Àngela Deyà-Martínez

Metabolic and renal adverse effects of antiretroviral therapy in HIV-infected children and adolescents.

Worldwide, the benefits of combined antiretroviral (ARV) therapy in morbidity and mortality due to perinatally acquired human immunodeficiency virus infection are beyond question and outweigh the toxicity these drugs have been associated with in HIV-infected children and adolescents to date. In puberty, abnormal body fat distribution is stigmatizating and leads to low adherence to ARV treatment. The other metabolic comorbidities (mitochondrial toxicity, dyslipidemias, insulin resistance and low bone mineral density) and renal toxicity, albeit nonsymptomatic in most children, are increasingly being reported and potentially put this population at risk for early cardiovascular or cerebrovascular atherosclerotic disease, diabetes, pathologic fractures or premature renal failure in the third and fourth decades of life. Evidence from available studies is limited because of methodological limitations and also because of several HIV-unrelated factors influencing, to some degree, the development of these conditions. Current recommendations for the prevention, diagnosis, monitoring and treatment of metabolic and renal adverse effects in HIV-children and adolescents are based on adult studies, observational pediatric studies and experts’ consensus. Healthy lifestyle habits (regarding diet, exercise and refraining from toxic substances) and wise use of ARV options are the only preventive tools for the majority of patients. Should abnormal findings arise, switches in one or more ARV drugs have proved useful. Specific therapies are also available for some of these comorbidities, although the experience in the pediatric age is still very scarce. We aim to summarize the epidemiological, clinical and therapeutic aspects of metabolic and renal adverse effects in vertically HIV-infected children and adolescents.

Immunological Changes in Blood of Newborns Exposed to Anti-TNF-α during Pregnancy

Background Although anti-TNF-α monoclonal antibodies are considered safe during pregnancy, there are no studies on the development of the exposed-infant immune system. The objective was to study for the first time the impact of throughout pregnancy exposure to anti-TNF-α has an impact in the development of the infant’s immune system, especially B cells and the IL-12/IFN-γ pathway. Methods Prospective study of infants born to mothers with inflammatory bowel disease treated throughout pregnancy with anti-TNF-α (adalimumab/infliximab). Infants were monitored both clinically and immunologically at birth and at 3, 6, 12, and 18 months. Results We included seven patients and eight healthy controls. Exposed infants had detectable levels of anti-TNF-α until 6 months of age; they presented a more immature B- and helper T-phenotype that normalized within 12 months, with normal immunoglobulin production and vaccine responses. A decreased Treg cell frequency at birth that inversely correlated with mother’s peripartum anti-TNF-α levels was observed. Also, a decreased response after mycobacterial challenge was noted. Clinically, no serious infections occurred during follow-up. Four of seven had atopia. Conclusion This study reveals changes in the immune system of infants exposed during pregnancy to anti-TNF-α. We hypothesize that a Treg decrease might facilitate hypersensitivity and that defects in IL-12/IFN-γ pathway might place the infant at risk of intracellular infections. Pediatricians should be aware of these changes. Although new studies are needed to confirm these results, our findings are especially relevant in view of a likely increase in the use of these drugs during pregnancy in the coming years.

Cystatin C: A Marker for Inflammation and Renal Function Among HIV-infected Children and Adolescents.

Background: Renal disease is a leading cause of morbidity in HIV-infected adults in the highly active antiretroviral therapy (HAART) era. Cystatin C has been proposed as a more sensitive marker of renal function, but it may be affected by ongoing inflammation. We aimed to study the cystatin C levels in a cohort of HIV-infected pediatric patients at 3 Spanish centers. Methods: This is a multicenter cross-sectional observational study. Renal function was assessed by means of first morning urine protein/creatinine and albumin/creatinine ratios and creatinine-estimated glomerular filtration rates (GFRs), together with the following inflammation markers: cystatin C, reactive C protein, &bgr;-2-microglobulin and 25(OH)-vitamin D levels. A control group of healthy children and adolescents was used. Results: Eighty-three patients (51 females, median age: 13.3 years; 32 males, median age: 13.6 years) and 44 controls (24 females, median age: 12.2 years; 20 males, median age: 10.9 years) were included. Among the former, mean CD4 cell count was 860/mm3, 29(35%) patients had a previous AIDS diagnosis, 73(88%) were on HAART and HIV viremia was undetectable in 61(73%). No differences in cystatin C levels were observed between the 2 groups. In HIV-infected patients, cystatin C levels correlated with GFR (r = −0.27; P = 0.01), age at first HAART (r = −0.21; P = 0.05), and &bgr;-2-microglobulin (r = 0.569; P < 0.01). In multivariate analysis, lower GFR (P = 0.014) and higher &bgr;-2-microglobulin levels (P = 0.001) remained as independent risk factors for higher cystatin C values. Conclusions: Cystatin C values were associated with GFR and &bgr;-2-microglobulin. Cystatin C may be useful as a marker of renal function in HIV-infected pediatric patients, independently of ongoing inflammation or viremia.

