[Antipsychotics and metabolic abnormalities in children and adolescents: a review of the literature and some recommendations]. / Antipsychotica en metabole afwijkingen bij kinderen en adolescenten; een literatuuroverzicht en aanbevelingen voor de praktijk.

BACKGROUND: Adult patients with schizophrenia and bipolar disorder have an increased risk of developing the metabolic syndrome. This is due to their psychiatric illness and to the use of antipsychotic drugs. Children and adolescents are being treated more and more with antipsychotics. The risk of metabolic abnormalities in this age group remains unclear. AIM: To investigate the relationship between psychotic disorders in childhood and metabolic abnormalities and to study the influence of the use of both typical and atypical antipsychotics on this relationship. METHOD: The PubMed database was searched for relevant articles published between 2000 and June 2009. RESULTS: So far, research into the relationship between psychiatric disorders and metabolic abnormalities in children and adolescents has been inadequate. The normal values and meaning of the components of the metabolic syndrome in children and adolescents have not yet been firmly established. Children and adolescents who use antipsychotics run a significantly higher risk of weight gain. The younger the child, the greater the risk. There are no data about the risk of developing diabetes mellitus type 2. The influence of typical antipsychotics on these conditions has not been investigated. CONCLUSION: The risk of significant weight gain due to the use of atypical antipsychotics is greater in younger children. The 'metabolic syndrome' concept is not applicable to children and adolescents. Very little is known about metabolic risks in the long term. Caution is called for in the prescription of antipsychotics for children and adolescents and further research is needed.

Children with unexplained chronic pain: substantial impairment in everyday life.

AIMS: To describe and quantify impairment in an outpatient population of children with chronic pain of unknown origin (UCP). METHODS: A total of 149 children who presented with pain of at least three months' duration and without a satisfactory explanation at presentation were studied. Number of somatic complaints (Children's Somatisation Inventory, CSI), pain intensity (VAS, 0-10 cm), functional disability (Child Health Questionnaire (CHQ-CF) and clinical history), and general health perceptions (CHQ) were determined. RESULTS: Mean age of the children was 11.8 years; 73% were girls. Overall, 72% suffered impairment in sports activities, 51% reported absence from school, 40% experienced limitations in social functioning, and 34% had problems with sleeping. Mean number of somatic symptoms differed significantly between boys (8.4) and girls (10.7). The CHQ-CF scores for physical functioning, role/social functioning, and general health perceptions were 76.4, 70.7, and 57.5, respectively, indicating substantial impairment on all domains. The mean pain intensity was 4.7 for current and 7.1 for worst pain. Children solely evaluated by a general practitioner prior to referral reported less, though still substantial, impairment. Low general health perceptions, impaired role/social functioning, high pain intensity, and having headache or musculoskeletal pain were independent predictors of having significant impairment. CONCLUSIONS: Referred children with UCP show substantial impairment on multiple domains in daily life.

Clinical and virologic response to combination treatment with indinavir, zidovudine, and lamivudine in children with human immunodeficiency virus-1 infection: a multicenter study in the Netherlands. On behalf of the Dutch Study Group for Children with HIV-1 infections.

OBJECTIVE: To evaluate the clinical, immunologic, and virologic response to indinavir, zidovudine, and lamivudine in children with human immunodeficiency virus-1 (HIV-1) infection. STUDY DESIGN: Twenty-eight HIV-1-infected children (3 months to 16 years of age) with or without prior treatment with reverse-transcriptase inhibitors and a HIV-1 RNA >5000 copies/mL and/or a CD4 cell count less than the lower limit of the age-specific reference value were treated with indinavir, zidovudine, and lamivudine. Pharmacokinetics of indinavir were determined in each child. RESULTS: The combination treatment was well tolerated in the majority of patients. Clinical improvement was seen in all patients. After 6 months of therapy, 70% of the patients had an HIV-1 RNA load below 500 copies/mL, whereas 48% of the children had a viral load below 40 copies/mL. Relative CD4 cell counts in relation to the lower limit of the age-specific reference value increased significantly from a median value of 79% at baseline to 106% after 6 months of therapy. The doses of indinavir necessary to achieve area under the curve values comparable to adult values varied from 1250 mg/m(2)/d to 2450 mg/m(2)/d. CONCLUSIONS: Highly active antiretroviral therapy consisting of indinavir, zidovudine, and lamivudine in children reduced HIV-1 RNA to less than 500 copies/mL in 70% of the children within 6 months. Improved CD4 cell counts were observed in most patients, as was a better clinical condition (no invasive or opportunistic infections, increased weight gain). Side effects of the triple therapy were mild. Highly active antiretroviral therapy can be used as successfully in children as in adults.

