Ventricular septal defect and aortic hypoplasia in congenital cytomegalovirus infection: occasional finding or underdetected correlation?

Background: While other viral infections occurring in early pregnancy are known to be associated with fetal cardiac malformations, little is known about CMV and its causative role. Only a few case repots have been described reporting a correlation between congenital CMV infection and cardiac defects.Case-report: We report the case of a 7-day-old neonate who was referred to our Pediatric Infectivology Department for maternal cytomegalovirus (CMV) seroconversion during the first trimester of pregnancy and confirmed congenital infection. At first evaluation, the baby presented with a cardiac murmur and signs of acute heart failure, along with jaundice and hypotonia. At cardiac ultrasound, a perimembranous doubly-committed ventricular septal defect and a reduced aortic isthmus diameter were revealed.Conclusion: Despite further large-scale prospective studies are needed to confirm or rule out this association, CMV DNA urine detection might be worth to be considered as part of the diagnostic process in neonates with isolated heart defects.

Furosemide use in Italian neonatal intensive care units: a national survey.

BACKGROUND: Furosemide is approved in full term neonates to treat edema associated with congestive heart failure, cirrhosis and renal diseases. It is often administered off-label in premature neonates, to treat respiratory conditions and at doses greater-than-recommended. We conducted a national survey on behalf of the Neonatal Pharmacotherapy Study Group of the Italian Society of Neonatology (SIN), to investigate its use in Italian neonatal intensive care units (NICUs), in conformity with current guidelines. METHODS: Between December 2016 and June 2017, a 14-item multiple-choice online questionnaire was sent to all NICU directors from the SIN directory. Gestational age, route of administration, posology, indications, referenced guidelines, adverse effects monitoring and the presence of Paediatric Cardiology or Cardiosurgery service on site were assessed. A chi-square test was performed 1) to evaluate differences in the distribution of responses between NICUs administering furosemide at doses higher-than-recommended; 2) to compare the proportion of NICUs administering furosemide at high doses in institutions with versus without a Paediatric Cardiology or Cardiosurgery service. RESULTS: The response rate was 50% (57/114). The intravenous and oral routes were chosen primarily; the intravenous administration in single doses predominated over continuous infusion. Its main therapeutic indications were congestive heart failure/overload (94.7%) and oligo-anuria (87.7%) however furosemide was also frequently used for broncopulmonary dysplasia (50.9%) and respiratory distress syndrome and/or transient tachypnea of the newborn (24.6%). In 28/57 NICUs furosemide was administered at doses higher-than-recommended. In most NICUs the same posology was used in term and preterm neonates. Compared to the total sample, a larger proportion of NICUs administering doses greater-than-recommended referenced current literature for reasons to do so (19.3 and 32.1% respectively). The presence of a Paediatric Cardiology or Cardiosurgery service on site did not correlate with the chosen posology. The majority of NICUs performed acoustic test and renal ultrasound for furosemide exposure greater than 2 weeks. CONCLUSIONS: In Italian NICUs, furosemide is commonly prescribed to term and preterm newborns for label and unlabeled indications. Doses greater-than-recommended are frequently administered. Such use is not necessarily inappropriate. More research is required to assess the efficacy and safety of unlabeled use.

Acute Inflammation and Elevated Cardiac Markers in a Two-Month-Old Infant with Severe Acute Respiratory Syndrome Coronavirus 2 Infection Presenting with Cardiac Symptoms.

Severe acute respiratory syndrome coronavirus 2 infection in children mainly shows a milder course. In complicated cases, it is unknown whether inflammation is predictive of disease severity, as in adults. Moreover, cardiac involvement is anecdotally described. We report the case of a 2-month-old infant with severe acute respiratory syndrome coronavirus 2 infection presenting with fever, tachycardia and elevated interleukin-6, who was diagnosed with myocarditis and treated with immunoglobulins.

Impact of the systematic introduction of low-cost bubble nasal CPAP in a NICU of a developing country: a prospective pre- and post-intervention study.

