Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus.

OBJECTIVE: To investigate the distribution of peripheral B cell subpopulations of children with active and inactive systemic lupus erythematosus (SLE) compared with healthy controls. METHODS: Peripheral B cell subpopulations of 11 children with SLE (6 with active and 5 with inactive disease) and 14 age matched normal healthy children were analysed. Active disease was diagnosed in children with a flare of SLE, who received treatment by i.v. cyclophosphamide or i.v. methylprednisolone pulse to control the disease. Additionally, the peripheral B cells of the children with SLE were compared with those of 13 consecutive patients with adult onset SLE. RESULTS: No major difference was found in the frequency and total number of CD27(-)/CD19(+) naïve B cells and CD27(+)/CD19(+) memory B cells between patients with active and inactive lupus and healthy controls, but there was a significant increase in CD27(high) expressing plasma blasts in patients with active SLE. These cells coexpress CD38(+), HLA-DR(dim), surface Ig(low) and lack the expression of CD20 but are clearly positive for intracellular Ig, indicative of early plasma cells. Most CD138(+) cells coexpress CD27(high)/CD19(+). The enhanced frequency of peripheral plasma blasts in children with active SLE is consistent with previous findings in adult patients with SLE, whereas a relative predominance of CD27(+) memory B cells was only identified in the adult patients. CONCLUSIONS: Profound abnormalities in the distribution of B cell compartments are more pronounced in older patients with SLE, but an enhanced frequency and cell number of peripheral plasma blasts is characteristic of both diseases during active stages. Thus detection of CD27(high) plasma blasts significantly correlates with active lupus in both children and adults.

Effect of low-dose cyclosporin a microemulsion on disease severity, interleukin-6, interleukin-8 and tumor necrosis factor alpha production in severe pediatric atopic dermatitis.

BACKGROUND: The release of cytokines [interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-alpha)] by skin cells is involved in the pathogenesis of atopic dermatitis (AD). OBJECTIVE: To evaluate the effect of low-dose cyclosporin A (CyA) on clinical symptoms and cytokine secretion in severe pediatric AD. METHODS: Ten children with severe AD (SCORAD index >50) were treated for 8 weeks with CyA. The initial dose of 2.5 mg/kg/day was titrated to a maximum of 5 mg/kg/day until a SCORAD reduction of >or =35% was achieved ("treatment response"). After stopping CyA all patients entered a 4-week follow-up period. Cytokine secretion (IL-6, IL-8 and TNF-alpha) from patients' PBMC was assessed by ELISA before and after CyA treatment and was compared with 18 healthy nonatopic controls. Only the data of patients, who responded to CyA and did not experience a relapse during the follow-up period, were evaluated for this paper. RESULTS: Seven patients responded to CyA without relapse during the follow-up period. The median SCORAD index in these patients improved from 71 at baseline to 22 after CyA treatment (p < 0.001). AD patients' PBMC produced more IL-6, IL-8 and TNF-alpha than PBMC of controls. Suppression of IL-6 (p < 0.05) and IL-8 (p < 0.05) production was observed after CyA treatment. TNF-alpha levels were unchanged by CyA in all patients. CONCLUSIONS: The reduction in severity of pediatric AD with CyA is associated with decreased production of IL-6 and IL-8, but not TNF-alpha by PBMC.

Low-dose cyclosporin A microemulsion in children with severe atopic dermatitis: clinical and immunological effects.

Cyclosporin A (CsA) is an effective and well-tolerated treatment for severe childhood atopic dermatitis (AD). By starting at a low dose, the therapeutic safety should be further increased. The aim of this study was to evaluate low-dose CsA in childhood AD with respect to clinical outcome and modulation of T-cell dysregulation. In an open prospective study, 10 children (age: 22-106 months) with severe AD (mean objective SCORAD score > 40 on two baseline measurements at a minimum interval of 2 weeks) were treated with CsA solution for 8 weeks. All patients received a starting dose of 2.5 mg/kg/day, which was increased stepwise in non-responders to a maximum of dose of 5 mg/kg/day. Disease activity was monitored using the SCORAD index. The frequency of cytokine-producing peripheral blood T lymphocytes was analyzed by intracellular cytokine staining, and T-cell numbers were measured by fluorescence-activated cell sorter (FACS) analysis. Twenty healthy age-matched children were included as controls for the immunological data. Nine of the 10 patients had a SCORAD reduction of at least 35%. In seven patients this was achieved with low-dose CsA at 2.5 mg/kg/day (n = 4) and 3.5 mg kg/day (n = 3). Seven of the nine responders experienced no relapse within the 4-week follow-up period. At baseline the percentage of interleukin-4 (IL-4), IL-13, and human leucocyte antigen (HLA)-DR-positive CD3(+) cells was higher in the patient group than in the controls. After CsA treatment there was a significant reduction in interferon-gamma (IFN-gamma), IL-2, IL-4, IL-13, and HLA-DR-positive CD3(+) cells. Hence, in severe pediatric AD, CsA microemulsion, when started at a low dose (2.5 mg/kg/day), improves clinical measures of disease, reduces T-lymphocyte cytokine production, and regulates T-cell activation.