[Team care: a necessity for a child with HIV infection]. / Teamzorg: een noodzaak voor het met HIV geïnfecteerde kind.

In four children, a boy aged 2.5 years, a girl of 4, her brother of 7 years and a girl aged 10 months, HIV infection was diagnosed. Since 1996 HIV-infected children in the Netherlands are treated with a combination of two nucleoside analogs and a protease-inhibitor. This therapy improves the quality of life, increases the life expectancy of HIV-infected children and is generally well tolerated. However, the current combination therapy is complex and puts a burden on the child and the family. Therefore, long term compliance will be difficult. Moreover, the majority of the families have extremely difficult social circumstances which interfere with an optimal medical treatment for the child. The parents of three of the children were refugees from African countries. Intensive support of the family by a team of health care and social workers is usually necessary to make antiretroviral combination therapy possible. Care directed at the individual needs of the child and family is crucial to help this vulnerable group of children and families in our society.

[Increase of reported HIV-1 infections in children in Netherlands, 1982-1997: more vertical transmission and a greater proportion of other than Dutch children]. / Toename van gemelde HIV-1-infectie bij kinderen in Nederland, 1982-1997: meer verticale transmissie en groter aandeel van allochtone kinderen.

OBJECTIVE: To document the trend of the yearly number of newly diagnosed paediatric HIV-1 infections in the Netherlands. DESIGN: Retrospective registration regarding the period January 1st 1982-December 31st 1994 and prospective registration regarding January 1st 1995-December 31st 1997. METHOD: Based on reports to the Dutch Paediatric Surveillance Unit (Nederlands Signaleringscentrum Kindergeneeskunde) numbers of paediatric HIV-1 diagnoses (0-18 years) in the Netherlands were determined prospectively. Retrospective figures were determined by asking the paediatricians also to report the HIV-1 infected children diagnosed before the first of January 1995. A comparison was made with data from the Inspectorate for Health Care (Inspectie voor de Gezondheidszorg). All reports were followed up with standard questionnaires. RESULTS: In both periods an increase in the number of newly diagnosed paediatric HIV-1 infections per year in the Netherlands was seen (1982-1994: 74 children; 1995-1997: 43 children). The majority of the parents of the HIV-1 infected children originated from outside the Netherlands (1982-1994: 57%; 1995-1997: 91%), often from HIV-endemic countries (1982-1994: 41%; 1995-1997: 77%). The main mode of infection was vertical transmission (1982-1994: 62%; 1995-1997: 84%); diagnosis in allochtonous children was made relatively late. CONCLUSION: The current rise in the absolute number of newly detected paediatric HIV-1 infections in the Netherlands is predominantly due to the growing group of children born to parents who originate from HIV-endemic countries.

[Invasive streptococcal infection as a complication of chickenpox]. / Invasieve streptokokkeninfectie als complicatie van waterpokken.

Two girls aged 11 months and 6 years, presented with an invasive group A streptococcal (GAS) infection during the course of primary varicella. The infant had severe cellulitis of the left arm and leg, fever and bacteraemia. She developed osteomyelitis of ulna and tibia. The 6-year-old girl had a fever > 38.5 degrees C, hypotension, an acute respiratory distress syndrome, liver function abnormalities, and positive cultures of blood and joints. Her clinical picture was compatible with a GAS-associated toxic shock syndrome. If during the course of primary varicella persistent fever, secondary fever or pain in one or more extremities occurs, invasive bacterial infection by GAS or Staphylococcus aureus should be considered, even in the absence of skin infection or cellulitis.

