A Selective Screening Strategy Performed in Pre-School Children and Siblings to Detect Familial Hypercholesterolemia.

(1) Background: Familial hypercholesterolemia (FH), a most common genetic disorder, is underdiagnosed and untreated, especially in children. Individuals with heterozygous familial hypercholesterolemia mostly present without clinical symptoms and are not informed about their high risk for myocardial infarction. Early diagnosis and treatment can prevent premature atherosclerosis and cardiovascular events in patients with FH. The aim was to evaluate the detection rate of pre-school children with FH at school doctor visits in Vienna and, moreover, to examine the frequency of FH identified in the children's siblings by this type of screening. (2) Methods: The selective FH- screening was implemented at the school enrolment examinations in the public primary schools of Vienna. The study period included the school years starting in 2017 to 2020. FH was suspected if a questionnaire on hypercholesterolemia, or cardiovascular events in the family history or on the presence of xanthomas or xanthelasma, was positive. Subsequently, lipid testing was performed on pre-school children and their siblings and elevated lipid screening was defined as either positive by LDL-C ≥ 160 mg/dL and/or non-HDL-C ≥ 190 mg/dL or as borderline by LDL-C ≥ 130 mg/dL and/or non-HDL-C ≥ 160 mg/dL. (3) Results: 66,108 pre-school children participated in the school enrolment examination in 868 public elementary schools in Vienna. In 512 (4%) children, the questionnaire caused suspicion of FH. 344 families agreed their participation in the study. Out of 344 (52% male) tested pre-school children, 20 individuals (40% male) had elevated blood lipid levels with a mean LDL-C of 155 ± 29 mg/dL and a non-HDL-C of 180 ± 24 mg/dL. Out of 291 (44% male) tested siblings, 17 individuals (41% male) showed elevated lipids with a mean LDL-C of 144 ± 19 mg/dL, and a non-HDL-C of 174 ± 19 mg/dL. (4) Conclusions: Screening is the key for early diagnosis and treatment of FH. We have implemented a pre-school screening strategy in cooperation with school physicians. We could identify 20 pre-school children and 17 siblings with an elevated lipid screening test. Full implementation of FH-screening in the pre-school examination visits in Vienna would help to detect high-risk children.

Selective screening for familial hypercholesterolemia in Austrian children - first year results.

BACKGROUND: Familial hypercholesterolemia (FH), the most frequent monogenetic hereditary disorder, is underdiagnosed and undertreated. Early identification of FH is essential because of the increased risk for premature cardiovascular diseases and childhood might be the optimal period for cholesterol screening. Aim of this selective screening was to detect familial hypercholesterolemia, the most frequent monogenetic hereditary disorder in children to guarantee early detection and treatment. The Austrian strategy for primary schools, to perform a pre-school examination by school physicians, allows to reach all children aged 5-7 years. METHODS: The screening was conducted within the school enrolment examinations in all 215 public primary schools in Vienna between January to May 2017. Positive cholesterol screening was defined by non-HDL-C > 160 mg/dL and/or LDL-C > 130 mg/dL. RESULTS: In total, 18,152 children had their school enrolment examination. From 133 tested pre-school children, nine individuals were positive-screened with a mean LDL-C of 161 ± 26 mg/dL, non-HDL-C of 181 ± 24 mg/dL and total cholesterol (TC) of 239 ± 23 mg/dL. From 85 siblings, four individuals were positively screened with a mean LDL-C of 150 ± 7 mg/dL, non-HDL-C of 184 ± 8 mg/dL and TC of 231 ± 10 mg/dL. Patients did not have any xanthomas, xanthelasms, arcus lipoides, or any cardiovascular comorbidities. CONCLUSIONS: Screening at early childhood by school physicians seems to be a successful strategy and possible. With this Austrian selective screening method, FH Kids Austria, we could find nine patients with positive raised level LDL-cholesterol and/or non-HDL cholesterol out of 133 blood tests. Prevention of cardiovascular diseases is essential and it is our duty to increase the awareness of this disease. Limitations of the FH Kids project were reduced participation of school physicians and refusal of the parents.

Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging.

Premature newborns are highly susceptible to severe bacterial infections. This is partially due to their immature innate immune system, characterized by decreased neutrophil and monocyte activity as well as by reduced concentrations of complement factors. However, additional mechanisms might be important for innate immunity and are still the subject of considerable debate. The importance of pattern recognition domains such as Toll-like receptors (TLR) has been fully acknowledged within the last few years. Therefore, we investigated age-related monocyte TLR4 expression and lipopolysaccharide-induced cytokine secretion from very low birth weight infants (VLBWI) and from newborns after wk 30 of gestation in comparison to healthy adults. In VLBWI, expression of TLR4 surface protein, detected by flow cytometry, and TLR4-specific mRNA, quantified by real time-PCR, were significantly reduced in comparison to mature infants and to adults. Reduced TLR4 expression was paralleled by significantly diminished ex vivo LPS stimulated IL-1beta, IL-6, and tumor necrosis factor-alpha secretion into whole blood. We conclude that, in VLBWI, the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response.

Monocyte switch in neonates: high phagocytic capacity and low HLA-DR expression in VLBWI are inverted during gestational aging.