Characterization of the Highly Prevalent Regulatory CD24hiCD38hi B-Cell Population in Human Cord Blood

The newborn’s immune system must transition from a sterile haploidentical uterus to the world full of antigens. Regulatory B-cells (Breg; broadly defined as CD19+CD24hiCD38hi) are tolerance promoters in the adult immune system. They can inhibit IFN-γ and IL-17 production by T-cells and are essential in different conditions, including pregnancy. Breg have still not been well characterized in umbilical cord blood, where we hypothesize that they are pivotal in the achievement of tolerance. We studied CD19+CD24hiCD38hi Breg in healthy umbilical cord blood (hUCB) compared to healthy peripheral adult blood (hAPB). Total numbers of Breg were increased in hUCB compared to hAPB (34.39 vs. 9.49%; p = 0.0002), especially in the marginal zone-like B-cell subset, in which the most marked difference could be observed between hUCB and hAPB (60.80 vs. 4.94%; p = 0.1). CD24hiCD38hi subset in hUCB produced IL-10 and inhibited T-cell IFN-γ [1.63 vs. 0.95 stimulation ratio (SR); p = 0.004] and IL-4 (1.63 vs. 1.44 SR; p = 0.39) production. Phenotypically, hUCB Breg cells presented IgMhiIgDhiCD5+CD10+CD27− markers, similar to those described in hAPB Breg cells, but they showed increased IgM concentration and decreased expression of CD22 and CD73 markers. Our work characterized the frequency, phenotype, and function of Breg in hUCB, which may contribute to understanding of immune tolerance during pregnancy, paving the way to a new approach to immune-related diseases in the fetus and the newborn.

Severe BCG-osis Misdiagnosed as Multidrug-Resistant Tuberculosis in an IL-12Rβ1-Deficient Peruvian Girl

PurposeMendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient’s prognosis.MethodsWe evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rβ1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species.ResultsWe identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rβ1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response.ConclusionsWe report the first Peruvian patient with IL-12Rβ1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.

Evans Syndrome as First Manifestation of Primary Immunodeficiency in Clinical Practice

Background: Evans syndrome (ES) is a rare immune disorder in children, manifested by simultaneous or sequential autoimmune cytopenias (ACs) of unknown cause and having a chronic course with periods of exacerbation and remission. Some primary immunodeficiencies (PIDs) may present with autoimmune manifestations without infections, masking suspicion of them. The PIDs that can typically manifest as ES are autoimmune lymphoproliferative syndrome and common variable immunodeficiency (CVID). Materials and Methods: Review of clinical charts and laboratory results of pediatric patients followed-up in the outpatient clinic of PID with a diagnosis of ES and humoral immunodeficiency. Results: Three pediatric patients, a boy and 2 girls, presented with corticosteroid-dependent ES. In the diagnostic approach, autoimmune lymphoproliferative syndrome was ruled out, and during follow-up, patients showed laboratory signs of humoral immune deficiency and were diagnosed with CVID. After initiating the recommended treatment for CVID with AC, patients improved without new exacerbations. Conclusions: These cases highlight the importance of detection of possible PID in the context of ES and the establishment of CVID treatment to control AC.

Sirolimus as an alternative treatment in patients with granulomatous-lymphocytic lung disease and humoral immunodeficiency with impaired regulatory T cells

One of the most frequent non‐infectious complications of humoral immunodeficiencies with a CVID‐like pattern is a particular form of inflammatory lung disease which is called granulomatous‐lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success.

B Regulatory Cells: Players in Pregnancy and Early Life

Pregnancy and early infancy represent two very particular immunological states. During pregnancy, the haploidentical fetus and the pregnant women develop tolerance mechanisms to avoid rejection; then, just after birth, the neonatal immune system must modulate the transition from the virtually sterile but haploidentical uterus to a world full of antigens and the rapid microbial colonization of the mucosa. B regulatory (Breg) cells are a recently discovered B cell subset thought to play a pivotal role in different conditions such as chronic infections, autoimmunity, cancer, and transplantation among others in addition to pregnancy. This review focuses on the role of Breg cells in pregnancy and early infancy, two special stages of life in which recent studies have positioned Breg cells as important players.

Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.

Adiponectin, Leptin and Inflammatory Markers in HIV-Associated Metabolic Syndrome in Children and Adolescents.

Background: Metabolic syndrome (MetS) is more common in HIV-infected adults and children than in the general population. Adipocytokines and inflammatory markers may contribute to the pathophysiology of this condition and could be useful indices for monitoring MetS. The objective of this study was to provide information on the prevalence of MetS and investigate the role of adipocytokines and other biomarkers in this syndrome in HIV-infected pediatric patients. Methods: A cross-sectional study was conducted between October 2013 and March 2014 in the outpatient clinics of 2 tertiary pediatric referral hospitals. Fifty-four HIV-infected children and adolescents were included. MetS was defined according to the International Diabetes Federation and modified National Cholesterol Education Program Adult Treatment Panel III criteria. Measurements included anthropometry, waist circumference, blood pressure, fasting lipids, glucose and insulin, adiponectin, leptin, interleukin-6, vitamin D and C-reactive protein and clinical lipodystrophy assessment. Results: Among the total, 3.7% of patients met the International Diabetes Federation criteria for MetS and 7.4% met the National Cholesterol Education Program Adult Treatment Panel III criteria. C-reactive protein and leptin levels were significantly higher and adiponectin level significantly lower in patients with MetS, regardless of the criteria used. Insulin resistance was observed in 40.7% of patients; abnormal quantitative insulin sensitivity check index values were found in 88.9%. Eighteen patients (33.3%) had vitamin D deficiency. Conclusions: The prevalence of MetS was similar to that observed in larger cohorts of HIV-infected patients in our setting. Adipocytokine dysregulation seems to be related to MetS in HIV-infected children. A high percentage of patients showed insulin resistance, which should be strictly monitored.