Family adversity and autonomic reactivity association with immune changes in HIV-affected school children.

OBJECTIVE: To explore whether primary school entry is associated with changes in immune system parameters in HIV-affected children. HIV-affected children are vulnerable to psychosocial stressors, regardless of their own HIV serological status. METHODS: Data from 38 HIV-positive and 29 HIV-negative children born to seropositive women were obtained. Measures included family adversity questionnaires, autonomic nervous system (ANS) reactivity, and enumerative and functional changes in peripheral blood immune parameters. RESULTS: In comparison with children who were HIV-negative, children who were HIV-positive at baseline had fewer CD4(+) T lymphocytes (mean [M] = 916 versus 1206 cells/mm(3) × 10(3); F = 7.8, p = .007), more CD8(+) cells (M = 1046 versus 720 cells/mm(3) × 10(3); F = 7.98, p = .006), and diminished natural killer cell cytotoxicity (M = -0.29 versus 0.41; F = 8.87, p = .004). School entry was associated with changes in immune parameters, but HIV status was not associated with the magnitude of changes. Changes in immune parameters after school entry were associated with family stress and preschool entry ANS reactivity. Highly ANS reactive children had either the greatest increase in CD8(+) cells after school entry or the greatest decrease, depending on reported levels of family adversity (B = 215.35; t = 3.74, p < .001). Changes in functional immune assays were significantly associated with the interactions between HIV status and ANS reactivity. CONCLUSIONS: These results suggest that autonomic reactivity is associated with increased immunological sensitivity to adverse or challenging social contexts among children affected by HIV.

The effect of prophylaxis on pediatric HIV costs.

The objective of this study was to determine and compare the cost to treat HIV(+) and HIV(-) pediatric patients both before and after HIV prophylaxis became the standard of care. Retrospective chart review of a pediatric HIV/AIDS specialty clinic's medical charts was conducted for clinical and healthcare utilization data on 125 children diagnosed from 1986 to 2007. Mean HIV-related costs were compared using bootstrapped t-tests for children born in the pre-prophylaxis (1979-1993) and prophylaxis eras (1994-2007). Patients were also stratified into two categories based on death during the follow-up period. Lastly, national cost-savings were estimated using mean costs, national number of at-risk births, and national perinatal HIV transmission rates in each era. For HIV(+) children, mean annual per patient treatment cost was $15,067 (95% CI: $10,169-$19,965) in the pre-prophylaxis era (n = 40) and $14,959 (95% CI: $9140-$20,779) in the prophylaxis era (n = 14); difference not statistically significant (p > 0.05). For HIV(-) children, mean annual per patient treatment cost was $204 (95% CI: $219-$627) for the pre-prophylaxis era (n = 2) and $427 (95% CI: $277-$579) for the prophylaxis era (n = 69); difference statistically significant (p < 0.05). A projected cost-savings of $16-23 million annually in the USA was observed due to the adoption of prophylaxis treatment guidelines in pediatric HIV care. The prophylaxis era of pediatric HIV treatment has been successful in decreasing perinatal HIV transmission and mortality, as reflected by clinical trials and national cost-savings data, and emphasizes the value of the rapid adoption of evidence-based practice guidelines.

Dendritic cells from humans with hypomorphic mutations in IKBKG/NEMO have impaired mitogen-activated protein kinase activity.

The covalent attachment of lysine 63-linked polyubiquitin to the zinc-finger domain of IKBKG/NEMO (also known as IKKγ) is necessary for full activation of NF-κB. Impairments of this biochemical mechanism explain the deleterious effects of hypomorphic NEMO mutations on NF-κB signaling function in humans suffering from X-linked ectodermal dysplasia and immunodeficiency. Nevertheless, the biological function of the NEMO zinc-finger domain in the regulation of mitogen-activated protein kinase (MAPK) activity is poorly understood. Here we show that dendritic cells from patients with EDI caused by a C-terminal E391X deletion of the zinc finger of NEMO exhibit impaired MAPK activation in response to lipopolysaccharide (LPS) stimulation. Interestingly, DCs from patients with a C417R missense mutation within the zinc finger domain of NEMO in which ubiquitination of NEMO is preserved are also defective in JNK and ERK activity following LPS stimulation. Our findings indicate that the structural integrity of the NEMO ZF domain is more important than its polyubiquitination for full activation of the MAPK. Furthermore, phosphorylation and polyubiquitination of upstream TAK1 were significantly reduced in the E391X zinc-finger deleted patients, indicating that the NEMO zinc finger may play an important role in assembling the proximal signaling complex for MAPK activation.

Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.

The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are increasingly well understood, little is known about autoimmune manifestations in NEMO patients. We therefore sought to examine serologic markers of systemic inflammation and intestinal pathology in a kindred of patients with the NEMO syndrome. We observed persistent elevation of erythrocyte sedimentation rates in five patients, and two were symptomatic, with a chronic but atypical enterocolitis. Though pathologic lesions in these two patients were consistent with acute inflammation, sustained clinical improvement was only achieved with systemic and/or topical glucocorticoid therapy. Our data suggest that some patients with the NEMO syndrome exhibit persistent elevation of inflammatory markers similar to systemic autoimmune diseases and may subsequently develop an atypical enterocolitis.

Altered iron metabolism in children with human immunodeficiency virus disease.

BACKGROUND: Despite the high prevalence of altered iron metabolism in children with human immunodeficiency virus (HIV) disease, these alterations have not been well studied. PROCEDURES: Twenty-six children with HIV disease underwent laboratory evaluation to determine the presence of anemia, and to classify the anemia as iron-deficiency anemia or anemia of chronic disease. RESULTS: Half of the children had an alteration in iron metabolism: 6 were iron deficient, 4 had hyperferritinemia, and 3 demonstrated hyperferritinemia with iron deficiency. CONCLUSIONS: These data indicate that alterations in iron metabolism are common even in the HAART era and warrant further study to identify individuals at risk for these alterations.

Brief Report: Markers of Spontaneous Preterm Delivery in Women Living With HIV: Relationship With Protease Inhibitors and Vitamin D.

BACKGROUND: Women living with HIV (WLHIV) have increased risk of spontaneous preterm delivery (SPTD). We sought to identify plasma predictors of SPTD and their correlations with factors that increase the risk of SPTD, such as vitamin D deficiency and use of protease inhibitors. DESIGN: Plasma was obtained from 103 WLHIV with SPTD (≤35 weeks gestation) and 205 controls with term deliveries (TDs; ≥37 weeds) matched to cases 2:1 by race and gestational age at blood draw. TNFα, IFNγ, IL6, IL8, IL1ß, IL18, IL17, granulocyte colony stimulating factor (GCSF), MCP1, IP10, sIL2Rα, sCD14, vascular endothelial factor a, monocyte colony stimulation factor, GROα, MMP9, IL10, TGFß, sCTLA4, and eicosanoids were compared between cases adjusting for known SPTD risk factors. RESULTS: Participants had similar demographic characteristics, but cases had higher plasma HIV RNA, lower CD4 cells, and more advanced HIV disease compared with controls. High sIL2Rα was associated with increased risk of SPTD. High sCD14, GCSF, PGF2α, and 5-HEPE were marginally associated with increased risk of SPTD. Women who initiated protease inhibitors-containing antiretroviral treatment before or during the first trimester had higher levels of GCSF and 5-HEPE compared with women without such exposure before plasma collection. Vitamin D insufficiency was associated with higher inflammatory sCD14 and PGF2α, and lower anti-inflammatory 5-HEPE. CONCLUSIONS: The best plasma predictor of SPTD in WLHIV was sIL2Rα, a marker of T-cell activation. Markers of monocyte activation and eicosanoids were marginally increased in WLHIV and SPTD, suggesting that they may also play a role in the pathogenesis of this disorder.

Antiretroviral therapy during pregnancy and the risk of an adverse outcome.

BACKGROUND: Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. METHODS: We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. RESULTS: After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). CONCLUSIONS: As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation.

JC virus granule cell neuronopathy in a child with CD40 ligand deficiency.

