Antoni Noguera

Hyperlactatemia in Human Immunodeficiency Virus–Uninfected Infants Who Are Exposed to Antiretrovirals

Objective. Exposure to nucleoside analogues in fetal or early life has been associated with rare clinically significant mitochondrial toxic effects, mainly neurologic symptoms. Lactate (LA) measurements have been used to monitor nucleoside-related mitochondrial toxicity. Our aim was to determine the prevalence, clinical evolution, and risk factors for hyperlactatemia in our cohort of human immunodeficiency virus (HIV)-uninfected children who were exposed to antiretrovirals. Methods. We conducted a prospective observational study of 127 HIV-uninfected infants who were born to HIV-infected women. Clinical symptoms suggesting mitochondrial dysfunction were analyzed in routine follow-up, and LA and alanine plasma levels were obtained at 6 weeks, 3 months, 6 months, and 12 months in all patients. Elevated alanine levels, together with hyperlactatemia, suggest chronic mitochondrial injury. Results. Most (85%) women received highly active antiretroviral therapy (HAART) during pregnancy (mean duration: 31 weeks) and zidovudine during labor (93%). Most (96%) children received zidovudine alone. Hyperlactatemia with hyperalaninemia was detected in 63 children in at least 1 of the measurements. Mean LA levels were significantly higher in children who were exposed to nucleoside analogue reverse transcriptase inhibitors than in control subjects (2.88 vs 1.61 at 6 weeks, 2.78 vs 1.49 at 3 months, 1.89 vs 1.39 at 6 months, and 1.71 vs 1.24 at 12 months; peak levels: 8.06, 10.1, 7.28, and 4.48 mmol/L, respectively). In 44 patients, LA levels progressed spontaneously to normality within the first year of life. Three girls presented a slight and self-limited delay in psychomotor development, with LA peak levels of 7.3, 4.0, and 4.6 mmol/L. Only the gestational use of didanosine was associated with a higher risk of hyperlactatemia. Conclusions. In our series, almost half of the children (63 of 127) who were exposed to nucleoside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleoside analogue–induced toxicity affected neurologic development.

Hyperlactatemia in human immunodeficiency virus-infected children receiving antiretroviral treatment.

Background. Hyperlactatemia and lactic acidosis occur in HIV-infected adults receiving antiretroviral treatment. Our objective was to determine the incidence, course and risk factors for hyperlactatemia in our HIV-infected pediatric patients. Design. A prospective observational study of venous lactate concentrations during a 28-month period in 80 HIV-infected children, most of whom were receiving antiretrovirals. Methods. Venous blood lactate concentrations were measured every 6 months under optimal sample-obtaining conditions. Alanine values from the same blood sample were performed when lactate concentrations were elevated. Hyperalaninemia is observed only when mitochondrial oxidative phosphorylation is chronically disturbed. Results. Twenty-three patients (29%) were identified with hyperlactatemia, in 9 of the cases with normal alaninemia, probably caused by difficult venous punctures. The other 14 children (17%) had pathologic alanine concentrations with a mean lactate peak of 2.67 mmol/l (range, 2.05 to 4.9 mmol/l); none of them showed metabolic acidosis, and they were all symptom-free. Treatment was continued in all cases, and lactate has progressed spontaneously to normal values in 5 patients. Conclusions. Symptom-free hyperlactatemia was observed in HIV-infected children receiving nucleoside analog reverse transcriptase inhibitors. In our study, only a younger age at the beginning of antiretroviral treatment was a statistically significant risk factor for hyperlactatemia. Random measurements of blood lactate concentrations should be included in the clinical follow-up of those HIV-infected children <3 years of age who are treated with nucleoside analog reverse transcriptase inhibitors, symptomatic or not.

Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen.

Recent updates of the guidelines on the prevention of human immunodeficiency virus mother-to-child transmission have shortened the neonatal zidovudine prophylactic regimens from 6 to 4 weeks. We present a prospective observational study in a large cohort of mother-infant pairs and report that the 4-week regimen allows an earlier recovery of the anemia in these otherwise healthy infants.

Effect of melatonin and diazepam on the dissociated circadian rhythm in rats.