[Vertical HIV-I-transmission. II. HIV-diagnosis in a child]. / Verticale HIV-I-transmissie. II. HIV-diagnostiek bij het kind.

In newborn children from HIV-infected women early establishment of HIV infection is of importance for optimal therapy of HIV-infected children and avoidance of unnecessary medication in uninfected children. A more than 95% reliable diagnosis of HIV infection can now be obtained at the age of four weeks by polymerase chain reaction (PCR) technology. Before this age a positive PCR result is relevant since it necessitates additional investigation such as measuring anti-HIV drug resistance and may lead to modification of anti-HIV treatment. Prophylaxis against Pneumocystis carinii is not needed if HIV infection can not be demonstrated by PCR after the age of four weeks.

An immunocompetent infant with cow's milk allergy and cytomegalovirus colitis.

UNLABELLED: A 5-week-old, severely ill, infant is described with diarrhoea and rectal bleeding, followed by vomiting and dehydration after introduction of a cow's milk formula. A diagnosis of cow's milk allergy was made because of the clinical presentation of an allergic enterocolitis, the rapid improvement after introduction of a hypo-allergenic formula and development of colic directly after rechallenge with cow's milk. Furthermore a highly specific IgE for alpha-lactalbumin strongly supported the diagnosis. Because of recurrent rectal bleeding a limited colonoscopy was performed at the age of 10 weeks. Surprisingly a second diagnosis of histopathologically proven cytomegalovirus (CMV) colitis was made. Extensive immunological screening revealed no signs of immunodeficiency. The child thrived without any treatment for CMV and developed normally. This is the first description of an immunocompetent infant with CMV colitis. CONCLUSION: It cannot be excluded that the allergic colitis facilitated the CMV colitis, or vice versa CMV colitis triggered cow's milk protein induced entero-colitis. Further attention should be given to children with bloody diarrhoea to establish a possible relationship between CMV infection and cow's milk protein allergy.

Antineutrophil cytoplasmic antibodies in juvenile chronic arthritis.

OBJECTIVE: To evaluate the diagnostic significance of antineutrophil cytoplasmic antibodies (ANCA) by assessing the prevalence of ANCA in juvenile chronic arthritis (JCA) (n = 93) of either oligoarticular, polyarticular, or systemic onset. To investigate the prevalence of ANCA in other diseases of childhood characterized by chronic inflammation (n = 44), such as cystic fibrosis, juvenile diabetes mellitus, and connective tissue diseases. METHODS: Indirect immunofluorescence on both ethanol and paraformaldehyde fixed neutrophils, ELISA for specific antigens, Western blotting using sonicated neutrophils. RESULTS: ANCA were detected in the sera from 35% of patients with JCA, and in only 7% of patients with other inflammatory diseases. Regarding the onset type of JCA, ANCA were present in 44% of patients with oligoarticular onset, in 36% with polyarticular onset, and in 16% with systemic onset. All but one ANCA positive serum sample produced a perinuclear fluorescence pattern on ethanol fixed granulocytes. However, on neutrophils fixed with paraformaldehyde either a cytoplasmic (14%) or a nuclear (23%) staining pattern was observed, suggesting that both cytoplasmic and nuclear autoantibodies occur in JCA. Further characterization studies showed that ANCA in JCA are not directed against proteinase 3, elastase, or myeloperoxidase. On Western blots ANCA in JCA incidentally showed reactivity with either lactoferrin (5%) or 2 polypeptides of 66/67 kDa (9%). CONCLUSION: Prevalence and antigenic specificity of ANCA in JCA are clearly different from adult onset rheumatoid arthritis or other juvenile chronic inflammatory disorders.

Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell-depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the alpha chain of the leukocyte function-associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell-depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

Problems and possible solutions in finding an unrelated bone marrow donor. Results of consecutive searches for 240 Dutch patients.