JC virus infection of the brain typically causes progressive multifocal leukoencephalopathy, a demyelinating disease that rarely involves gray matter. This report presents a case of cerebellar degeneration associated with JC virus infection in a male with CD40 ligand deficiency resulting in hyperimmunoglobulin M type 1. This patient exhibited a progressive cerebellar ataxia with progressive atrophy of the cerebellar cortex in association with the presence of JC virus in the spinal fluid. JC virus infection should be considered in the differential diagnosis of ataxia in children with inherited immunodeficiencies.

Ophthalmic manifestations of perinatally acquired HIV in a US cohort of long-term survivors.

BACKGROUND/AIMS: To determine the ophthalmic manifestations of HIV in a cohort of long-term survivors of perinatally acquired HIV. METHODS: Twenty-two patients with perinatally acquired HIV who were aged ≥12 years were prospectively studied at a university clinic. They underwent complete ophthalmic examinations and fundus photography. Their medical histories, medications and CD4 counts were abstracted from the medical records. To evaluate for keratoconjunctivitis sicca, both HIV patients and 44 healthy controls (matched by age, gender and contact lens wear) underwent Schirmer testing and ocular surface staining. RESULTS: Nine male and 13 female HIV patients with mean age of 16.6 years (SD, 3.4) were examined. Of the 22 HIV patients, 21 had been treated with highly active antiretroviral therapy (HAART). Only one patient had a CD4 count nadir of <200 cells/µL. The mean visual acuity of the eyes of the HIV subjects was 20/22 (SD, 1.6 lines). No patient had cytomegalovirus retinitis. Four of the 22 (18%) HIV patients had strabismus. HIV subjects and controls had similar rates of abnormal Schirmer (9% and 14%, p=0.62) and ocular staining scores (p=0.29). CONCLUSIONS: In the post-HAART era, long-term survivors of perinatally acquired HIV exhibited little vision-threatening disease, but had a high prevalence of strabismus.

Increasing women's leadership in academic medicine: report of the AAMC Project Implementation Committee.

The AAMC's Increasing Women's Leadership Project Implementation Committee examined four years of data on the advancement of women in academic medicine. With women comprising only 14% of tenured faculty and 12% of full professors, the committee concludes that the progress achieved is inadequate. Because academic medicine needs all the leaders it can develop to address accelerating institutional and societal needs, the waste of most women's potential is of growing importance. Only institutions able to recruit and retain women will be likely to maintain the best housestaff and faculty. The long-term success of academic health centers is thus inextricably linked to the development of women leaders. The committee therefore recommends that medical schools, teaching hospitals, and academic societies (1) emphasize faculty diversity in departmental reviews, evaluating department chairs on their development of women faculty; (2) target women's professional development needs within the context of helping all faculty maximize their faculty appointments, including helping men become more effective mentors of women; (3) assess which institutional practices tend to favor men's over women's professional development, such as defining "academic success" as largely an independent act and rewarding unrestricted availability to work (i.e., neglect of personal life); (4) enhance the effectiveness of search committees to attract women candidates, including assessment of group process and of how candidates' qualifications are defined and evaluated; and (5) financially support institutional Women in Medicine programs and the AAMC Women Liaison Officer and regularly monitor the representation of women at senior ranks.

Pediatric HIV costs across three treatment eras from 1986 to 2007.

OBJECTIVE: Life has changed dramatically for infants exposed perinatally to HIV to HIV primarily because of a successful translational research program that has also affected treatment costs. We compared treatment costs among HIV+ patients in an HIV/AIDS specialty clinic across 3 treatment eras: monotherapy (pre-1990), combination therapy (1990-1996), and highly active antiretroviral therapy (HAART) (1997-2007). We also estimated cumulative health care costs among pediatric HIV/AIDS patients born in each era. PATIENTS AND METHODS: Data on health care use were collected from medical records of 126 infants born to HIV+ mothers during a 21-year period (1986-2007) (728 person-years). The Drug Topics Red Book 1999 was used for drug costs, the Current Procedural Terminology Medicare Fee Schedule codes for outpatient costs, and the Healthcare Cost and Utilization Project Kids' Inpatient Database for inpatient costs. Generalized estimating equations and bootstrapped ordinary least-squares models were used to determine 2007 costs, cumulative costs, and cost savings. RESULTS: Lifetime cost savings with HAART were $6.7 to $23.3 million, depending on incidence. Average total costs per HIV+ person per month were $1306 ($318 for drugs, $896 for total medical) in the monotherapy era, $2289 ($891 for drugs, $1180 for total medical) in the combination-therapy era, and $1814 ($1241 for drugs, $320 for total medical) in the HAART era. Total costs during the HAART era were 25.2% lower than costs during the combination-therapy era, because the 34% higher HAART drug costs were compensated for by total medical costs (inpatient+outpatient) that were 57% lower, which was a significant change (P<.001). The cumulative costs for treatment of an HIV+ patient were highest during the monotherapy era ($196,860) and lowest during the HAART era ($181,436). CONCLUSIONS: Our results show that the cost burden for the treatment of HIV+ pediatric patients has decreased over time. This historical examination of treatment-era costs demonstrates the value of technologic advances in treatment.