Abstract:  The main structures involved in the circadian system in mammals are the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN contain multiple autonomous single‐cell circadian oscillators that are coupled among themselves, generating a single rhythm. However, under determined circumstances, the oscillators may uncouple and generate several rhythmic patterns. Rats exposed to an artificially established 22‐h light–dark cycle (T22) express two stable circadian rhythms in their motor activity that reflect the separate activities of two groups of oscillators in the morphologically well‐defined ventrolateral and dorsomedial SCN subdivisions. In the experiments described in this paper, we studied the effect of melatonin and diazepam (DZP) administration in drinking water on the dissociated components of rat motor activity exposed to T22, to deduce the possible mechanism of these drugs on the circadian system. In order to suppress the endogenous circadian rhythm of melatonin, in some of the rats the pineal gland or the superior cervical ganglia were removed. The results show that melatonin or DZP treatment increased the manifestation of the light‐dependent component to the detriment of the manifestation of the non‐light‐dependent component and that melatonin, but not DZP, shortens the period of the non‐light‐dependent component. These findings suggest that both DZP and melatonin favor entrainment to external light, and that melatonin could also act on the SCN, producing changes in the period of the circadian cycle.

Severe enterovirus disease in febrile neonates

INTRODUCTION Fever in newborn infants may be due to an invasive infection with potential morbidity and mortality. Our aim was to describe the characteristics and outcome of group of febrile neonates with severe enterovirus infection compared to a group of neonates with severe bacterial infection. PATIENTS AND METHODS Prospective study including all neonates (<29 days old) admitted to a teaching hospital for fever (>38 degrees C), with positive bacterial cultures or enterovirus detection in sterile samples, from September 2003 to December 2004. Clinical information, analytical data at admission (complete leukocyte count and C-reactive protein concentrations), blood, urine, and cerebrospinal fluid culture results, molecular detection of enterovirus by polymerase chain reaction (PCR), and outcome were recorded. RESULTS Invasive bacterial infections were observed in 62 patients: urinary tract infection (n=57, including 8 cases of bacteremia), sepsis (n=3), and meningitis (n=2). Molecular tests for enterovirus were positive in 10 patients. C-reactive protein values were significantly higher in neonates with bacterial infection than in those with enterovirus infection (62,3 versus 9mg/L, P=0,008). Two patients with Streptococcus agalactiae meningitis, 1 with Staphylococcus aureus sepsis and 3 with enterovirus infection (manifested as myocarditis, hepatitis, and meningoencephalitis) required admission to the pediatric intensive care unit. Among these, 1 newborn with S. agalactiae and 2 of the 3 with enterovirus infection died. CONCLUSIONS In our series, enterovirus infection was an important cause of severe invasive disease. Specific viral diagnosis can contribute to the management of febrile neonates.

Acute oxcarbazepine overdose in an autistic boy

Oxcarbazepine (OXC), a 10-keto analogue of carbamazepine, is an antiepileptic drug licensed for the treatment of partial seizures in children and adults, as monotherapy or adjunctive therapy [1]. In humans, OXC is rapidly metabolized in liver to 10-monohydroxy-carbazepine (MHD), its active metabolite. MHD blocks voltage-sensitive sodium channels, stabilizing hyperexcited neuronal membranes, thereby inhibiting repetitive firing and decreasing the propagation of synaptic impulses [2]. Recently, successful use of OXC in the management of disruptive behaviours in autistic patients has also been reported [3].

Alterations of motor activity circadian rhythm in rats with adjuvant arthritis.

&NA; Adjuvant arthritis in rats produces alterations in the motor activity circadian rhythm. Specifically arthritic animals show a decrease in the total daily motor activity and an advance in the acrophase of the rhythm. Slight changes are also observed in the power content of the circadian harmonic as well as in the amplitude.

Evolution of mitochondrial DNA content after planned interruption of HAART in HIV-infected pediatric patients.