BACKGROUND: The use of Nasal Continuous Positive Airway Pressure Ventilation (NCPAP) has begun to increase and is progressively replacing conventional mechanical ventilation (MV), becoming the cornerstone treatment for newborn respiratory distress syndrome (RDS). However, NCPAP use in Lower-Middle Income Countries (LMICs) is poor. Moreover, bubble NCPAP (bNCPAP), for efficacy, cost effectiveness, and ease of use, should be the primary assistance technique employed in newborns with RDS. OBJECTIVE: To measure the impact on in-hospital newborn mortality of using a bNCPAP device as the first intervention on newborns requiring ventilatory assistance. DESIGN: Prospective pre-intervention and post-intervention study. SETTING: The largest Neonatal Intensive Care Unit (NICU) in Nicaragua. PARTICIPANTS: In all, 230 (2006) and 383 (2008) patients were included. INTERVENTION: In May 2006, a strategy was introduced to promote the systematic use of bNCPAP to avoid intubation and MV in newborns requiring ventilatory assistance. Data regarding gestation, delivery, postnatal course, mortality, length of hospitalisation, and duration of ventilatory assistance were collected for infants assisted between May and December 2006, before the project began, and between May and December 2008, two years afterwards. OUTCOME MEASURES: The pre- vs post-intervention proportion of newborns who died in-hospital was the primary end point. Secondary endpoints included rate of intubation and duration of NICU stay. RESULTS: Significant differences were found in the rate of intubation (72 vs 39%; p < 0.0001) and the proportion of patients treated exclusively with bNCPAP (27% vs 61%; p <0.0001). Mortality rate was significantly reduced (40 vs 23%; p < 0.0001); however, an increase in the mean duration of NICU stay was observed (14.6 days in 2006 and 17.5 days in 2008, p = 0.0481). The findings contribute to the evidence that NCPAP, particularly bNCPAP, is the first-line standard of care for efficacy, cost effectiveness, and ease of use in newborns with respiratory distress in LMICs. CONCLUSIONS: This is the first extensive survey performed in a large NICU from a LMICs, proving the efficacy of the systematic use of a bNCPAP device in reducing newborn mortality. These findings are an incentive for considering bNCPAP as an elective strategy to treat newborns with respiratory insufficiency in LMICs.

Tenofovir-induced renal tubular dysfunction in vertically HIV-infected patients associated with polymorphisms in ABCC2, ABCC4 and ABCC10 genes.

Tenofovir disoproxyl fumarate is a known cause of kidney tubular dysfunction in HIV-infected patients. Recent studies reported significant association between specific allelic variants in ABCC2, ABCC4 and/or ABCC10 genes and the development of kidney tubular dysfunction in HIV-infected adults. We describe the first 2 cases of vertically HIV-infected patients affected by kidney tubular dysfunction associated with polymorphisms in the ABCC genes.

Cholecalciferol supplementation in HIV-infected youth with vitamin D insufficiency: effects on vitamin D status and T-cell phenotype: a randomized controlled trial.

OBJECTIVES: In addition to its known effects on bone metabolism, vitamin D may regulate immune function. DESIGN: We performed a randomized controlled trial (RCT) to test whether cholecalciferol supplementation can improve vitamin D status and affect the T-cell phenotype in HIV-infected youth with vitamin D insufficiency. METHODS: Fifty-two HIV-infected patients aged 8 to 26 years and with serum 25(OH) D <30 ng/mL were randomized to receive orally vitamin D3 100,000 IU or placebo every 3 months for 4 doses. Serum 25(OH)D, 1,25(OH)2D, PTH, and CD4+ T cells were assessed 3 months before baseline and at 0, 3, 6, 9, and 12 months, while Th1-, Th2-, Th17-, and Treg-subsets and T-lymphocyte vitamin D receptor were assessed at 0, 3, and 12 months. RESULTS: Forty-eight subjects (25 receiving vitamin D and 23 receiving placebo) completed the RCT. Cholecalciferol supplementation produced an early (3 months) decrease in PTH, a concomitant increase in 25(OH)D, and a later (6 months) increase in 1,25(OH)2D levels, all persisting at 12 months. The frequency of vitamin D insufficiency at 12 months was 20% versus 60% in the intervention versus placebo group (P = .007). Cholecalciferol supplementation had no effect on CD4+ T-cell counts but was associated with a decreased Th17:Treg ratio at 3 months. CONCLUSIONS: In our cohort of HIV-infected youth, a 12-month cholecalciferol supplementation increased 25(OH)D and 1-25(OH)2D and decreased PTH levels but had no effect on CD4+ T-cells. However, it was associated with changes in CD4+ T-cell phenotype, warranting further investigation.

