alter the immunogenicity of PRN and FHA. Further study is required to determine the effects of such storage on vaccine protective efficacy.

Regulation of human neutrophil-mediated cartilage proteoglycan degradation by phosphatidylinositol-3-kinase.

The ability of neutrophils to degrade cartilage proteoglycan suggests that the neutrophils that accumulate in the joints of rheumatoid arthritis patients are mediators of tissue damage. The regulatory mechanisms which are relevant to the proteoglycan-degrading activity of neutrophils are poorly understood. Since phosphatidylinositol 3-kinase (PI3-K), protein kinase C (PKC), the extracellular signal-regulated protein kinase (ERK)1/ERK2 and cyclic adenosine monophosphate (cAMP) have been reported to regulate neutrophil respiratory burst and/or degranulation, a role for these signalling molecules in regulating proteoglycan degradation was investigated. Preincubation of human neutrophils with GF109203X (an inhibitor of PKC), PD98059 (an inhibitor of MEK, the upstream regulator of ERK1/ERK2) or with forskolin or dibutyryl cAMP, failed to suppress proteoglycan degradation of opsonized bovine cartilage. In contrast, preincubation of neutrophils with wortmannin or LY294002, specific inhibitors of PI3-K, inhibited proteoglycan degradation. Incubation of neutrophils with cartilage resulted in the activation of PI3-K in neutrophils, consistent with a role for PI3-K in proteoglycan degradation. Activation of PI3-K and proteoglycan degradation was enhanced by tumour necrosis factor-alpha. Degradation caused by neutrophils from the synovial fluid of rheumatoid arthritis patients was also inhibited by wortmannin. These data demonstrate that the proteoglycan degradative activity of neutrophils required PI3-K but not PKC or the ERK1/ERK2/ERK5 cascades and was insensitive to increases in intracellular cAMP concentrations.

Expression of the costimulator molecules, CD40 and CD154, on lymphocytes from neonates and young children.

Differential expression of the costimulator molecules CD40 and CD154 on neonatal lymphocytes may be one explanation for limited T-dependent antibody responses in human neonates. CD40 was expressed at similar levels on resting B cells from adults, young children (2-20 months of age) or cord blood. CD40 expression was higher on cord blood B cells compared to adult B cells after stimulation with PMA and ionomycin, but similar on adult and cord blood B cells activated by CD3-stimulated T cells. In contrast to previous reports, cord blood T cells stimulated with PMA and ionomycin expressed adult levels of CD154 initially, but this expression was more transient on cord blood T cells. When adult and cord blood mononuclear cells were stimulated with CD3 mAb, T cells from some cord blood specimens showed different kinetics of CD154 expression compared with adult T cells. However, some cord blood specimens showed adult patterns of T cell CD154 expression. When mononuclear cells were depleted of B cells and monocytes prior to stimulation with CD3 mAb, the MFI and percentage of T cells expressing CD154 increased, with adult and cord T cells showing similar patterns of expression. These results show some differences in expression of CD40 and CD154 between neonatal and adult lymphocytes, but do not directly account for the relative deficiencies of humoral immunity in neonates.

Expression of the costimulator molecules, CD80, CD86, CD28, and CD152 on lymphocytes from neonates and young children.

The expression of CD80, CD86, CD28, and CD152 were examined on peripheral blood lymphocytes from adults, neonates (cord blood lymphocytes) and young children (2-20 months of age). There was no difference in the expression of CD80 or CD86 between adult and neonatal B cells, either resting or activated. A higher percentage of resting T cells expressed CD28 in neonates and young children compared to adults. CD28 expression was similar on adult and neonatal T cells activated with PMA and ionomycin. However, CD28 was expressed at greater intensity on a higher percentage of neonatal T cells than adult T cells stimulated with CD3. CD152 expression was lower on neonatal T cells than adult T cells stimulated with PMA and ionomycin and undetectable on neonatal T cells stimulated with CD3. In contrast, intracellular CD152 was equivalent in adult and neonatal T cells stimulated with PMA and ionomycin, suggesting trafficking of CD152 to the cell surface may be differentially regulated in neonatal T cells. Since the T cell response is determined by the balance of signals received from CD28 and CD152, high levels of CD28 expression and lower surface expression of CD152 on neonatal T cells may represent specialisation to promote activation of neonatal T cells.

