Oseltamivir pharmacokinetics and clinical experience in neonates and infants during an outbreak of H1N1 influenza A virus infection in a neonatal intensive care unit.

Detailed oseltamivir pharmacokinetics have yet to be reported in neonates and infants; this group is at high risk of serious influenza-associated complications. Extrapolation of doses from older patients is complicated by rapid organ and drug-metabolizing enzyme maturation. A pharmacokinetic study has been conducted during an influenza A(H1N1) outbreak in a neonatal intensive care unit. Each included patient provided 4 samples for oseltamivir and 4 samples for its active metabolite oseltamivir carboxylate. A population pharmacokinetic model was developed with NONMEM. Allometric weight scaling and maturation functions were added a priori to scale for size and age based on literature values. Nine neonates and infants were recruited. A physiologically parameterized pharmacokinetic model predicted typical day 1 area under the curve (AUC(0-12)) values of 1,966 and 2,484 µg · h/liter for neonates and infants of ≤ 37 weeks of postmenstrual age (PMA) and >37 weeks of PMA treated with 1 mg/kg of body weight and 2 mg/kg, respectively. The corresponding steady-state AUC(0-12) values were 3,670 and 4,559 µg · h/liter. Premature neonates treated with 1 mg/kg and term babies treated with 2 mg/kg should have average oseltamivir carboxylate concentrations in a range similar to that for adults treated with 75 mg, corresponding to >200-fold above the half-maximal inhibitory concentration (IC(50)) value for influenza A(H1N1) from the start of therapy.

Inhaled colistin for the treatment of tracheobronchitis and pneumonia in critically ill children without cystic fibrosis.

Data regarding the role of inhaled colistin in critically ill pediatric patients without cystic fibrosis are scarce. Three children (one female), admitted to the intensive care unit (ICU) of a tertiary-care pediatric hospital in Athens, Greece, during 2004-2009 received inhaled colistin as monotherapy for tracheobronchitis (two children), and as adjunctive therapy for necrotizing pneumonia (one child). Colistin susceptible Acinetobacter baumannii and Pseudomonas aeruginosa were isolated from the cases' bronchial secretions specimens. All three children received inhaled colistin at a dosage of 75 mg diluted in 3 ml of normal saline twice daily (1,875,000 IU of colistin daily), for a duration of 25, 32, and 15 days, respectively. All three children recovered from the infections. Also, a gradual reduction, and finally total elimination of the microbial load in bronchial secretions was observed during inhaled colistin treatment in the reported cases. All three cases were discharged from the ICU. No bronchoconstriction or any other type of toxicity of colistin was observed. In conclusion, inhaled colistin was effective and safe for the treatment of two children with tracheobronchitis, and one child with necrotizing pneumonia. Further studies are needed to clarify further the role of inhaled colistin in pediatric critically ill patients without cystic fibrosis.

Hepatitis B-specific T helper cell responses in uninfected infants born to HBsAg+/HBeAg- mothers.

Vertically transmitted hepatitis B virus (HBV) usually causes chronic infection. While combined active-passive immunoprophylaxis in neonates of hepatitis B surface antigen-positive (HBsAg(+)) mothers at birth prevents vertical transmission, it is not yet clear whether neonates encounter the virus or its products in the absence of hepatitis B e antigen (HBeAg). This study was undertaken to investigate HBV antigen-specific T-cell responses in vaccinated neonates of HBsAg(+)/HBeAg(-) mothers. Blood was collected from 46 HBsAg(+) mothers and their neonates (subjects) as well as 24 age-matched controls. All neonates of HBsAg(+) mothers received appropriate immunoprophylaxis, and HBsAg and hepatitis B surface antibody (anti-HBs) antibody titers were determined after completion of the vaccination course. Peripheral blood mononuclear cells (PBMCs) from infants at birth, 1 and 6 months of age were stimulated with recombinant HBsAg, hepatitis B core antigen (HBcAg) and mitogen, and interferon (IFN)-γ concentrations were determined by ELISA. HBsAg-induced production of IL-2, IL-5, IL-6 and IL-10 was assessed using a cytometric bead array kit on cells from 6-month-old neonates post-vaccination. All neonates were HBsAg(-) and responded to vaccination. Increased IFN-γ production following HBcAg stimulation was seen in 30.4% of neonates born to HBsAg(+)/HBeAg(-) mothers. Subjects demonstrated significantly higher IL-2 production post-HBsAg stimulation, whereas IL-5, IL-6 and IL-10 cytokine responses were not significantly different. Almost one-third of uninfected neonates developed viral antigen-induced IFN-γ production, suggesting that they had been exposed to virions or viral derivatives. This encounter, however, did not impair their T-cell responses to vaccination.