Antiretroviral therapy and pregnancy: effect on cortical bone status of human immunodeficiency virus-infected Caucasian women as assessed by quantitative ultrasonography.

Treatment with antiretroviral agents (ARVs) during pregnancy is important to prevent mother-to-child transmission of the human immunodeficiency virus (HIV), but their use has been associated with low bone mineral density in adult patients. Currently, there are no data regarding the bone status of HIV-infected women who received ARV during pregnancy. The aim of this study was to evaluate cortical bone status at delivery in a group of HIV-infected women who received ARV during pregnancy and to monitor the changes occurring during the first year postpartum. We studied 33 HIV-infected and 116 HIV-uninfected healthy Caucasian women within 4 days from delivery. Follow-up measurements were performed at 4 and 12 months postpartum in 17 HIV-infected and 55 healthy women. Cortical bone status was evaluated by quantitative ultrasonography at the mid-tibia, and bone measurements were expressed as the speed of sound (SOS). HIV-infected women after delivery had a median SOS of 3,985 (3,567-4,242) m/s, while the median SOS of healthy women was 4,025 (3,643-4,250) m/s. The difference was not significant (t = 0.39, P = 0.69). No significant differences were observed between ARV-exposed and control subjects at 4 and 12 months. Our data suggest that ARV during pregnancy and the first year after delivery does not affect negatively cortical bone status.

Splenomegaly and variceal bleeding in a ten-year-old HIV-infected girl with noncirrhotic portal hypertension.

Noncirrhotic portal hypertension is an uncommon liver disease of unknown origin, increasingly described in HIV-infected adults. Prolonged antiretroviral exposure, in particular to didanosine, and thrombophilic predisposition have been suggested as potential pathogenic factors. Data are limited in children. We describe a 10-year-old HIV-infected girl with noncirrhotic portal hypertension who presented with progressive spleen enlargement and variceal bleeding.

Exposure to antiretroviral agents during pregnancy does not alter bone status in infants.

The use of combined antiretroviral agents during pregnancy is important to prevent mother-to-child transmission of human immunodeficiency virus (HIV). Antiretroviral treatment (ARV) is associated with reduced bone mass and altered bone metabolism in HIV-infected patients. There are no data regarding the effect of ARV exposure during pregnancy on newborns and infants. We therefore studied 38 subjects born from HIV-infected mothers, and we measured the speed-of-sound (SOS) at the tibia by quantitative ultrasonography (QUS) just after birth. QUS measurements at mid-tibia is easily performed in infants with the appropriate probe. Nevertheless, at this skeletal site only cortical bone is present, and therefore QUS measurements reflect the status of only one kind of bone tissue. We also measured bone alkaline phosphatase (BAP) and C-terminal telopeptide of type I collagen (CTX) in the cord blood as bone formation and resorption markers, respectively. SOS measurements were repeated at 4 and 12 months of age. As a control group we studied 94 subjects born from HIV-negative mothers. At birth the median (range) SOS of ARV-exposed neonates was 3006 (2870-3168) m/s, while that of control subjects was 3007 (2757-3311) m/s. The difference was not significant. BAP concentration of ARV-exposed was 103.6 (31.6-182.8) U/L, not different from that of control subjects (104.4 [43.2-227.2] U/L). CTX concentrations were 1.07 (0.26-2.8) ng/mL, and 1.38 (0.34-4.2) ng/mL in ARV-exposed and control subjects, respectively. SOS measurements at 4 months and 12 months of age were available for 17 ARV-exposed subjects and for 57 control subjects. SOS values changed significantly over time in both groups (F=6.1; P<0.0001). No differences were present between ARV-exposed and control subjects at 4 and 12 months. Our study suggests that ARV exposure during intrauterine life does not affect negatively bone metabolism and bone development, and that the changes occurring in bone QUS measurements during the first year of life in ARV-exposed subjects are similar to those occurring in healthy control infants.

