Specific patterns of CD4-associated immunosenescence in vertically HIV-infected subjects.

Vertical transmission of human immunodeficiency virus (HIV) represents an important world-wide health problem although the incidence in developed countries has been drastically reduced by the extensive use of highly active antiretroviral therapy. Vertically HIV-infected subjects have been exposed to the virus during the maturation of their immune systems and have suffered a persistent chronic activation throughout their lifetime; the consequences of this situation for their immune system are not fully understood. The objective of this study was to analyse immunosenescence-related parameters in different CD4 T-cell subsets. Fifty-seven vertically HIV-infected subjects and 32 age-matched healthy subjects were studied. Activation (HLA(-) DR(+) ), senescence (CD28(-) CD57(+) ) and proliferation (Ki67(+) ) were analysed on different CD4 T-cell subsets: naive (CD45RA(+) CD27(+) ), memory (CD45RO(+) CD27(+) ), effector memory (CD45RO(+) CD27(-) ) and effector memory RA (CD45RA(+) CD27(-) ). Compared with healthy subjects, vertically HIV-infected subjects showed increased naive and memory CD4 T-cell frequencies (p 0.035 and p 0.010, respectively) but similar frequencies of both effector subsets. Whereas naive CD4 T cells were not further altered, memory CD4 T cells presented increased levels of senescence and proliferation markers (p <0.001), effector memory CD4 T cells presented increased levels of activation, senescence and proliferation markers (p <0.001) and effector memory RA CD4 T cells presented increased levels of activation and senescence (p <0.001) compared with healthy subjects. Despite long periods of infection, vertically HIV-infected subjects show specific patterns of immunosenescence, revealing a preserved CD4 T-cell homeostasis for subset differentiation and distribution. Nevertheless, excepting the naive subpopulation, all subsets experienced some immunosenescence, pointing to uncertain consequences of the future aging process in these subjects.

Opportunistic infections and organ-specific diseases in HIV-1-infected children: a cohort study (1990-2006).

OBJECTIVES: Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV infection in children, but there are few studies in the literature about the incidence of clinical manifestations after HAART in this population, compared with adults. The aim of this study was to describe the influence of the widespread use of HAART on the development of opportunistic infections and organ-specific diseases in HIV-infected children. METHODS: An observational study of a cohort of 366 vertically HIV-infected children followed from 1990 to 2006 was carried out. According to the main antiretroviral protocol used, three calendar periods (CPs) were defined and compared: CP1 (1990-1996: no patients on HAART), CP2 (1997-1999: <60% on HAART) and CP3 (2000-2006: >60% on HAART). RESULTS: Children experienced a progressive increase in CD4 T cell count (P<0.05) and a decrease in HIV viral load from 1996 onwards (P<0.05). Similarly, rates of death, AIDS, opportunistic infections (bacteraemia, candidosis, cryptosporidiosis and bacterial pneumonia) and organ-specific diseases (wasting syndrome, thrombocytopenia, cardiomyopathy, lymphoid interstitial pneumonia and HIV-associated encephalopathy) were lower in CP2 and CP3 than in CP1. CONCLUSIONS: This study provides evidence of improved clinical outcomes in HIV-infected children over time and shows that mortality, AIDS, opportunistic infections and organ-specific diseases declined as HAART was progressively instituted in this population.

Update on the treatment of primary immunodeficiencies.