To evaluate the efficiency of our protocol for finding an HLA matched unrelated bone marrow donor, search results obtained between 1990 and 1995 for 240 Dutch patients were analyzed. The percentage of patients for whom, according to information given by the registries, a fully split-HLA antigen matched donor is available, increased from 24% in 1990 to over 70% in 1995. As a result the percentage of patients transplanted rose from about 24% in 1990-1991 to 44% in 1994-1995. The median time between the start of the search and transplantation was about 6 months. The systematic use of Bone Marrow Donors Worldwide (BMDW) which comprises the HLA groups of all volunteer bone marrow donors in Europe, Israel, South Africa, North America, Canada, India, Australia and New Zealand has been essential in this context. While searching for a suitable donor several problems were encountered such as unavailability of donors (12%) and discordant typing results (8%; range < 1% to > 25%). Thus it is advisable to select several donors for a patient. For 86% of patients with at least one HLA identical donor on the serological level for HLA-A,-B,-DR,-DQ, an HLA-DRB1/3/4/5, and -DQB1 identical donor could be identified. As expected, patients with two frequent haplotypes in strong linkage disequilibrium had the best chance of obtaining an HLA matched donor. Unexpectedly, patients with only one such haplotype had an almost similar chance. It could be calculated that HLA-DR typing of HLA-A,-B identical donors was rarely cost-effective after 1992. Only 12 of the 75 transplanted patients (16%) typeable at DNA level for class II, turned out to be completely matched for HLA-A,-B,-C,-DRB1/3/4/5,-DQB1,-DPB1 and had a negative MLC test. In the group of patients transplanted with a fully matched donor and for whom a CTLp test was performed, only 7% (4/54) of the tests were negative. Search results for patients of non-European origin were dismal, with only four of 26 patients referred being transplanted. In summary, of the 240 patients for whom the Europdonor office searched for a donor, about one-third were transplanted, one-third had a potential donor but did not reach transplantation, while for the remaining one-third of patients no suitable donor could be found.

Autoreactivity to human heat-shock protein 60 predicts disease remission in oligoarticular juvenile rheumatoid arthritis.

OBJECTIVE: To determine whether T lymphocyte reactivity to endogenous human hsp60 plays a regulatory role in the course of oligoarticular juvenile rheumatoid arthritis (JRA). METHODS: A prospective, longitudinal study of T cell reactivity to HSP in 15 patients with newly diagnosed HLA-B27 negative oligoarticular JRA was performed. Results were compared with those in a group of 20 patients with newly diagnosed polyarticular or systemic JRA or with acute arthritis caused by other systemic diseases or viral infections, as well as with those in a group of 9 healthy control subjects. RESULTS: In 86% of the patients with oligoarticular JRA (13 of 15), significant T lymphocyte proliferative responses to hsp60 were found in peripheral blood mononuclear cells and/or synovial fluid mononuclear cells within 3 months after the onset of arthritis. Only 5% of the patients in the rheumatologic disease control group (1 of 20) showed such positivity. All patients with oligoarticular JRA and positive responses to human hsp60 developed a remission of their disease within 12 weeks. During this period of remission, blood samples were taken from 8 patients and showed significantly lower and even negative responses to hsp60, compared with active disease, when all 8 patients had good responses. CONCLUSION: The results show that significant proliferative responses to human hsp60 can be found early in the course of oligoarticular JRA. Furthermore, these responses correlate with disease activity in such a manner that T cell reactivity to human hsp60 seems to be associated with disease remission.

Juvenile chronic arthritis: T cell reactivity to human HSP60 in patients with a favorable course of arthritis.

Synovial fluid and peripheral blood mononuclear cell proliferative responses to the 60-kD human heat shock protein (HSP60) were studied in 23 patients with juvenile chronic arthritis (JCA) and 7 non-JCA control patients. All patients showed active arthritis at the time of study. The patients were divided into two groups according to the presence (group A) or absence (group B) of T lymphocyte reactivity to human HSP60. We show that reactivity to human HSP60 is primarily, though not exclusively, occurring in patients with a remitting course of disease, i.e., the subgroup of HLA-B27 negative JCA patients with an oligoarticular onset. Immunohistochemical analysis of HSP expression in synovial membranes showed a significantly higher intensity of staining in JCA patients than in non-JCA controls. The results suggest that, in accordance with the earlier observation made in experimental models, T lymphocyte reactivity to human HSP60 in this subgroup of JCA patients may be part of T cell regulatory mechanisms that control the development of arthritis.