Late clinical manifestation of cerebral tuberculomas in two children with tuberculous meningoencephalitis.

UNLABELLED: We report on two children with cerebral tuberculomas leading to late dramatic clinical exacerbation after appropriate antituberculous chemotherapy and high-dose corticosteroids. A 6-year-old girl with tuberculous meningoencephalitis initially fully recovered. However, after 9 months of continuous therapy she presented with acute increased intracranial pressure caused by tuberculomas requiring rapid drainage of CSF. A 16-year-old boy with miliary pulmonary tuberculosis and severe meningoencephalitis had reached a stable condition for more than 10 months although still suffering from a left-dominant spasticity and motor dysphasia. Fifteen months after initiation of therapy he presented with an acute central paralysis of the left facial nerve, progressive hemiplegia, severe ataxia and increasing lethargy caused by a cerebral tuberculoma with a perifocal oedema. Prolonged treatment with antituberculous chemotherapy and high-dose corticosteroids led to complete recovery in the younger patient and marked improvement in the older patient who remains severely handicapped. CONCLUSION: Patients with initially successful treatment of central nervous system tuberculosis should undergo an alert follow-up for the development of late cerebral tuberculomas. Treatment should consist of prolonged courses of antituberculous chemotherapy and high-dose corticosteroids.

Evidence for a disease-promoting effect of Staphylococcus aureus-derived exotoxins in atopic dermatitis.

BACKGROUND: The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization with Staphylococcus aureus. Some strains of S aureus secrete exotoxins with T-cell superantigen activity (toxigenic strains), and abnormal T-cell functions are known to play a critical role in AD. OBJECTIVE: Our purpose was to examine the impact of superantigen production by skin-colonizing S aureus on disease severity. METHODS: In a cross-sectional study of 74 children with AD, the presence and density of toxigenic and nontoxigenic strains of S aureus was correlated with disease severity. In a subgroup of patients the T-cell receptor Vbeta repertoire of peripheral blood and lesional T cells was investigated and correlated with individual superantigen activity of skin-colonizing S aureus. RESULTS: Fifty-three percent of children with AD were colonized with toxigenic strains of S aureus producing staphylococcal enterotoxin C, staphylococcal enterotoxin A, toxic shock syndrome toxin-1, staphylococcal enterotoxin B, and staphylococcal enterotoxin D in decreasing frequency. Children colonized with toxigenic S aureus strains had higher disease severity compared with the nontoxigenic and S aureus-negative groups. Patients colonized with toxigenic S aureus exhibited shifts in the intradermal T-cell receptor Vbeta repertoire that correspond to the respective superantigen-responsive T-cell subsets. CONCLUSION: The data demonstrate that S aureus-released exotoxins can modulate disease severity and dermal T-cell infiltration.

Prevalence and role of serum IgE antibodies to the Staphylococcus aureus-derived superantigens SEA and SEB in children with atopic dermatitis.

BACKGROUND: The skin of patients with atopic dermatitis exhibits a striking susceptibility to colonization and infection with Staphylococcus aureus. In this context it has been previously shown that S aureus-derived superantigens could function as classic allergens, inducing production of functionally relevant specific IgE antibodies. OBJECTIVE: The aim of this study was to determine the prevalence and the role of circulating staphylococcal enterotoxin A (SEA)- and staphylococcal enterotoxin B (SEB)-specific IgE antibodies in children with atopic dermatitis. METHODS: In a cross-sectional study of 58 children with atopic dermatitis, the presence of IgE antibodies to SEA and SEB was correlated with the severity of the disease and the total and other unrelated allergen-specific IgE titers and density of colonization with S aureus strains on atopic skin and episodes of superficial S aureus skin infections. RESULTS: Twenty of 58 children (34%) were sensitized to superantigens (45% to SEB, 10% to SEA, 45% to SEA and SEB). In this group, severity of atopic dermatitis and levels of specific IgE to food and air allergens were significantly higher. The degree of disease severity correlated to a higher extent with the presence of SEA/SEB-specific antibodies than with total serum IgE levels. Density of colonization with superantigen-secreting S aureus strains was higher in the superantigen IgE-positive group. Sixty-three percent of these children experienced repeated episodes of superficialS aureus skin infections. CONCLUSIONS: Sensitization to S aureus-derived superantigens may be involved in disease exacerbation. The presence of SEA/SEB-specific antibodies had additional explanatory value for disease severity and therefore may be helpful in the characterization of children with severe atopic dermatitis.