Anti-influenza serum and mucosal antibody responses after administration of live attenuated or inactivated influenza vaccines to HIV-infected children.

BACKGROUND: Live-attenuated influenza vaccine (LAIV) prevents more cases of influenza in immune-competent children than the trivalent inactivated vaccine (TIV). We compared the antibody responses to LAIV or TIV in HIV-infected children. METHODS: Blood and saliva obtained at enrollment, 4 and 24 weeks postimmunization from 243 HIV-infected children randomly assigned to TIV or LAIV were analyzed. RESULTS: Both vaccines increased the anti-influenza neutralizing antibodies at 4 and 24 weeks postimmunization. At 4 weeks postimmunization, TIV recipients had 2-fold to 3-fold higher neutralizing antibody titers than LAIV recipients, but the proportions of subjects with protective titers (≥ 1:40) were similar between treatment groups (96%-100% for influenza A and 81%-88% for influenza B). Both vaccines increased salivary homotypic IgG antibodies, but not IgA antibodies. Both vaccines also increased serum heterosubtypic antibodies. Among HIV-specific characteristics, the baseline viral load correlated best with the antibody responses to either vaccine. We used LAIV-virus shedding as a surrogate of influenza infection. Influenza-specific humoral and mucosal antibody levels were significantly higher in nonshedders than in shedders. CONCLUSIONS: LAIV and TIV generated homotypic and heterosubtypic humoral and mucosal antibody responses in HIV-infected children. High titers of humoral or mucosal antibodies correlated with protection against viral shedding.

Regulatory T cells and their role in rheumatic diseases: a potential target for novel therapeutic development.

Regulatory T cells have an important role in limiting immune reactions and are essential regulators of self-tolerance. Among them, CD4+CD25high regulatory T cells are the best-described subset. In this article, we summarize current knowledge on the phenotype, function, and development of CD4+CD25high regulatory T cells. We also review the literature on the role of these T cells in rheumatic diseases and discuss the potential for their use in immunotherapy.

Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants.

This study aimed to determine lamivudine disposition in infants and to construct an appropriate dose adjustment for age, given the widespread use of lamivudine for both the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and the treatment of HIV-infected infants. Using a pooled-population approach, the pharmacokinetics of lamivudine in HIV-exposed or -infected infants from four Pediatric AIDS Clinical Trials Group studies were assessed. Ninety-nine infants provided 559 plasma samples for measurement of lamivudine concentrations. All infants received combination antiretroviral therapy including lamivudine dosed at 2 mg/kg of body weight every 12 h (q12h) for the first 4 to 6 weeks of life and at 4 mg/kg q12h thereafter. Lamivudine's apparent clearance was 0.25 liter/h/kg at birth, doubling by 28 days. In the final model, age and weight were the only significant covariates for lamivudine clearance. While lamivudine is predominantly renally eliminated, the serum creatinine level was not an independent covariate in the final model, possibly because it was confounded by age. Inclusion of interoccasion variability for bioavailability improved the individual subject clearance prediction over the age range studies. Simulations based on the final model predicted that by the age of 4 weeks, 90% of infant lamivudine concentrations with the standard 2 mg/kg dose of lamivudine fell below the adult median concentration. This population pharmacokinetic analysis affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg q12 h at the age of 4 weeks for infants with normal maturation of renal function will provide optimal lamivudine exposure, potentially contributing to more successful therapy.

Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women.

Human immunodeficiency virus-infected women (n=16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.

Antibody responses to hepatitis A virus vaccine in HIV-infected children with evidence of immunologic reconstitution while receiving highly active antiretroviral therapy.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines and may require revised immunization regimens. We investigated the safety and immunogenicity of 2 doses of hepatitis A virus (HAV) vaccine followed by a booster dose in HIV-infected children receiving stable highly active antiretroviral therapy. METHODS: A total of 235 children with CD4+ T cell percentages > or = 20% received 2 vaccine doses 24 weeks apart, and 117 received a third vaccine dose after 104 weeks. Anti-HAV antibody titers were measured at baseline and at 32, 104, and 112 weeks after the first vaccination. Subjects with antibody titers > or = 20 mIU/mL were defined as being seropositive. High and low antibody responses were defined as titers > or = 250 and <250 mIU/mL, respectively. RESULTS: Of 151 subjects who were HAV seronegative at baseline, 97% seroconverted after 2 vaccine doses, and 47% had low antibody responses. At 104 weeks, 90% of subjects had antibody titers > or = 20 mIU/mL, and those with low antibody responses were more likely to lose protective antibody titers. A third vaccine dose generated significantly higher antibody titers than those observed after the second vaccine dose. Undetectable HIV RNA at baseline was associated with higher anti-HAV antibody titers after the second vaccine dose. Antibody titers after the second and third vaccine doses were weakly correlated with CD4+ T cell percentages at the time when each vaccine dose was administered. In the 45 subjects who were HAV seropositive at baseline, responses to 2 and 3 vaccine doses were higher than those in subjects who were HAV seronegative at baseline, but the responses showed similar correlations. There were no serious adverse events associated with the vaccine. CONCLUSIONS: HIV-infected children with CD4+ T cell percentages > or = 20% responded better to the HAV vaccine if they had undetectable HIV RNA. The standard 2-dose immunization regimen generated low antibody titers with limited persistence. A third vaccine dose was safe and increased the antibody titers, suggesting that an increase in immunizations may be warranted in this population.

Impaired integrin-dependent function in Wiskott-Aldrich syndrome protein-deficient murine and human neutrophils.

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency that manifests as increased susceptibility to many pathogens. Although the spectrum of infections suffered by WAS patients is consistent with defects in neutrophil (PMN) function, the consequences of WAS protein (WASp) deficiency on this innate immune cell have been unclear. We report that deficiency of WASp in both human and murine PMNs resulted in profound defects in clustering of beta2 integrins, leading to defective adhesion and transendothelial migration under conditions of physiologic shear flow. Wild-type PMNs redistributed clustered beta2 integrins to the uropod of the cell during active migration, whereas WASp-deficient cells remain unpolarized. The WASp-deficient PMNs also showed reduced integrin-dependent activation of degranulation and respiratory burst. PMNs from a WAS patient manifested similar defects in integrin clustering and signaling. These results suggest that impaired beta2 integrin function in WASp-deficient PMNs may contribute substantially to the clinical immunodeficiency suffered by WAS patients.

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is characterized by impaired lymphocyte development and function resulting from the adenosine metabolism defect. Enzyme replacement therapy with polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) minimizes infectious complications of ADA-deficient patients who have not received bone marrow transplantation. In PEG-ADA therapy, enzymatically active ADA continuously circulates to act as a metabolic sink, detoxifying the adenosine and deoxyadenosine metabolites that accumulate to high levels in the absence of ADA. Studies have shown that upon the initiation of PEG-ADA therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase and protective immune function develops. However, the long-term efficacy is unknown. This retrospective study was designed to assess the long-term effectiveness of PEG-ADA treatment, based on evaluation of the immune function of nine ADA-deficient SCID patients (age 5-15) treated over the past decade. The results showed that the lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements. A gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. To this date, these low numbers and functions of lymphocytes had been adequate to provide protective immunity. These patients should be followed closely to detect a premature decline in immune function with aging in future decades of PEG-ADA therapy.