In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers.

BACKGROUND: Growth impairment and bone toxicity due to tenofovir disoproxil fumarate (TDF) fetal exposure has been described mainly in animals. We evaluated growth pattern and bone health in TDF-exposed HIV-uninfected children born to HIV-infected mothers, defined as seroreverters (SR). METHODS: This was a multicentre observational cross-sectional cohort study enrolling 68 SR who were in utero exposed to an antiretroviral regimen including (TDF+) or not including (TDF-) tenofovir. Neonatal data and duration of antiretroviral exposure were recorded. At enrolment, anthropometric measures, tibial speed of sound (SOS) by quantitative ultrasound and several parameters of bone metabolism were assessed. RESULTS: Gestational age and median in utero antiretroviral exposure were similar in subjects exposed to TDF (n=33) and those non-exposed (n =35). Age at enrolment was comparable in the two groups (TDF-exposed range 11.8-76.2 months and TDF non-exposed range 11.8-77.9 months). The incidence of low weight and length measurements (<10th percentiles) at birth was similar in TDF-exposed and TDF non-exposed. Normal growth development was found in both groups of subjects at enrolment. The median (0.6; range -2.4-2.6) SOS z-score of TDF-exposed was similar to the median (0.8; range -2.2-4.4) SOS z-score of TDF non-exposed (Student's t=0.84; P=0.40). Parameters of bone metabolism were similar in the two groups. CONCLUSIONS: Exposure to TDF during pregnancy does not impair growth patterns, bone health and markers of bone metabolism in SR infants and young children born to HIV-infected women.

Long-term immunogenicity after one and two doses of a monovalent MF59-adjuvanted A/H1N1 Influenza virus vaccine coadministered with the seasonal 2009-2010 nonadjuvanted Influenza virus vaccine in HIV-infected children, adolescents, and young adults in a randomized controlled trial.

Few data are available on the safety and long-term immunogenicity of A/H1N1 pandemic influenza vaccines for HIV-infected pediatric patients. We performed a randomized controlled trial to evaluate the safety and long-term immunogenicity of 1 versus 2 doses of the 2009 monovalent pandemic influenza A/H1N1 MF59-adjuvanted vaccine (PV) coadministered with the seasonal 2009-2010 trivalent nonadjuvanted influenza vaccine (SV) to HIV-infected children, adolescents, and young adults. A total of 66 HIV-infected patients aged 9 to 26 years were randomized to receive one (group 1) or two (group 2) doses of PV coadministered with 1 dose of SV. The main outcome was the seroconversion rate for PV at 1 month. Secondary outcomes were the geometric mean titer ratios and the seroprotection rates at 1 month for all vaccines, seroconversion rates at 1 month for SV, and longitudinal changes of antibody titers (ABTs) at 1, 2, 6, and 12 months for all vaccines. Groups 1 and 2 had similar CD4 counts and HIV RNA levels during the study. The seroconversion rate for PV was 100% at 1 month in both groups. ABTs for PV were high during the first 6 months and declined below seroprotection levels thereafter. Longitudinal changes in ABTs were similar in groups 1 and 2 for both PV and SV. The side effects of vaccination were mild and mostly local. In HIV-infected children, adolescents, and young adults, the immune response triggered by a single dose of PV was similar to that obtained with a double dose and was associated with long-term antibody response.

Long-term renal safety of tenofovir disoproxil fumarate in vertically HIV-infected children, adolescents and young adults: a 60-month follow-up study.