A general review of advances in the treatment of Primary Immunodeficiencies (PID) has been performed. Treatment with immunoglobulins is indicated in cases of humoral immunodeficiencies and in selected cases of combined immunodeficiencies. The use of intramuscular immunoglobulins in the treatment of PID was abandoned after obtaining the intravenous immunoglobulins, since these are much more effective and have fewer adverse effects. Now subcutaneous immunoglobulins are also available. Immunoglobulins help to keep the patients free of symptoms and infections as these substances are able to neutralise infectious agents, modulate and promote the immune response and favour phagocytosis. Adverse effects have been reported in 5-15 % of patients receiving IVIg, and patients with deficiencies of subclasses of IgG with IgA deficiency and/or anti-IgA antibodies are at risk of severe reactions. No severe adverse effects of subcutaneous immuneglobulins have been reported and the medication can be self-administered. The efficacy and safety of IVIg and SCIg are similar and SCIg administered at home is associated with better quality of life. Stem Cell Transplantation (SCT) in Primary Immunodeficiencies is aimed at restoring the number and/or function of lymphocytes or phagocytes. Matched, related or unrelated donors, or related haploidentical donors are selected. HLA class II mismatched unrelated donors are avoided owing to the risk of severe graft versus host disease (GVHD). Stem cells are obtained from bone marrow, cord blood or peripheral blood. Prophylactic immunossupression (as well as donor T lymphocyte depletion in haploidentical and unrelated donors) is performed to avoid or minimize GVHD. Less toxic "reduced intensity" protocols now exist for pre-transplantation conditioning, indicated to avoid graft rejection if there is residual T-lymphocyte immunity in the host. In the majority of Severe Combined Immunodeficiencies (SCID), SCT results in T lymphocytes graft and the antibody immunodeficiency persists in many cases. The results are better the earlier it is performed, with the absence of previous infections, and with the degree of matching. The patient must be maintained in a laminar flow room with broad anti-infectious prophylaxis and with the intravenous administration of gammaglobulin for a variable period. Many other complications can be expected. Gene therapy. Patients with PID are ideal candidates, as they are monogenic, the haematopoietic cells are easily obtained and virus replication is easy within them. Vectors (viruses) "infect" the stem cells of the patient's bone marrow, producing the transfection of the wild (healthy) gene in these cells. Encouraging results have been achieved in X-linked SCID as there are a number of patients who are considered "cured", although neoplastic processes have occurred due to the activation of proto-oncogenes close to the point of insertion of the external gene, using retroviruses as vectors; there are now trials with adenovirus, physical methods (direct injection...) and chemical methods (viral modification, artificial viruses...). Gene therapy has also been performed in patients with Chronic Granulomatous Disease and trials will improve in the future with changes in protocols used in oncology and infectious diseases.

Prevalencia de resistencia a fármacos antirretrovirales en España / Prevalence of resistance to antiretroviral drugs in Spain

Introducción La aparición de resistencias a los antirretrovirales (ARV) compromete la eficacia del tratamiento antirretroviral (TAR) en los niños infectados por el virus de la inmunodeficiencia humana (VIH). Métodos Se realizó un estudio transversal en 86 niños divididos en 4 grupos según su historia de TAR previo: 1. inhibidores de la retrotranscriptasa análogos de nucleósido (NRTI); 2. NRTI e inhibidores de la retrotranscriptasa no análogos de nucleósido (NNRTI); 3. NRTI e inhibidores de la proteasa (IP); 4. NRTI, NNRTI e IP. Resultados En el grupo 1 (11 niños) la mediana de TAR fue de 35 meses (26-108). En 10 pacientes se detectaron mutaciones asociadas a los análogos de timidina (NAM) y en 2 pacientes se halló el complejo de multirresistencia Q151M. Los 3 niños del grupo 2, recibieron 9, 32 y 42 meses respectivamente de TAR con NNRTI. En un paciente de este grupo se aislaron 3 NAM y en otro el complejo Q151M. 2 pacientes tenían la mutación K103N. En el grupo 3 (36 niños) la media de duración de tratamiento con NRTI e IP era de 48,0 ± 27,6 y 23,0 ± 14,6 meses, respectivamente. El 94 % de los pacientes de este grupo, tenían NAM y un paciente tenía el complejo Q151M. En el grupo 4 (36 niños) el tiempo previo de TAR era de 70,0 ± 36,1 meses (NNRTI: 13,0 ± 12,1 meses; IP: 39,0 ± 14,3 meses). Todos los pacientes tenían NAM y 3 pacientes tenían el complejo Q151M. Las mutaciones K103N y Y181C se hallaron en 24 (67 %) y 10 (28 %) de los pacientes, respectivamente. Un total de 32 pacientes (90 %) tenían alguna mutación primaria a IP. Conclusiones La aparición de resistencias a los ARV es frecuente en niños, siendo de rápida aparición con los NNRTI