Prevalence of circulating immune complexes in patients with cystic fibrosis and arthritis.

We report the clinical and laboratory characteristics of eight patients with cystic fibrosis (CF) and arthropathy. Five patients had frequently relapsing, episodic arthritis; one had chronic arthritis with high titers of rheumatoid factors that could not be distinguished from juvenile chronic arthritis. In two patients the arthropathy did not relapse. Forty-six patients with CF but without arthropathy, seen during the same 1-year period, served as control subjects. Results of lung function tests and sputum cultures were similar in both groups. The sera of six of the eight patients with CF-arthropathy had high levels of circulating immune complexes, measured both by C1q-binding and the indirect granulocyte phagocytosis test, whereas only 1 of 12 control patients tested had positive C1q binding (p < 0.023). Serum complement levels were normal in both groups. Synovial biopsies, performed in three patients, showed only scanty lymphocytic infiltrates; immunofluorescent staining showed deposits of IgM, IgG, and components of complement C1q, C3, and C4. These findings suggest that the arthropathy found in CF is an immune-mediated phenomenon.

Antibodies to human HSP60 in patients with juvenile chronic arthritis, diabetes mellitus, and cystic fibrosis.

The 60-kD heat shock protein (hsp60) has been implicated in the etiology and pathogenesis of both experimental and naturally occurring autoimmune diseases such as juvenile chronic arthritis (JCA). Human hsp60 is expressed in inflamed synovial tissue, and T lymphocytes both from peripheral blood and synovial fluid show reactivity to human hsp60. Because the anti-hsp60 B lymphocyte response has been less well studied, we have determined the occurrence of IgG anti-human hsp60 antibodies in patients with JCA and various other autoimmune diseases of childhood. Serum IgG anti-human hsp60 antibodies in JCA patients were significantly higher compared with control children (358 and 163 U/mL, respectively). Within the group of JCA patients, the highest antibody titers were found in the subgroup with a polyarticular onset of JCA. IgG anti-human hsp60 antibody levels in synovial fluid were 3- to 4-fold higher compared with paired serum samples. Because this difference was not found for total IgG or for irrelevant antibodies (anti-polyribosylribitol phosphate), this suggests local anti-hsp60 antibody production in the synovial compartment. The occurrence of anti-hsp60 antibodies is not specific for JCA but also is found in children with systemic lupus erythematosus and in cystic fibrosis, whereas mixed connective tissue disease and insulin-dependent diabetes are negative in this respect. Whether the anti-human hsp60 antibodies are directed toward species-specific sequences or to conserved sequences of the hsp60 molecule remains to be determined.

[The treatment of 12 HIV-infected children with zidovudine]. / Behandeling van 12 met HIV geïnfecteerde kinderen met zidovudine.

12 HIV-infected children were treated with a high dose of zidovudine (800/mg/m2/day) during a mean follow up period of 18 months. After starting treatment with zidovudine there was a subjective improvement and an increase in body weight, and a significant decline in serum HIV-antigenemia (p < 0.01) and serum IgG levels (p < 0.05). Zidovudine was generally well tolerated but there was serious hematological toxicity. In 9 patients (75%) dose reduction was necessary because of severe anemia (3 patients) or leucopenia (6 patients). Because of the high incidence of these side effects the starting dose of zidovudine was reduced to 600 mg/m2/day. These results confirm that zidovudine can safely be used to treat HIV-infected children. The main limitation is serious hematological toxicity which appears to be dose-related.

Heat-shock proteins and juvenile chronic arthritis.

Heat-shock proteins are a category of proteins that are synthesized under stressful conditions (such as increased temperatures) both by prokaryotic and eukaryotic cells. Heat-shock proteins are a major target of the immune response and thus can be considered dominant antigens. Under physiological circumstances the response to heat-shock proteins is considered to play a role in the overall defence against bacterial infections. An aberrant immune response against heat-shock proteins may lead to autoimmunity, as illustrated by adjuvant arthritis in Lewis rats. Current evidence also points towards a role of T cell immunity against heat-shock proteins in the development of human autoimmune diseases such as juvenile chronic arthritis.