Leo J. Gerards

Severe neonatal parechovirus infection and similarity with enterovirus infection

Background: Enteroviruses (EV) are an important cause of neonatal disease including hepatitis, meningoencephalitis, and myocarditis that can lead to death or severe long-term sequelae. Less is known about severe neonatal infection caused by the parechoviruses (PeV) of which type 1 (PeV1) and type 2 (PeV2) were previously known as echovirus 22 and echovirus 23. They belong to the same family of Picornaviridae as the EV. Of the PeV, so far only PeV3 has been associated in 2 recent reports with severe neonatal infection including involvement of central nervous system. Methods: We compared the clinical signs, diagnosis, laboratory data, cerebral imaging, and neurodevelopmental outcome of 11 neonates with PeV infection with 21 infants with EV infection treated in our hospital between 1994 and 2006. The diagnosis of EV infection or PeV infection was confirmed by a positive EV and/or PeV real time-polymerase chain reaction on blood, cerebrospinal fluid, (CSF) or stool or a viral culture of stool, nasopharyngeal swab, and/or CSF. Results: The 32 infants presented with sepsis-like illness and the most frequent signs were: fever, seizures, irritability, rash, and feeding problems. All patients received antibiotic treatment. Eleven of 21 infants infected with EV and 7 of 11 infants infected with PeV were full-term. Differentiation between the infants infected with EV and PeV on the basis of fever, irritability, rash, and seizures was not possible. Myocarditis was exclusively seen in 4 patients infected by EV. Eight of 11 patients with a PeV infection had meningoencephalitis of whom only 1 infant developed pleocytosis in the CSF. Serum C-reactive protein and CSF protein values were significantly higher in infants with EV infection than in those with PeV infection. Cerebral imaging of all infants with EV or PeV cerebral infection showed mild to severe white matter abnormalities. In 1 infant with EV infection and 3 infants with PeV infection, neurodevelopmental delay occurred. Mortality and long-term sequelae were mainly associated with myocarditis in the infants who were infected with EV (4 of 21). Conclusions: It is not possible to distinguish neonatal PeV from EV infection on the basis of clinical signs. Neonates with PeV or EV infection present with sepsis-like illness and the most frequent signs are fever, seizures, irritability, rash, and feeding problems.

Inflammatory Mediators for the Diagnosis and Treatment of Sepsis in Early Infancy

Interleukin-6 (IL-6), interleukin-8 (IL-8), and procalcitonin (PCT) are important parameters in the diagnosis of sepsis and for differentiating between viral and bacterial infection in children. We compared the value of IL-6, IL-8, and PCT with C-reactive protein (CRP) in the diagnosis and treatment of late-onset sepsis among infants admitted to the neonatal intensive care unit (group I) and febrile infants admitted to general hospitals from home (group II). Group I was divided into subgroups Ia, positive blood culture (all Gram-positive cocci); Ib, negative blood culture; and Ic, controls. Group II was divided into subgroups IIa, systemic enterovirus infection, and IIb, no enterovirus infection. Enterovirus was identified by real-time (RT) polymerase chain reaction (PCR) and/or by culture in blood and cerebrospinal fluid (CSF). The positive predictive values of IL-6, IL-8, and PCT (78%, 72%, and 83%, respectively) were better than that of CRP (63%) in the diagnosis of neonatal sepsis. After 48 h of antibiotic treatment, IL-6 and IL-8 levels significantly decreased and PCT stabilized in clinically recovered patients, suggesting that these markers may be useful in distinguishing patients in which antibiotic treatment may be discontinued. Among infants of subgroup IIa, 80%–90% had normal values of IL-6, IL-8, and PCT, whereas CRP was increased in 40%. In conclusion, IL-6, IL-8, and PCT are better parameters than CRP in the diagnosis and follow-up of neonatal sepsis due to coagulase-negative staphylococci (CoNS) and in the exclusion of bacterial infection among those with enteroviral infection among febrile infants presenting from home.

Clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a 12-year period.

Background: The incidence of viral infections in patients treated in the neonatal intensive care unit (NICU) is not well-known. We summarized the data of all patients with laboratory-confirmed viral infections admitted at the NICU of our hospital during the period of 1992–2003. Objectives: To determine the incidence of viral infections among infants hospitalized in a NICU, the associated clinical manifestations and their outcome. Methods: Retrospective analysis of epidemiologic, virologic and clinical data from infants with proven viral infection. The diagnosis viral infection was confirmed by positive viral culture and/or polymerase chain reaction from clinical samples. Results: Viral infection was confirmed in 51 of 5396 infants (1%) admitted to the NICU; 20 (39%) had an enterovirus and parechovirus (EV/PEV) infection, 15 (29%) a respiratory syncytial virus (RSV) infection, 5 (10%) a rotavirus infection, 3 (6%) a cytomegalovirus (CMV) infection, 2 (4%) an adenovirus infection, 2 (4%) a parainfluenza virus infection, 2 (4%) a herpes simplex virus infection, 1 (2%) a rhinovirus infection and 1 (2%) a rubella virus infection. Three of the infants presented at birth with symptomatic rubella virus, CMV or herpes simplex virus infection. RSV infection developed mostly in hospitalized infants (60%), and 93% of infections occurred during the winter (November–March). The clinical presentations of EV/PEV disease were sepsis-like illness, prolonged seizures in term infants and gastrointestinal disease in preterm infants. RSV, parainfluenza virus, rhinovirus and CMV caused respiratory disease, predominantly in preterm infants. Gastrointestinal disease was seen only in preterm infants with adenovirus, rotavirus or EV/PEV infection. Mortality and serious sequelae were high in patients infected with EV/PEV (10 and 15%, respectively). Conclusions: The incidence of viral infection in the NICU was 1%. Enteroviral infections were the most frequently diagnosed infections, occurred often in term infants born at home and presented with sepsis-like illness or seizures. Preterm infants hospitalized from birth mainly developed gastrointestinal disease caused by rotavirus and adenovirus infection or respiratory disease caused by RSV, parainfluenza and CMV infection. Enteroviruses were responsible for the highest mortality and development of serious sequelae.

Molecular epidemiology of coagulase-negative staphylococci causing sepsis in a neonatal intensive care unit over an 11-year period

ABSTRACT Coagulase-negative staphylococci (CoNS) are the major causative microorganisms in neonatal nosocomial sepsis. Previous studies have shown that CoNS sepsis in the neonatal intensive care unit (NICU) is caused by predominant molecular types that are widely distributed among both neonates and staff. Some of these molecular types may persist in the NICU for years. The purpose of the present study was to determine the dynamic behavior of CoNS strains causing sepsis over a prolonged period of time by determining the molecular types of all blood isolates from septicemic infants over a period of 11 years (1991 to 2001). The results show that neonatal CoNS sepsis is increasingly caused by a few predominant molecular clusters. The most striking finding was that in recent years one molecular cluster emerged as the predominant cause of neonatal CoNS sepsis, responsible for no less than 31% (20 of 65) of blood isolates in 2001. Antibiotic resistance, particularly beta-lactam resistance, is probably an important selective force considering the high mecA gene carriage of CoNS blood isolates (70 to 92%). We conclude that neonatal CoNS sepsis is increasingly caused by a limited number of predominant molecular CoNS types and that antibiotic resistance is probably a major selective force.

Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir.