Medical student education in paediatrics and child health: where are we going?

In most undergraduate medical curricula, learning is becoming less content based and the emphasis is changing to problem based learning, continuing self directed learning, and the use of a wide range of learning resources. Particular needs in paediatrics and child health are an increasing emphasis on learning in ambulatory care and community based health facilities, and on assessment processes which are formative and reflect the learning objectives appropriately. A wide range of resources is needed for learning at a time when teaching hospital and health system facilities face significant financial restraints.

Somatic hypermutation of immunoglobulin genes in human neonates.

The antibody response in the young infant is limited in several ways; in particular, responses generally are of low affinity and restricted to IgM. This raises the question whether the affinity maturation process, consisting of somatic mutation of immunoglobulin genes coupled with selection of high-affinity variants, is operative in the neonate. Re-arranged V(H)6 genes were amplified by polymerase chain reaction (PCR) from cord blood and from peripheral blood of infants. Heteroduplex analysis detected mutation in only 2/18 cord blood samples, while mutations were seen from about 10 days of age onwards. Cloning and sequencing of mutated neonatal V(H)6 genes showed that mutated sequences contained relatively few mutations (one to three mutations per sequence) compared with published values of about 10 in adult IgM sequences. Selection was not evident in the majority of neonatal samples. Thus mutation can occur in the human neonate, but is minimal and generally not accompanied by selection. The age at which affinity maturation develops effectively is yet to be defined.

The antigen receptor complex on cord B lymphocytes.

The neonatal immune system responds to a restricted range of antigens, producing largely IgM antibody of low affinity. Comparison of the components of the B-cell antigen receptor complex shows significantly elevated membrane levels of IgM in neonatal B cells, compared with adult cells. CD79, which acts as the signal transducer for membrane immunoglobulin, is elevated in parallel with IgM, while IgD is elevated to a lesser degree. CD19, CD21, CD22 and CD81, which are all involved in transmitting activation signals when immunoglobulin is engaged, are not elevated. CD32, which is involved in negative regulation of activation, is present at reduced levels on cord B cells. The elevation of B-cell membrane IgM persists during infancy. Neonatal B cells respond in vitro to interleukin-4 (IL-4) by further elevation of membrane IgM levels. The elevated level of membrane IgM may make neonatal B cells easier to trigger by low concentrations of antigen, but in vitro activation and immunoglobulin modulation experiments did not show significant differences between cord and adult B-cell responses to anti-IgM.

The Fas antigen (CD95) on human lymphoid cells: epitope analysis with ten antibodies.

The expression of CD95 antigen was examined on adult and cord blood lymphocytes using a highly sensitive immunofluorescence/flow cytometric procedure. CD95 was expressed by the majority of circulating blood T cells in adults, and by a smaller proportion of CD4+ and CD8+ T cells in cord blood. The majority of circulating B cells did not react with seven CD95 antibodies, but three antibodies did stain B cells. In tonsil sections, CD95 was expressed throughout the tissue but germinal centres showed generally stronger staining than the surrounding follicular mantle and interfollicular areas. This was confirmed by flow cytometry, which showed expression preferentially on B cells with a germinal centre phenotype. Because different antibodies stained different proportions of B cells, CD95 epitopes were examined by inhibition, additive binding and protease susceptibility studies using a panel of ten CD95 antibodies. B cells apparently reacting selectively with CD95 antibodies were sorted and CD95 mRNA was reverse transcribed to cDNA and analyzed, in order to confirm the presence of CD95 in cells which reacted selectively and to explore the possible existence of CD95 isoforms. The major cDNA band was identical in the two populations. Inhibition of N-glycosylation suggested that the epitopes detected differentially could not be accounted for by differential N-glycosylation.

Pneumocystis carinii pneumonia in childhood systemic lupus erythematosus.