Neurodevelopmental outcome after prenatal exposure to opiates.

UNLABELLED: To study the developmental effects of prenatal exposure to opiates, a prospective follow up study of 34 drug-exposed (opiates and nicotine) and 42 reference infants (nicotine exposure only) was conducted from January 1992 to September 1995. At the time of delivery, 12 of 34 mothers used opiates without medical control. Twenty-two mothers participated in a methadone maintenance programme. At 1 year, the average Griffiths Developmental Quotient (DQ) was lower in the drug-exposed group (mean: 100.5 vs. references 107.9; P < 0.001). This difference was mainly due to lower subscales "locomotor" (mean 100.8 vs. 111.4; P < 0.05) and "intellectual performance" (mean 100.8 vs. 108.5; P < 0.05) in the drug-exposed group. Severe developmental retardation mean DQ (-2 SD) was diagnosed in 2 drug-exposed infants. Mild developmental retardation (mean DQ: 1 SD- > 2 SD) was found in 7 drug-exposed and in 3 reference infants (P < 0.05). Neurological abnormalities were found more frequently in the drug-exposed group (11 vs. 3 infants; P < 0.01). Among the opiate-exposed infants, the subscales "hearing and speech" and "intellectual performance" were lower in the uncontrolled drug-using than in the methadone group. The 17 fostered infants showed no difference in developmental outcome compared with the 10 infants living with their biological parents (mean DQ: 100.0 versus 101.3). CONCLUSIONS: At 1 year infants prenatally exposed to opiates are at risk for mild psychomotor developmental impairment.

Role of T cells in atopic dermatitis. New aspects on the dynamics of cytokine production and the contribution of bacterial superantigens.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease. Influx of activated T cells into the skin lesions represents a hallmark in AD. Recent results indicate a dynamic T-cell-derived cytokine production in AD. In addition to the well-known TH-2 component, chronic lesions and late-phase allergic responses are characterized by an TH-1/TH-0 cytokine pattern. Although there is no doubt that aeroallergens can contribute to the elicitation of acute- and late-phase allergic responses in AD, their role in the immunopathogenesis is controversally discussed. Recent attention has been given to the long-known phenomenon of persistent colonization of AD skin with S. aureus and the potential role of S. aureus-derived superantigens. Evidence from several in vitro and in vivo studies suggests that such bacterial superantigens have the potency to trigger chronic T-cell-mediated skin inflammation. Although these data are certainly suggestive, further clinical studies are required to elucidate the role of bacterial superantigens in initiation, maintenance and, especially, chronicity of skin inflammation.

[Immunologic findings in HIV infected children with bacterial infections]. / Immunologische Befunde bei HIV-infizierten Kindern mit bakteriellen Infektionen.

BACKGROUND: Bacterial infections are a major cause of illness in HIV-infected children. HIV-infected children with severe dysfunction of cellular and humoral immunity are particularly vulnerable. METHODS AND PATIENTS: We conducted a retrospective study to analyse the incidence and spectrum of bacterial infections in HIV-infected children compared to HIV-exposed but not infected controls related to their immunological status. Data collected during 1985 to May 1993 were evaluated considering 333 HIV-infected and 81 controls. RESULTS: During observation time 359 episodes (29% of the visits) of purulent rhinitis were diagnosed in HIV-infected children compared to the controls (53 episodes/8%); p = 0.0001. Comparable results were seen in otitis media. 178 episodes/14% were found in HIV-infected children and 66 episodes/10% in the controls (p = 0.001). 53 episodes/5% of bacterial pneumonia were represented in HIV-infected versus 11 episodes/2% in controls (p = 0.001). The increase of lymphocyte immune defect correlated to an increase of bacterial infections. This alterations were particularly observed in HIV-infected children with bacterial pneumonia. Severe dysfunction of cellular immunity was found in children with recurrent pneumonia compared to children with only one episode of bacterial pneumonia. The proliferate response of peripheral blood lymphocyte to pokeweed mitogen (13,351 cpm versus 3080 cpm); p = 0.009 and Concanavalin A (12,607 cpm versus 2470 cpm); p = 0.01 was significantly reduced in both groups, although the defect was much more pronounced in the group with the recurrent pneumonia. CONCLUSIONS: Our observations results showed that bacterial respiratory tract infections occurred significantly more frequently in HIV-infected children compared to an age related control group. Not only the occurrence of opportunity infections but also severe bacterial infections especially recurrent pneumonia are associated with a defect in cell-mediated immunity.