Dendritic cells in uninfected infants born to hepatitis B virus-positive mothers.

Plasmacytoid dendritic cells (pDCs) play a central role in antiviral immunity, detecting viruses via Toll-like receptors (TLR) and producing in response vast amounts of type I interferons (IFNs). Hepatitis B virus (HBV) causes chronic infection after vertical transmission. This study investigated whether an HBV-infected maternal environment might influence DC numbers and pDC function in uninfected infants. Blood was collected from inactive HBsAg carrier and control mothers and their infants at birth and 1 and 6 months of age. HBV DNA was measured in maternal and neonatal perinatal sera using real-time PCR. The circulating frequencies of myeloid DCs (mDCs) and pDCs were determined in the babies by flow cytometry. Peripheral blood mononuclear cells (PBMCs) and cord blood pDCs were stimulated with resiquimod, and alpha interferon (IFN-alpha) production and the pDC phenotype were assessed. The effect of the common-cold virus, rhinovirus (RV), on resiquimod stimulation was also determined. HBV DNA was detected in 62.3% of the mothers and 41% of their infants. DC numbers and pDC functions were similar between subjects and controls and were not correlated with maternal or neonatal viremia. RV infection did not induce pDC maturation until the age of 6 months, and it reduced TLR7-dependent resiquimod-induced IFN-alpha production similarly in both groups. Although the DC system is immature at birth, DCs of uninfected neonates of HBV-positive mothers are competent to initiate and maintain T-cell responses. RV is a weak inducer of IFN-alpha production until the age of 6 months and inhibits IFN-alpha responses triggered by the TLR7 pathway.

Intravenous colistimethate (colistin) use in critically ill children without cystic fibrosis.

INTRODUCTION: The increasing frequency of infections caused by multidrug-resistant (MDR) Gram-negative bacteria has led to the reappraisal of colistimethate use. METHODS: We present a case series of critically ill pediatric patients without cystic fibrosis who received intravenous colistimethate treatment. All available relevant medical records were reviewed. RESULTS: Seven children without cystic fibrosis (mean age 7.7 years; 2 female), admitted to the intensive care unit of a tertiary-care pediatric hospital in Athens, Greece, were identified to have received intravenous colistimethate during October 2004 to May 2008. MDR Acinetobacter baumannii, Pseudomonas aeruginosa, and/or Klebsiella pneumoniae were isolated from blood and/or bronchial secretions specimens in 6 of 7 reported patients. All isolates were susceptible to colistin. All 7 patients received intravenous colistimethate in a dosage of 5 mg/kg daily (divided in 3 equal doses, administered every 8 hours). Five children received colistimethate for 10 days and the remaining 2 for 2 and 23 days, respectively. The infections caused by MDR Gram-negative bacteria were improved in 6 children with microbiologically documented infections. Five of the 7 children were discharged from the ICU. The remaining 2 children died (1 of them had received colistimethate for 2 days); their death was not attributed to MDR Gram-negative infection. No nephrotoxicity or other type of toxicity of colistimethate was noted in this case-series. CONCLUSIONS: Although the small number of included cases precludes any firm conclusions, our study suggests that colistimethate may have a role for the treatment of infections caused by MDR Gram-negative bacteria in critically ill pediatric patients.

Kawasaki disease: an overview.

PURPOSE OF REVIEW: Kawasaki disease is an acute, self-limited vasculitis of childhood. The increasing frequency of the disease as well as the deficiency of specific diagnostic means renders its diagnosis and treatment an area of intense investigation. The purpose of this review is to summarize all the known features of Kawasaki disease and also give an insight to the latest findings. RECENT FINDINGS: Kawasaki disease is one of the leading causes of acquired heart disease in children while its cause remains essentially unknown. Viruses, bacterial conventional as well as superantigens, and genetic polymorphisms have been implicated in the etiology of the disease. Markers of inflammation, such as CCL2 and CCXCL10, contribute to the pathology and the diagnosis of Kawasaki disease. Intravenous administration of immunoglobulin remains the mainstay of therapy for Kawasaki disease. Nevertheless, forms of the disease refractory to intravenous administration of immunoglobulin therapy may respond to aspirin, corticosteroids, cyclophosphamide, and/or plasmapheresis. SUMMARY: The present review covers evidence regarding the history of Kawasaki disease, the epidemiology, etiology, pathology, genetic influences, and long-term sequela. It also includes an evaluation of contemporary diagnostic techniques and optimal therapeutic approaches with an emphasis on recent publications.