OBJECTIVE: Although Pneumocystis carinii pneumonia (PCP) is known to occur in adults with systemic lupus erythematosus (SLE), this infection has rarely been described in childhood SLE. We describe 3 children with SLE who developed PCP and describe risk factors for this complication. METHODS: A retrospective case review. RESULTS: All 3 children had severe active SLE with organ involvement requiring immunosuppressive therapy, but the clinical presentations of PCP differed in each patient. They shared some of the known risk factors for opportunistic infection in adults with SLE, including lymphopenia, but severe lymphopenia (< 0.35 x 10(9)/1) was not seen. CONCLUSION: PCP is an uncommon but serious complication of childhood SLE, and should be considered in the presence of respiratory symptoms, however subtle. The role of oral chemoprophylaxis is discussed.

Juvenile psoriatic arthritis: followup and evaluation of diagnostic criteria.

OBJECTIVE: To describe the course of juvenile psoriatic arthritis (JPsA) defined by the "Vancouver Criteria." METHODS: A retrospective review of JPsA in 63 children, (44 girls, median age at onset 4.5 yrs; 19 boys, median age at onset 10.1 yrs) who fulfilled the Vancouver Criteria, as follows. Definite JPsA: arthritis with psoriasis, or arthritis with 3 of 4 minor criteria (nail pits, dactylitis, psoriasis-like rash, family history of psoriasis); probable JPsA: arthritis with 2 of the minor criteria. RESULTS: At last followup, 50 children had definite JPsA and 13 had probable JPsA. Rheumatoid factor was absent in all; antinuclear antibody was present in 50%. Thirty-eight children were followed for > 5 yrs, 18 for > 10 yrs, and 7 for > 15 yrs. Forty-four children had active arthritis; 32% were in functional class I, 38% in class II, 22% in class III, and 8% in class IV. Of the 46 patients with oligoarticular onset, 21 remained oligoarticular, and 25 became polyarticular. Arthritis in the small joints of the hands and feet increased in frequency, with arthritis eventually occurring in proximal interphalangeal joints in 63%, metacarpophalangeal or metatarsophalangeal joints in 55%, and distal interphalangeal joints in 27%. Dactylitis occurred in 35%, most commonly in 2nd toes and index fingers. Nine patients (14%) developed chronic anterior uveitis. Eleven of 24 patients (46%) who initially had probable JPsA evolved to definite JPsA after a median of 2.1 yrs. Five developed psoriasis and the remainder developed additional minor criteria. The 13 patients with a current diagnosis of probable JPsA did not differ significantly from the 50 patients with definite JPsA with respect to number of joints involved at onset or during the disease course. Patients with psoriasis (n = 41) did not differ from those with definite JPsA without psoriasis (n = 9) with respect to the number of joints involved at onset or during the disease course, functional class, or need for 2nd line therapy. CONCLUSION: JPsA defined by the Vancouver Criteria is a relatively common chronic arthropathy of childhood that differs clinically, serologically, and genetically from both juvenile rheumatoid arthritis and juvenile ankylosing spondylitis.

Anaesthesia and recently vaccinated children.

Most countries have active vaccination programmes for children aged two months and older. It is likely that many children presenting for medical procedures which require general anaesthesia have been vaccinated recently. Although there is no evidence suggesting increased risks associated with anaesthetizing recently vaccinated children there are many theoretical reasons why this situation needs critical assessment and review. After vaccination there is local swelling and pain at the site of the injection and the most common side effects seen are fever, malaise, headache, rash and myalgia which may last from one day to three weeks. Anaesthesia, stress and trauma are known to suppress the immune system. It is suggested that if possible, children should not be subjected to anaesthesia for elective procedures within two to three weeks after vaccination. Urgent procedures should be managed according to anaesthetic principles which will minimize the effect of anaesthesia on the physiological system affected by the immunization process at the time. Paediatric anaesthesia risk management programmes should include vaccination data to enable the risks of anaesthesia in recently vaccinated children to be analysed.

Reduced expression of the interleukin-2-receptor gamma chain on cord blood lymphocytes: relationship to functional immaturity of the neonatal immune response.