Introduction The development of resistance to antiretroviral therapy (ART) reduces the effectiveness of these drugs in HIV-infected children. Methods We performed a cross-sectional study in 86 vertically HIV-infected children, divided into four groups according to prior treatment: group 1: nucleoside reverse transcriptase inhibitor (NRTI), group 2: NRTI and non-nucleoside reverse transcriptase inhibitor (NNRTI), group 3: NRTI and protease inhibitor (PI), group 4: NRTI, NNRTI and PI. Results In group 1 (11 children), the median treatment duration was 35 months (26 to 108). Nucleoside-associated mutations (NAMs) were found in 10 of these patients and the Q151M multiresistance mutation was found in two. The three children in group 2 were treated for 9, 32 and 42 months with NRTI and NNRTI. One child showed three NAMs and another showed Q151M. Two children had the K103N mutation. Group 3 (36 children) received treatment with NRTI and PI for 48.0 ± 27.6 and 23.0 ± 14.6 months, respectively. NAMs were observed in 94 % of the patients in this group, and one child showed the Q151M mutation. In group 4 (36 children) total treatment duration was 70.0 ± 36.1 months (13.0 ± 12.1 months with NNRTI, and 39.0 ± 14.3 months with PI). NAMs were observed in all patients in this group, and Q151M was found in three children. K103N and Y181C were detected in 24 (67 %) and 10 (28 %) of the children respectively, while 32 (90 %) showed primary mutations to PI. Conclusions A high prevalence of resistance mutations to NRTI and early appearance of resistance to NNRTI were observed in treated children

Síndrome de Sweet / Sweet's syndrome

El síndrome de Sweet o dermatosis neutrofílica febril aguda forma parte del grupo de las dermatosis neutrofílicas, enfermedades con diagnóstico anatomopatológico, y consiste en el infiltrado de la dermis o de la epidermis por neutrófilos. Su etiología más frecuente es la idiopática, seguida de la paraneoplásica, y parece estar mediada por mecanismos inmunológicos. Su manifestación clínica principal es la aparición de lesiones eritematovioláceas dolorosas que pueden cursar con fiebre (AU)

[Role of cytokines and chemokines in the non-progression of HIV infection in vertically infected children]. / Papel de las citocinas y las quimiocinas en la no progresión de la infección por VIH-1 en niños infectados verticalmente.

BACKGROUND: To study the cytokine production in vertically HIV-1-infected children with more of 7 years of HIV infection and different pattern of progression. PATIENTS AND METHODS: We study 32 HIV-1-infected children: 8 NA children (age > 7 years, asymptomatic or with light symptoms, without antiretroviral treatment and TCD4+ > 25%); 10 NE1 children (> 6 years, symptomatic, with antiretroviral treatment and TCD4+ > 25%); 14 NE2-3 children (> 6 years, symptomatic, with antiretroviral treatment and TCD4+ < 25%) and 16 (C) controls, children non-VIH+. The peripheral mononuclear cells of HIV-infected children (PBLs) were cultivated and cytokine production was quantified in the supernatant. RESULTS: The non-stimulated PBMC from HIV-infected children produced more TNF-alpha and less IL-2 that C-group. The production of IFN-gamma was lower in the groups NE1 and NE2-3 than in C-group. The production of IFN-gamma was higher in group NA than in NE2-3. In the phytohaemagglutinin (PHA) stimulated PBLs, the production of TNF-alpha was higher in NA and NE1 than in controls. The production of IL-2 was similar in NA and NE1 than in controls. The production of IL-2 was similar in NA and NE1 than in control group, but the groups NE2-3 produced less IL-2 than control and NE1 groups. The production of IFN-gamma and RANTES were significantly higher in NA than in controls. The groups NE1 and NE2-3 produced lower levels of IL-5 than control and NA groups. The groups NE2-3 produced lower levels of IL-10 than control group. The ratio IFN-gamma/IL-5 and IFN-gamma/IL-10 were higher in group NA than in control and NE1. CONCLUSIONS: In non-progressors HIV-infected children the immune response is conserved and we have observed an increased Th1 response, while in progressors HIV-infected children receiving antiretroviral treatment we could observe a diminished Th2 response. Moreover, our data clearly indicate that the decrease of IL-2 is an early marker of HIV-infection.