HAART-related long-term toxicities, many of them ascribed to mitochondrial (mt) toxicity of the nucleoside analogues, are being increasingly reported in HIV-infected children. HIV infection can also cause mt damage. Case series include 13 vertically HIV-infected pediatric patients (9 girls, median age 10.5 years) with optimal long-term response to a first-line HAART regimen who underwent planned treatment interruption (PTI). MtDNA content from peripheral blood mononuclear cells was assessed by means of a real-time PCR technique at PTI and 12 months later and expressed as an mtDNA/nuclear DNA ratio, together with lactate levels. At PTI, patients had remained a median time of 4.7 years on HAART and 4.3 years with complete suppression of viral replication. The main reason leading to PTI was treatment fatigue. One month after PTI, HIV plasmatic viral load had increased to 4.8 log copies/ml and stabilized thereafter. During the 12-month study period, all children remained free from any HIV-related clinical event. A progressive and significant decrease in median CD4 cell counts and percentages was observed 12 months after PTI. One year after PTI, the median mtDNA/nuclear DNA ratios had increased from 0.76 to 1.08 (p = 0.002) and lactate levels had decreased (from 1.12 to 0.73 mmol/liter; p = 0.019). Changes in mtDNA did not correlate with changes in lactate levels. No relationship was found between the evolution in mt toxicity markers and the rest of the clinical, immunological, and virological variables. In this series, PTI led to a partial restoration of mtDNA levels and a significant decrease in lactate values.

Mother-to-child transmission of hepatitis C virus infection in Barcelona, Spain: a prospective study

Hepatitis C virus (HCV) infection is the main cause of chronic hepatitis worldwide. With the implementation of blood product screening for HCV, mother-to-child-transmission (MTCT) has become the main route of acquisition of HCV in children. We aim to describe the seroprevalence of HCV infection among pregnant women and the rate of and risk factors for HCV MTCT in our setting. A prospective observational study was conducted on all children born to HCV-infected mothers from January 1999 to December 2005 in a pediatric teaching hospital in Barcelona, Spain. Informed consent was obtained from each mother and no intervention in the delivery procedure or feeding after birth was made, except on HIV–HCV coinfected mothers. In our center, anti-HCV antibodies are routinely measured during the first trimester of pregnancy by thirdgeneration enzyme-linked immunosorbent assay (ELISA; Axsym HCV version 3.0, Abbott, Wiesbaden, Germany), and positive results are later confirmed by means of a thirdgeneration recombinant immunoblot assay (RIBA version 3.0, Chiron, Emeryville, CA) and polymerase chain reaction (PCR) techniques (HCV-RNA viral load quantification; HCV Monitor, Roche Molecular Systems, Basel, Switzerland; limit <600 IU/mL). Variables relevant to this study include the mother’s age and the HCV mode of transmission; third trimester HCV viral load and alanine aminotransferase (ALT; normal range: 2–36 IU/mL) plasmatic levels; gestational age at birth, mode of delivery, total duration of labor, and the duration of membrane rupture; and the infant’s gender, birth weight, and type of feeding. In accordance with current guidelines [5], the children were considered to be HCV-infected if positive HCV antibodies persisted beyond the age of 18 months and/or they had two or more positive qualitative PCR results. HCV infection was excluded on the basis of two or more negative PCR qualitative results and/or HCV antibody seroreversion at or after 18 months. Indeterminate infection status was applied to children not fulfilling any of these criteria. Categorical variables were expressed as percentages, and continuous variables as means and standard deviations. Seroprevalence rate and other proportions of interest, along with their 95% confidence intervals, were estimated. During the study period, 128 out of 26,214 pregnant women were found to be HCV-infected, i.e., a prevalence of 0.49% (95% CI: 0.40–0.57). There were 144 children born to these 128 mothers, including three sets of twins and one set of triplets, and 11 pairs of siblings. Data regarding gestation, birth, and neonatal variables are summarized in Table 1. Most of the 18 HIV–HCV co-infected mothers, who accounted for 21 gestations and 22 newborns, received combined antiretroviral treatment and underwent elective cesarean section (17 out of 21 and 12 out of 21 gestations, respectively). All of the infants received prophylactic Eur J Pediatr (2007) 166:1297–1299 DOI 10.1007/s00431-006-0392-9

Rotavirus Gastroenteritis Leading to Secondary Bacteremia in Previously Healthy Infants

and resources, share ideas, and use common tools. We certainly recognize that each city, state, and region must modify their pediatric preparedness initiatives on the basis of resources available. The casual reference of pediatric guidelines in a disaster plan will not suffice. It will become quickly apparent when a pediatric health care community collaborates together that there is much skill available. However, that skill must be matched with a desire to implement change. Our Pediatric Subcommittee began as an idea and has become a model center of excellence.2 We challenge other cities to embrace the guidelines,1 form a pediatric multidisciplinary group, and collaborate. These efforts will be worthwhile, such as the guidelines. Only together can guidelines and action affect change and, ultimately, improve the care of children during a disaster.