Mutation of the interleukin-2 (IL-2) receptor gamma chain, which also serves as a component of the receptor complexes for IL-4, 7, 9 and 15, results in severe immune deficiency. We hypothesized that the immunological immaturity of healthy neonates might be associated with low levels of expression of this receptor molecule. Using monoclonal antibody and a highly sensitive immunofluorescence method, we showed that IL-2 receptor gamma chain is expressed at significantly lower levels on cord blood cells compared with adult cells. IL-2-dependent T-cell activation in vitro was reduced in cord blood cells compared with adult cells, but B-cell responses to IL-4 were not obviously impaired. The lower level of expression of the gamma chain and some other cytokine receptor chains may contribute to the immunological immaturity of the newborn, by selectively depressing particular immunological mechanisms.

Adverse outcomes of bacterial meningitis in school-age survivors.

OBJECTIVE: To determine the outcomes of bacterial meningitis in school-age survivors. DESIGN: Prospective cohort study. SETTING: Teaching pediatric hospital. CHILDREN: During 1983 through 1986, 158 meningitis survivors, ages 3 months to 14 years, treated at a single center were enrolled. Between 1991 and 1993, 130 children, 82% of the original cohort, were evaluated at a mean age of 8.4 years and a mean of 6.7 years after their meningitis. OUTCOME MEASURES: Blinded neurologic, neuropsychologic, audiologic, behavior, and socio-demographic assessments were compared with those from grade- and sex-matched control children. Multivariate analyses adjusted for age at testing and socio-demographic variables. RESULTS: There was a systematic increase in risk of abnormality or poorer functioning for children with meningitis, compared with control children, across all categories tested, which was significant for fine motor function, Intelligence quotient (IQ) scores, and tests of school behavior, neuropsychologic function, and auditory figure-ground differentiation. Eleven children who had experienced meningitis (8.5%) had major deficits (IQ < 70, seizures, hydrocephalus, spasticity, blindness, or severe to profound hearing loss); a further 24 (18.5%) cases and 14 (10.8%) control children had minor deficits (IQ 70 to 80, inability to read, mild to moderate hearing loss, abnormalities in speech discrimination, or school behavior problems). Overall, children who had meningitis were at greater risk (26.9%) for disability. Children with acute neurologic complications had more adverse outcomes than those with uncomplicated meningitis and control children (39% vs 18% vs 11%, respectively). CONCLUSIONS: One in four school-age meningitis survivors has either serious and disabling sequelae or a functionally important behavior disorder, neuropsychologic or auditory dysfunction adversely affecting academic performance. As a group, survivors function less well than their classroom peers, and risk is greatest for, but not confined to, those who had acute neurologic complications. All survivors require careful follow-up, at least until school age.

Atlantoaxial subluxation in children with seronegative enthesopathy and arthropathy syndrome: 2 case reports and a review of the literature.

We describe 2 HLA-B27 positive children with seronegative enthesopathy and arthropathy (SEA) syndrome who developed spontaneous (nontraumatic) atlantoaxial subluxation early in their disease course. Neither child had evidence of spinal cord compression but both had progressive atlantoaxial subluxation in spite of conservative treatment. Both underwent elective posterior cervical (C1-C2) fusion.

Activation of the neutrophil bactericidal activity for nontypable Haemophilus influenzae by tumor necrosis factor and lymphotoxin.

Previous studies have suggested that, in vivo, activated T lymphocytes and neutrophils are important in immunity to nontypable Haemophilus influenzae. We now extend this work by showing that neutrophils pretreated with products of activated T lymphocytes or activated macrophages show significantly enhanced killing of nontypable H. influenzae. Lymphotoxin, a product of activated T lymphocytes, significantly enhanced the neutrophil-mediated killing of nontypable H. influenzae, and tumor necrosis factor, produced by activated T lymphocytes as well as macrophages stimulated by activated T lymphocytes, also significantly increased the bactericidal activity of neutrophils. These cytokine-induced effects were seen with short pretreatment times of neutrophils and were maximal by 30 min. The killing of H. influenzae by neutrophils required the presence of heat-labile opsonins. In the absence of these opsonins, both tumor necrosis factor and lymphotoxin were unable to promote the killing of the bacteria by neutrophils. Furthermore, the results showed that tumor necrosis factor-primed neutrophils displayed significantly increased expression of CR3 and CR4 that was associated with increased phagocytosis of complement-opsonized nontypable H. influenzae. These cytokines may play an important role in immunity toward nontypable H. influenzae by stimulating neutrophil bactericidal activity.