[Generalized molluscum contagiosum in an African child with AIDS]. / Mollusca contagiosa generalisata bei einem afrikanischen Kind mit Aids.

A 12-year-old girl from Zaire with AIDS (CDC: P2 D1) presented with a generalized molluscum contagiosum infection. She had suffered from systemic cryptococcosis and from cryptosporidiosis several months before admission. While molluscum contagiousum infection is usually a self-limiting disease in immunocompetent persons, a fulminant appearance and persistence of giant mollusca occurs with advanced immunodeficiency. Histological and immunohistological examinations showed a severe diminution of Langerhans and T cell populations that might enhance the dissemination of the infection. Molluscum-like lesions of cryptococci have been described, and cutaneous cryptococcosis is the main condition to be considered in the differential diagnosis. Further differential diagnoses should include American and African histoplasmosis, and the cutaneous manifestations of mycobacterial infections, of toxoplasmosis and of Pneumocystis carinii infection.

[Epidemiologic and clinical aspects of HIV infection in homosexual patients and intravenous drug addicts in a comparative study]. / Epidemiologische und klinische Aspekte der HIV-Infektion bei homosexuellen Patienten und intravenös Drogenabhängigen im Vergleich.

The clinical course of HIV-infection was analysed in a group of homosexual patients (n = 76, 72%) compared to intravenous drug abusers (IVDA, n = 30, 28%) in a retrospective cross-sectional study. The mean age of homosexual patients was 37.5 years compared to 28 years for IVDA. The following diseases are found significantly more frequently in homosexual patients compared to IVDA: Pneumocystis-carinii pneumonia (PCP) 17.1% vs. 0% (p < 0.05); Kaposi' sarcoma 16% vs. 0% (p < 0.05); diarrhoea 47.4% vs. 23.3% (p < 0.05); oral candidiasis 51.3% vs. 23.3% (p < 0.01); non-specific pneumonia of bacterial aetiology or due to unknown organisms 30% vs. 0% (p < 0.001) und seborrhoeic dermatitis 13.2% vs. 0% (p < 0.05). In contrast, viral hepatitis, non-specific abscesses and gonorrhoea were seen significantly more often in IVDA. The data show clearly that the spectra of HIV-associated diseases and HIV-unconnected diseases are significantly different in the two main groups. A risk-oriented preventive prophylaxis of HIV-related diseases and other infections is therefore required for each of these groups.

[AIDS in Germany: clinical manifestations of AIDS]. / AIDS in der Bundesrepublik Deutschland: Die klinische Manifestation von AIDS.

Since 1982, voluntary anonymous reports that meet the criteria of the WHO/CDC-AIDS definition are being collected by the Federal Health Office. By December 31st, 1989 a total of 4,306 AIDS cases has been registered. More than 80% of the reported cases are homo- and bisexual men and injection drug-users. The remaining cases are divided between hemophiliacs, persons who get infected by heterosexual contacts, blood transfusion recipients, and children infected pre- or perinatally. In 16% of all cases AIDS was diagnosed only on the basis of a Kaposi's sarcoma (KS) and in another 6% on the basis of KS and an opportunistic infection (OI). KS occurred mostly in homo- and bisexual men. The relative proportion of KS has steadily decreased from 30% up to 1986 to less than 20% in 1989. The overall incidence of KS decreased mainly due to the decrease of KS in homosexual men with AIDS. OI were diagnosed in 70% of the cases. Pneumocystis-carinii-pneumonia is most frequent (47%), followed by candida-oesophagitis (19%) and toxoplasmosis of brain in 9.5%. A malignant lymphoma was diagnosed in 3% of the cases. Furthermore, HIV-encephalopathy was seen in 2.8% and HIV-wasting-syndrome in 1.6% of cases. There is a different spectrum of diseases at the first manifestation of AIDS diagnosed in injecting drug-users. The reasons for this may be due to different life-style in this group.

[Time-related incidence of AIDS--epidemiological developments in various groups with increased risk of HIV infection]. / Die Inzidenz von AIDS im Zeitverlauf--epidemiologische Entwicklung in einzelnen Gruppen mit erhöhtem Risiko für eine HIV-Infektion.

It is no longer possible to depict the number of AIDS cases over time as an exponential curve. In the group of homosexual/bisexual men, who still account for nearly 70% of all cases, the increase in the logistic model has reached a maximum (turning point of the logistic function). Nevertheless, in this group increasing numbers of cases are still to be expected. In the case of injecting drug users no such turning point can yet be detected with sufficient statistical accuracy.