Liposomal amphotericin B for the treatment of visceral leishmaniasis.

During the past decade, liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). The World Health Organization convened a workshop to review current knowledge and to develop guidelines for liposomal amphotericin B use for VL. In Europe, liposomal amphotericin B is widely used to treat VL. In Africa and Asia, the VL disease burden is high and drug access is poor; liposomal amphotericin B is available only through preferential pricing for nonprofit groups in East Africa. Clinical trials and experience demonstrate high efficacy and low toxicity for liposomal amphotericin B (total dose, 20 mg/kg) in immunocompetent patients with VL. Combination trials in areas with antileishmanial drug resistance, and treatment and secondary prophylaxis trials in VL-human immunodeficiency virus-coinfected patients, are important to safeguard the current armamentarium and to optimize regimens. The public health community should work to broaden access to preferential liposomal amphotericin B pricing by public sector VL treatment programs.

The significance of Ureaplasma urealyticum as a pathogenic agent in the paediatric population.

PURPOSE OF REVIEW: Ureaplasma urealyticum is a frequent commensal in the lower genital tract of sexually active women. It may be transmitted perinatally from the colonized mother to her offspring, often resulting in prematurity and neonatal disease. The microorganism also sustains a causative role for infectious diseases in older children. RECENT FINDINGS: U. urealyticum infection can be diagnosed by culture, polymerase chain reaction, and the detection of specific antibodies. Neonatal infection has been implicated in various pathological conditions including pneumonia, chronic lung disease, central nervous system disorders, sepsis, osteomyelitis and even death. Older children may present with wheezing, pneumonitis, pertussis-like syndrome and different forms of arthritis. Large well-designed trials have demonstrated that the regular administration of antibiotics to vaginally colonized women are not beneficial in terms of preventing preterm labour. Macrolide-containing antibiotic regimens are, however, recommended for preterm premature rupture of the membranes. Erythromycin treatment of ureaplasma respiratory colonized premature infants shows no reduction in the incidence of chronic lung disease. Treatment of central nervous system infections, sepsis and arthritides includes tetracyclines, fluoroquinolones and anti-inflammatory agents, respectively. SUMMARY: This review covers recent evidence concerning the role of U. urealyticum as a pathogen during childhood. It also includes an evaluation of contemporary diagnostic techniques and optimal therapeutic approaches.

Intrauterine infection with parvovirus B19 and CMV: implications in early and late gestation fetal demise.

In utero viral infections have been associated with an adverse pregnancy outcome and may have a causative role in the unexplained fetal death file. Parvovirus B19 and cytomegalovirus are among the most common pathogens implicated in fetal loss cases. Parvovirus B19 has been reported to account for cases of spontaneous abortions, intrauterine fetal death and nonimmune hydrops fetalis, whereas cytomegalovirus accounts for nonimmune hydrops fetalis, intrauterine growth retardation and congenital anomalies. This review aims to summarize the current literature in an attempt to underline the need for routine screening, close follow-up and prevention. A better understanding of the pathogenetic mechanisms of viral infections during the crucial time of organogenesis, along with early detection, may contribute to the reduction in stillbirth rate.

Immunologic markers in the neonatal period: diagnostic value and accuracy in infection.

Diagnosis of early-onset neonatal infection has led to the development of several screening tests including C-reactive protein, a very commonly used marker, and cytokines (mainly interleukin-6 and -8), alone or in combination with C-reactive protein, based on the premise that their increases in response to infection may precede that of C-reactive protein. In recent years the search for diagnostic tests has turned to procalcitonin, a propeptide of calcitonin, which appears to be a promising marker of infection in newborn infants. Additionally, specific leukocyte cell surface antigens (mainly CD11b and CD64), detected by flow cytometry, are evaluated as markers of neonatal infection, since their expression on the cell membrane increases in substantial quantities after leukocyte activation by bacteria or their cellular products. This review aims to examine the role of these newly available immunologic indices and to assess their validity as diagnostic markers of infection during the neonatal period.

Otitis media with effusion: an effort to understand and clarify the uncertainties.

Otitis media with effusion--defined as the accumulation of middle-ear effusion behind an intact tympanic membrane without signs or symptoms of acute infection--is one of the most common causes of hearing loss in children in developed countries, potentially leading to language deficits. Although treatment of chronic or relapsing otitis media with effusion is considered imperative, none of the preventative or nonsurgical management measures currently available have proven effective. Tympanostomy tube placement remains the recommended treatment option for high-risk children or for cases of unresponsive otitis media with effusion. This can be attributed to the uncertainties surrounding its pathogenesis. Multiple factors and several possible pathogenetic models have been proposed to explain the production and persistence of middle-ear effusion; only a few of them are supported by sufficient evidence. In this review, the authors will present current knowledge on the pathogenesis, consequences, diagnosis and management of otitis media with effusion. An effort will be made to clarify those aspects sufficiently supported by evidence-based studies, and to underline those that remain unfounded.