Identificación de mujeres embarazadas infectadas por el vih-1: significado de pruebas serológicas indeterminadas / Identification of HIV-1 infected pregnant women: interpreting results from indeterminate western-blot test

Objetivo: Investigar el significado de ensayos de screening positivos y western-blot indeterminados en mujeres embarazadas. Sujetos y métodos: Realizamos un estudio de diagnóstico de infección por VIH en una gestante primípara y tres multíparas, de edades entre 26 y 32 años, con ensayos de screening VIH-positivos. Ninguna refirió prácticas de riesgo para la infección por VIH. Utilizamos técnicas de detección directa del VIH: antigenemia p24 y carga viral en plasma y detección del provirus por PCR, cultivo viral y cuantificación de células T CD4+ en células mononucleares de sangre periférica. Resultados: En las cuatro gestantes, el ensayo de western-blot fue indeterminado (p24-p55; p24 o p55). Al realizar las técnicas de detección directas del VIH, en ninguna de las muestras obtuvimos resultados positivos. Conclusión: Ninguna de las gestantes con ensayos de screening positivos y western-blot indeterminados estaban infectadas por el VIH. Es necesario realizar ensayos de detección directa del VIH para un diagnóstico definitivo (AU)

[Dynamics of immunoglobulin production in non infected children born from HIV-1 infected mothers: effect of zidovudine]. / Dinámica de producción de inmunoglobulinas en niños no infectados nacidos de madres infectadas por el VIH-1: efecto de la zidovudina.

BACKGROUND: To evaluate the possible effect of zidovudine (ZDV) on inmunoglobins production in infants born to HIV-1 infected women. SUBJECTS AND METHODS: We have studied the immunoglobulins serum levels in 57 non-infected children born to HIV-infected mothers. The children were divided into two groups: group A, 28 children born to HIV-1 infected mothers that received ZDV on protocol 076 conditions, and group B, 29 children born to mothers that did not receive anti-HIV-1 drugs. Quantification of serum IgG, IgA and IgM was performed by nephelometric techniques. RESULTS: The median time to reach normal IgA values at 12 months, was 25.57 months (confidence interval [CI] 95%: 22.01-29.12) in the children of group A and 12.67 months (CI 95%: 9.90-15.44) in the children of group B (p = 0.01). The median time to reach normal IgM values at 12 months was 15.93 months (CI 95%: 15.21-16.65) in group A children versus 11.20 months (CI 95%: 8.51-13.89) in group B (p = 0.11). The median time to reach normal IgG values at 12 months was 19.67 months (CI 95%: 13.12-16.22) in group A children versus 12.73 months (CI 95%: 11.16-14.30) in group B (p = 0.05). The normal IgA levels were reached 2.36 (CI 95%: 1.16-4.81) times later in group A than in group B children (p = 0.02), whereas normal IgG levels were reached 1.88 (CI 95%: 0.94-3.78) times later in group A than in group B of children. CONCLUSIONS: Our results indicate that treatment of pregnant mothers with ZDV clearly affect the ability of their newborns to produce inmunoglobulins, which may have important practical implications for their vaccination protocols.

Immunological and virological markers of disease progression in HIV-infected children.