Pre-term neonates are at high risk to develop early-onset sepsis which possibly is caused by an immature immune system. Monocytes play a pivotal role as professional phagocytic and antigen-presenting cells in the innate immunity. In the present study, we investigated in monocytes from cord blood the expression of human leukocyte antigen (HLA)-DR as a marker for antigen-presenting capability, the expression of the high-affinity receptor for IgG (FcgammaRI/CD64), and the capacity to phagocytize non-opsonized Escherichia coli. We compared 70 infants in three groups according to their gestational age (group I: 20 very low birth weight infants (VLBWI), 24-31 weeks of gestation; group II: 25 pre-term infants, 32-36 weeks of gestation, and group III: 25 term neonates). The expression of CD64 as well as the phagocytic capacity of monocytes from cord blood were highest in VLBWI (p < 0.05 and p < 0.01, respectively). In contrast, HLA-DR expression was significantly (p < 0.05) diminished in VLBWI, which possibly leads to a reduced antigen-presenting capacity. We conclude that monocytes have different functional properties during gestational aging, which perhaps participate in the high incidence of infections in VLBWI.

Cervicofacial lymphadenitis due to atypical mycobacteria: a surgical disease.

Despite the increasing prevalence of cervicofacial lymphadenitis due to atypical mycobacteria (AMB) in children, the true nature of AMB infection in clinical practice is poorly understood. The purpose of our study was to define the most common signs and symptoms, and to establish a workable scheme of diagnosis and treatment. Patients fulfilling the criteria of AMB infection (i.e., clinical signs, positive cultures or polymerase chain reaction, histologic features) were included in the study. All children underwent a standard surgical procedure, depending on pretreatment and the course of the disease. Sixteen infants presented with characteristic unilateral lymphadenopathy predominantly involving the submandibular area (13/16). Eight children had been initially treated at various institutions by fine-needle puncture or incision, and 7 of the 16 patients had received antituberculous multidrug treatment for a varying length of time. Complete excision of the affected lymph nodes was the definitive treatment in all patients. Three children had transient marginal mandibular nerve paralysis that resolved within a few months in all cases. Recognition of the characteristic features of AMB adenitis may permit early diagnosis and appropriate surgical treatment.

Decreased phagocytic capacity of cord blood monocytes in second- and third-born multiplets.

OBJECTIVE: To assess the risk to second- and third-borns of developing perinatal infections based on a diminished first-line immune response in comparison to the first-born. STUDY DESIGN: 11 sets of twins and 2 sets of triplets (27-39 weeks of gestation, 740-3,560 g birth weight) admitted consecutively to our neonatal care unit were investigated. All were delivered by cesarean section. Phagocytosis and the expression of TNF-alpha and IL-1 in cord blood were determined immediately and 72 h after birth from peripheral blood monocytes by FACS analysis and ELISA. RESULTS: In all second- and third-borns, phagocytosis of cord blood monocytes was significantly decreased in comparison to the first-borns (p < 0.001, p < 0.015). 72 h after birth phagocytosis determined from peripheral blood showed no significant difference between the first-borns and the second- and third-borns. Cytokine expression revealed no significant differences dependent on birth order. CONCLUSION: We suggest that the observed temporarily diminished first-line immune response of second- and third-born multiplets might be the result of a short-term reduced cellular oxygenation during delivery, but has no influence on further immunological deficiency leading to a higher risk of perinatal infections.

Monocyte phagocytosis as a reliable parameter for predicting early-onset sepsis in very low birthweight infants.

BACKGROUND: Septic complications lead to a high mortality rate in very low birthweight infants (VLBWI). Therefore, prognostic markers for the development of sepsis attach importance to start an efficient therapy as early as possible. AIMS: Functional and phenotypical variables of blood monocytes in the cord and peripheral blood were investigated to evaluate the parameters for predicting early-onset and late-onset sepsis (nosocomial infections). STUDY DESIGN: In a prospective study, 25 VLBWI were investigated. METHODS: In the cord blood taken immediately after birth, the capacity of the monocytes to phagocytose non-opsonized E. coli bacteria by flow cytometry and the ex-vivo production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 (enzyme-linked immunoassay (ELISA)) after lipopolysaccharide (LPS) stimulation were measured. At the third day, the HLA-DR expression on the monocytes (flow cytometry) and the LPS-induced cytokine production were measured from the peripheral blood. RESULTS: Five VLBWI already developed early septic complications after 24-72 h, while the other three infants had late-onset sepsis 10-18 days after birth. The prognostic significance for early-onset sepsis was highest for the decreased monocyte phagocytic capacity (sensitivity and specificity: 100%) and for the LPS-induced formation of TNF-alpha and IL-1 beta in cord blood. Moreover, in septic VLBWI, the HLA-DR expression on the monocytes was lowered on day 3 after birth. The prognostic significance for late-onset sepsis was highest for TNF-alpha and IL-1 beta levels in the peripheral blood on the third day after birth. CONCLUSIONS: The determination of phagocytosis in the cord blood seems to be a reliable parameter for predicting early-onset sepsis and offers the possibility for a forward start of an antibiotic therapy.