Maternal genital colonization with Ureaplasma urealyticum promotes preterm delivery: association of the respiratory colonization of premature infants with chronic lung disease and increased mortality.

BACKGROUND: Infection of the chorioamnion with Ureaplasma urealyticum has been associated with low birth weight. Respiratory tract colonization in preterm infants has been associated with the development of chronic lung disease (CLD). The purpose of the present study was to determine the frequency of colonization of the mother's vagina and the preterm infant's respiratory tract and to associate U. urealyticum with premature birth and with development of CLD in the newborn. METHODS: The present prospective study involved 126 mothers with preterm delivery and 125 mothers with full-term delivery, as well as their offspring. Vaginal secretion specimens were obtained from each mother before delivery. Rhinopharyngeal secretion or tracheal lavage specimens were collected after the birth of each premature and full-term infant and then periodically during hospitalization. RESULTS: Vaginal Ureaplasma colonization occurred among 36.5% of mothers with preterm delivery and among 38% of mothers with full-term delivery. The rate of vertical transmission was 33% and 17% for mothers with preterm delivery and mothers with full-term delivery, respectively. The transmission rate for infants, according to birth weight, was as follows: 60%, for infants with a birth weight of <1000 g; 50%, for infants with a birth weight of 1000-1500 g; and 15.3%, for infants with a birth weight of > or =1500 g (P=.001). The median gestational age of preterm infants born to colonized mothers was 28.5 weeks, and that of preterm infants born to noncolonized mothers was 32 weeks (P<.0001). The median birth weight of colonized preterm infants was 1135 g, and that of noncolonized infants was 1670 g (P<.0001). Twenty-four percent of preterm infants and 10% of full-term infants were colonized with U. urealyticum. Of colonized preterm infants, 27% developed CLD, compared with 9% of noncolonized infants (P=.03). Mortality was significantly higher among colonized preterm infants (P=.003). CONCLUSIONS: The rate of vertical transmission is highest among preterm infants with a birth weight of <1500 g. Vaginal colonization with Ureaplasma organisms is associated with premature delivery. Colonization of the respiratory tract of infants is associated with the development of CLD and with increased mortality.

Chronic cough in children: recent advances.

Recurrent cough in children is a very common symptom of respiratory disease. Most children who cough, however, have normal pulmonary function. This article presents a diagnostic framework for chronic cough and a recommended management plan in order to avoid over investigation and over treatment of a generally benign and self-remitting condition. Pathophysiology of cough and recent advances in treatment options are also included.

Mycoplasma pneumoniae and Legionella pneumophila in community-acquired lower respiratory tract infections among hospitalized children: diagnosis by real time PCR.

Mycoplasma pneumoniae and Legionella pneumophila are increasingly recognized as important agents of community-acquired lower respiratory tract infections (LRTI). Mycoplasma pneumoniae has been also recognized as a cause of nosocomial infections. The aim of this study was to investigate the role of real time polymerase chain reaction (PCR) for the rapid diagnosis of these infections among hospitalized children with community-acquired LRTI. During 2001, 65 children were prospectively studied. Microbiological investigation consisted of capillary PCR with a LightCycler for M. pneumoniae and L. pneumophila in induced sputum or throat swab specimens, IgM enzyme immunoassay for M. pneumoniae and immunofluorescence for L. pneumophila in paired sera. Serology testing showed acute M. pneumoniae infection in 18 (27.5%) patients and L. pneumophila in 1 (1.5%). M. pneumoniae was also detected in sputum specimen by capillary PCR in 9 (50%) serologically diagnosed cases, including 4 (22%) with non-diagnostic IgM levels in the acute phase. Capillary PCR and IgM enzyme immunoassay diagnosed together 15 (83%) M. pneumoniae cases in the acute phase. It is concluded that M. pneumoniae is an important cause of LRTI necessitating hospitalization among children in Greece. Capillary PCR in sputum may diagnose M. pneumoniae LRTI in the acute setting and direct therapy and isolation of patients.

Q fever in children in Greece.