BACKGROUND AND OBJECTIVE: Sporadic cases of renal toxicity have been reported in HIV-infected children treated with tenofovir disoproxil fumarate (TDF). We assessed the long-term renal safety of TDF in a cohort of vertically HIV-infected children, adolescents and young adults. METHODS: We evaluated 26 HIV-infected children, adolescents and young adults, aged 4.9-17.4 years at baseline, every 6 months for 60 consecutive months. At the baseline visit, they had an undetectable viral load and a good immune reconstitution and were being treated with lamivudine, stavudine and a protease inhibitor (PI). At the same visit, stavudine was replaced with TDF and the PI with efavirenz. Serum creatinine, estimated glomerular filtration rate (GFR), urine protein to creatinine ratio, serum phosphate, ratio of the maximum rate of tubular phosphate reabsorption to the GFR (TmPO(4)/GFR), urine glucose, and urine α(1)-microglobulin to creatinine ratio were used as markers of renal function. The outcome-time relationships were studied using generalized estimating equations (GEEs). In addition to time (continuous, ten equally spaced intervals), sex, age at baseline and CD4+ T-cell count were used as covariates. RESULTS: A moderate reduction in GFR was observed only once in an underweight female patient. There was no occurrence of proteinuria, hypophosphataemia or glycosuria. Moreover, TmPO(4)/GFR was stable and the urine α(1)-microglobulin to creatinine ratio was always within normal limits. CONCLUSION: TDF had an excellent renal safety profile in HIV-infected children, adolescents and young adults regularly followed up for 60 months.

Antiretroviral drugs in HIV-infected children.

Availability of highly active antiretroviral therapy has dramatically increased survival rates and substantially modified the course of HIV infection, which has now become a chronic disease both in adults and in children. Treatment strategies in paediatric patients have to face with specific challenges associated with selection of a successful antiretroviral drug regimen, long-lasting maintenance of adherence to therapy, short and long-term drug-related toxicities and emerging of extensive drug resistance. This review shows an up-to-date picture of the ultimate advances of antiretroviral therapy in HIV-infected children.

Antiretroviral therapy and bone mineral measurements in HIV-infected youths.

Reduced bone mass measurements are often found in HIV-infected youths. Both in vitro and human studies demonstrated a role of antiretroviral treatment in determining bone mass alteration. Nevertheless, the data regarding the responsibility of different antiretroviral drugs on bone health in children and adolescents are highly controversial. The purpose of the current study was to relate antiretroviral treatment to bone mass measurements in a large cohort of HIV-infected children and adolescents. Bone mineral content (BMC) was measured in 86 HIV-infected youths (aged 4.8-22.1 years), and in 194 healthy controls (aged 4.9-21.9 years). Fifteen patients were naive to antiretroviral treatment, 11 were receiving a dual nucleoside reverse transcriptase inhibitor (NRTIs) combination, 32 a protease inhibitor (PI)-based antiretroviral treatment, and 28 a non-nucleoside reverse transcriptase inhibitor (NNRTIs)-based regimen. Comparisons between healthy and HIV-infected children and adolescents have been performed by multiple regression analyses to correct for differences in age, sex, and anthropometric measurements. Patients receiving a PI-based treatment had lumbar spine and whole body BMC values significantly lower than healthy children (P<0.05). BMC measurements of patients on other therapeutic regimens or naive to antiretroviral treatment did not differ significantly from those of healthy children. Among patients receiving a PI-based regimen, those receiving full dose Ritonavir had significantly lower lumbar spine BMC values compared to other patients. Lumbar spine and whole body BMC measurements of patients receiving a Stavudine-containing regimen were lower compared to healthy controls, naive patients, and patients on other antiretroviral regimens. Multivariate analyses showed that patients receiving both Stavudine and full dose Ritonavir had significantly lower BMC values both at the lumbar spine (P=0.0033), and in the whole skeleton (P=0.05). In conclusion, antiretroviral treatment may have a detrimental effect on bone health of HIV-infected youths: the use of Ritonavir full dose alone or in combination with Stavudine is associated to lower bone mass measurements. The use of antiretroviral regimens including these drugs should thus be monitored closely in HIV-infected youths.