Polymerase chain reaction (PCR), virus culture and antigen detection assays are useful for early detection of vertically transmitted human immunodeficiency virus type 1 (HIV-1) infection in infants under 12 months of age. Sixty-four children born to HIV-1-seropositive mothers were evaluated. Thirteen children (20.3%) were repeatedly positive by PCR analysis. There was 100% concordance between the results obtained from PCR and culture assays. Measurement of p24 antigen in serum was, in contrast, a less sensitive marker of HIV infection: only 5/13 infants had positive p24 antigen results. We have investigated the relationship among the HIV-1 biological phenotype, replicative capacity of viral isolates, HIV RNA copy number in plasma, p24 antigenaemia, CD4 T lymphocyte counts and the clinical status in 13 HIV-infected infants. Six out of 13 HIV-1 isolates from these patients were classified as rapid/high and seven as slow/low. We have found a significantly positive correlation between the replication rate of HIV isolates and their capacity to induce syncytia in vitro. The HIV-1 isolates with rapid/high and syncytium-inducing phenotype, and isolates with slow/low and non-syncytium-inducing phenotype were obtained from infants who had HIV-1 RNA copy number ml(-1) plasma values of 27654-83520 and 1342-34321, respectively. Levels of HIV-1 RNA were measured in sequential plasma samples from three HIV-infected infants and their biological properties determined in vitro. Our findings indicate that infants who carried viruses with more cytophatic biological phenotype and who had higher viral RNA copy numbers in blood were more likely to have lower CD4+ T cell counts and more likely to develop full-blown AIDS.

Elevated levels of circulating intercellular adhesion molecule 1 and tumor necrosis factor alpha in the serum of children vertically infected with HIV-1.

OBJECTIVE: To evaluate serum levels of circulating intercellular adhesion molecule-1 (cICAM-1) and tumor necrosis factor-alpha (TNF-alpha) levels in HIV-1-infected children at different stages of infection in children treated or not treated with Zidovudine (ZDV). DESIGN: Serum levels of cICAM-1 and TNF-alpha, determined by enzyme immunoassays, were evaluated in 52 HIV-1-infected children, aged between 1 month and 13 years; 35 children were not treated with ZDV and 17 were treated with ZDV. RESULTS: cICAM-1 (596 +/- 41 ng/ml) and TNF-alpha (284 +/- 29 pg/ml) levels were significantly elevated in HIV-1-infected children compared with HIV-1-uninfected age-matched controls (cICAM = 295 +/- 17 ng/ml; TNF-alpha = 4.8 +/- 0.89 pg/ml). No significant differences in either parameter were observed between children at different stages of HIV-1 disease. By contrast, a marked statistically significant, reduction of cICAM and TNF-alpha levels was observed in HIV-infected children undergoing antiretroviral therapy. CONCLUSIONS: Serum levels of cICAM-1 and TNF-alpha were significantly elevated in HIV-1-infected children regardless of their clinical stage. Moreover, antiretroviral treatment appeared to reduce the serum levels of cICAM-1 and TNF-alpha.

Relationship of virologic, immunologic, and clinical parameters in infants with vertically acquired human immunodeficiency virus type 1 infection.

We have investigated the relationship among the HIV-1 biologic phenotype, replicative capacity of virus isolates, HIV-RNA copy number in plasma, p24 antigenemia, CD4+ T lymphocyte counts in peripheral blood, and the clinical status in a cohort of 13 HIV-infected children younger than 12 mo of age, born of HIV-1 seropositive mothers. Six out of 13 HIV-1 isolates from these patients were classified as rapid/high and seven as slow/low. We have found a significantly positive correlation between the replication rate of HIV isolates and their capacity to induce syncytia in vitro. Most of the serial HIV-1 isolates obtained from infants with AIDS had the rapid/high phenotype and induced syncytia, whereas only two out of 23 HIV-1 isolates obtained from infants without AIDS showed these properties. In sequential analysis of HIV-1 isolates from infants with AIDS, the presence of viral isolates with rapid/high and SI phenotype was associated with higher levels of HIV-1 RNA in plasma, CD4+ T cell depletion, and clinical progression. By contrast, infants whose viruses exhibited nonsyncytium-inducing phenotype throughout the follow-up showed lower levels of HIV RNA, stable CD4+ T cell counts, and mild symptomatic HIV infection. Our findings indicate that infants who carried viruses with more cytopathic biologic phenotype and who had higher viral RNA coy numbers in blood were more likely to have lower CD4+ T cell counts and more likely to have AIDS.