The aim of this study was to investigate the incidence, epidemiology, and clinical manifestations of Q fever among hospitalized children in Greece. During a two-year period, 1,200 children with various clinical manifestations were prospectively tested for Coxiella burnetii infection by indirect immunofluorescence. Acute Q fever was diagnosed in eight (0.67%) patients. No chronic case of infection was detected. Multivariate analysis showed that children 11-14 years old and children reporting consumption of cheese from rural areas were at increased risk for this illness. Clinical manifestations of acute Q fever were pneumonia (two patients), meningitis (two), prolonged fever (two), hepatitis (one), and hemolytic-uremic syndrome (one). Q fever accounted for 2.9% of the cases with prolonged fever, 1.2% of the cases of meningitis, and 0.5% of the cases of pneumonia. Fever and headache were the most common symptoms at presentation. Our study indicates that Q fever is a rare cause of hospitalization during childhood.

Failure to eradicate Group A beta-haemolytic streptococci (GABHS) from the upper respiratory tract after antibiotic treatment.

The clinical efficacy, safety and bacteriological eradication of Group A beta-haemolytic streptococci (GABHS) from the throat was studied after treatment of streptococcal tonsillopharyngitis with three commonly used oral antibiotics in a prospective, open labelled, comparative, randomised trial of 265 evaluable patients seen in one centre. All three antibiotics were administered in the recommended doses; penicillin V q8 hourly and clarithromycin q12 hourly were given for 10 days and cefprozil q12 hourly for 5 days. Clinical results and adverse events were similar for all three antibiotics used, with a prompt clinical outcome of >95%. Cefprozil had the best bacteriological eradication rate (failed to eradicate: 13.2, 15.1, 2.3; relapses: 13.2, 11.4, 5.7%, for penicillin, clarithromycin and cefprozil, respectively). Oral penicillin remains a clinically effective and safe antibiotic for the treatment of streptococcal pharyngitis. However, compliance and convenience for parents and children when they are asked to follow a 10 days course, especially when the patient has improved from the second or third day, together with the high incidence of bacteriological eradication failures, is an issue.

Neonatal necrotizing enterocolitis: an overview.

PURPOSE OF REVIEW: Necrotizing enterocolitis represents a disease entity that remains quite challenging for neonatologists all around the world, in that its aetiology has yet to be revealed, but it is the cause of death for many premature infants each year, affecting up to 28% of very low birthweight infants. This is an attempt to improve the management of affected babies and stimulate more research concerning new diagnostic tools. RECENT FINDINGS: Current trends in the field of (early) diagnosis, such as: (1) imaging techniques, e.g. contrast radiography, portal vein ultrasonography, magnetic resonance, radionuclide scanning; (2) gastrointestinal tonometry; (3) the detection of biochemical markers, cytokines, growth factors; and (4) the determination of the mean peak hydrogen: carbon dioxide ratio excreted in breath, are only some of those mentioned. Various novel preventive techniques are also presented, among which platelet-activating factor acetyl hydrolase activity enhancement, platelet-activating factor receptor antagonists and probiotics, such as Bifidobacterium infantis and Lactobacillus acidophilus, seem quite promising. Regarding treatment, the use of oxygenated perfluorocarbon has added to the limited alternatives available. These data along with other recent discoveries concerning the risk factors and pathogenesis of this disease create a full picture of the current opinion on this topic. SUMMARY: Keeping in mind that the key to confronting such a devastating disorder as necrotizing enterocolitis is early diagnosis and prevention, both clinically applicable and experimental advances are presented with the hope of improving the survival rates of patients affected.

The evolving epidemiology of invasive meningococcal disease: a two-year prospective, population-based study in children in the area of Athens.

In response to an increase in the incidence in invasive meningococcal disease (IMD) due to Neisseria meningitidis, a system of hospital- and laboratory-based surveillance was used in a prospective epidemiological and clinical assessment of IMD in children 0-13 years of age hospitalized in the Athens area between 1 January 1999 and 31 December 2000. The annual incidence of laboratory-confirmed disease was 10.2/100,000. Serogroup B strains were predominant. There was a sharp decrease in serogroup C from 19% of cases in 1999 to 3% in 2000 (P=0.013). Of note was the emergence of serogroup A responsible for 7% of the cases. The overall case fatality rate was 4.5%, but 2.8% for microbiologically confirmed cases. A remarkable decrease in disease severity assessed by admissions to intensive care units was noted during the second study year. Polymerase chain reaction-based methods for detection of meningococcal DNA were the sole positive laboratory test in 45% of the cases and the only test on which serogroup determination was based in 52% of groupable cases. The epidemiological and clinical profile of meningococcal disease appears to be rapidly evolving and close monitoring is required particularly for input into decisions regarding use of meningococcal vaccines.