Molluscum contagiosum, involving the upper eyelids, in a child infected with HIV-1.

BACKGROUND: Infection with molluscum contagiosum has been reported in pediatric and adult patients with acquired immune deficiency syndrome (AIDS), but rarely affecting eyelids. We have studied the viral phenotype, HIV-1 plasma viremia, p24 antigenemia, alterations of cellular immune function, and the ophthalmological status in a 5-year old human immunodeficiency virus type 1 (HIV-1)-infected girl, who developed multiple molluscum lesions, bilaterally involving upper eyelids with extension over the face and nose. METHODS: Detailed ophthalmological examination and immunological and virological studies were performed in a pediatric patient with HIV-1 vertical infection having extensive infection with molluscum contagiosum. RESULTS: The pediatric patient was emetropic; tricomegalia was present bilaterally, and alteration of the microvessels of the conjunctiva (microangiopathy) was observable in both eyes and structural (fibrilar) degeneration of the vitreous architecture in both eyes. There was no ophthalmoscopic sign of infectious retinitis or retinal microangiopathy. She had lymphopenia, very low percentage and absolute number of CD4+ T cells but increased percentage of CD8+ T cells. The in vitro lymphocyte proliferative response to phytohemagluttinin (PHA) was depressed as compared to healthy controls. She had high levels of viral HIV RNA in her plasma and of p24 antigen in her serum, and the phenotype of the isolated HIV-1 was determined to be syncytium-inducing (SI). CONCLUSION: Although healthy persons may develop molluscum contagiosum, usually unilateral, as far as we are aware this report is the first to document a case of molluscum contagiosum with bilateral eyelid involvement in an HIV-1-infected pediatric patient. Our observations suggest that this type of infection may be present in HIV-infected children, associated with high viral load and possibly an SI viral phenotype, severe immunoregulatory abnormalities, and poor clinical status.

Rosacea-like demodicosis in an HIV-positive child.

A second case of rosacea-like demodicosis in an HIV-positive child was seen at our center. No such cases have previously been published. The present case is a 2-year-old boy, the son of an HIV-positive mother, who responded well to oral erythromycin and topical metronidazole. The frequency of rosacea-like eruptions in HIV-negative children is very low. However, the incidence of these eruptions in HIV-positive children may have been underestimated. The pathogenic role of Demodex mites is discussed as well as the possible mechanisms for an exaggerated reaction.

Sepsis in children with human immunodeficiency virus infection. The Madrid HIV Pediatric Infection Collaborative Study Group.

The aims of this retrospective study were to review the frequency and patterns of bacterial sepsis in children infected with human immunodeficiency virus. The charts of 233 human immunodeficiency virus-infected children cared for during a 10-year period in 4 tertiary hospitals in Madrid were reviewed. There were 43 episodes of sepsis in 31 (13%) children. Twenty of them had acquired immunodeficiency syndrome, 10 were class PA2 and 1 was class P1B. The most common organisms recovered were: nontyphoidal Salmonella, 10 cases (23%); Streptococcus pneumoniae, 9 cases (21%); Staphylococcus epidermidis, 6 cases (14%); Escherichia coli, 5 cases (12%); Enterococcus faecalis, 4 cases (9%); Campylobacter jejuni, 2 cases (5%). In 28 episodes of bacteremia there were other sites of associated infection: pneumonia, 6 cases; urinary tract infection (UTI), 5 cases; gastrointestinal disease, 4 cases; catheter-related bacteremia, 12 cases. Eight patients had more than 1 episode of bacteremia. The rate of complications was high: 6 children had septic shock; and 2 of them developed disseminated intravascular coagulation. There was 1 death directly related to sepsis.