Abstract Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. Some congenitally infected infants will develop sequelae later in life, especially sensorineural hearing loss (SNHL) and mental retardation. There is no generally accepted antiviral therapy for the treatment of symptomatic congenital CMV infections yet. We present a neonate with symptomatic congenital CMV infection, who was treated with intravenous (iv) ganciclovir (GCV) during 18 days and subsequently with oral valganciclovir (VGCV) for 5.5 months, in an attempt to prevent development of SNHL. GCV was given intravenously 10 mg/kg/day in two doses and VGCV doses ranged from 280–850 mg/m2 bidaily (bid). Our experience shows that it is not possible to give a fixed dosing regime for VGCV in neonates and that continuous adaptation of dose is necessary to achieve stable target levels of GCV and to keep the viral load in urine at undetectable level. At 18 months of age no hearing deterioration has occurred. While the current findings are encouraging, the limitations of a single case report with a relatively short follow-up emphasizes the need for further prospective randomized studies to evaluate pharmacokinetics, efficacy and safety of VGCV therapy in neonates with congenital CMV infection.

The predictive value of CRP and I/T-ratio in neonatal infection

C-reactive protein (CRP) and immature: total neutrophil ratio (I/T-ratio) were evaluated as tests to detect neonatal sepsis in a prospective study in 185 neonates. The positive predictive values (P.P.A.) of CRP and I/T-ratio when used for screening for infection were 20-30% in early onset and 50-60% in late onset infection. In patients with clinical signs of infection the P.P.A. of CRP and I/T-ratio was 35-45% in early onset and 65-70% in late onset infection. For the whole group of patients the negative predictive accuracy (N.P.A.) of both CRP and I/T-ratio was high, in early as well as in late onset infection (90-98%). Based on incidence rates of 7.5% and 23% for early and late onset infection respectively the chance that the infant was not infected was already 92.5% and 77% for the two types of infection. In conclusion, CRP and I/T-ratio determination are of limited value as diagnostic tests in neonatal infection.

Antibody responses and opsonic activity in sera of preterm neonates with coagulase-negative staphylococcal septicemia and the effect of the administration of fresh frozen plasma.

Coagulase-negative staphylococcal septicemia is the most prominent nosocomial infection in neonatal intensive care units. Immaturity of host defenses in premature neonates is assumed to constitute an important risk factor. Opsonophagocytosis is considered to be the key host defense system against staphylococci with IgG antibodies as a major opsonin. For this reason we have studied serum IgG antibody titers and opsonic activity to coagulase-negative staphylococci in 20 infants with septicemia and 40 matched control subjects. In addition, we assessed the effect of administration of fresh frozen plasma (FFP) on IgG antibody titer and serum opsonic activity in 12 patients with septicemia. IgG antibodies, quantified by ELISA and opsonic activity, determined by flow cytometry, were expressed as a percentage of the value of pooled normal human reference serum. Both patients and control subjects showed low IgG titers (median, 21%; range, 1-192%) and a low opsonic activity (median, 33%; range, 8-484%) at birth. During the first 2 postnatal wk IgG titers decreased significantly in septicemia patients (from a median of 30 to 17%, p = 0.025), but not in control subjects, whereas opsonic activity remained unchanged. The titer of IgG antibodies increased significantly in septicemia patients after FFP administration (from a median of 17 to 41%, p = 0.002), whereas the effect on opsonic activity was unpredictable, showing a moderate increase in 10 out of 12 infants, and in 2 patients even a substantial decrease (>50%), despite adequate opsonic activity in the corresponding FFP batches. Immunoblotting of sepsis isolates with the corresponding patient sera demonstrated that septicemic infants may generate IgG antibodies against their blood isolate. Neonates who acquire coagulase-negative staphylococcal septicemia cannot be distinguished from control subjects on the basis of IgG antibodies and opsonic activity to staphylococci either at birth or during the first 2 postnatal wk. The administration of FFP to septicemia neonates has an unpredictable effect on opsonic activity and therefore does not seem to be a useful addition to antibiotic therapy.

Prevalence of molecular types and mecA gene carriage of coagulase-negative Staphylococci in a neonatal intensive care unit: relation to nosocomial septicemia.

ABSTRACT Molecular typing of isolates revealed that neonatal coagulase-negative staphylococcal (CONS) septicemia is most frequently caused by predominant, antibiotic-resistant CONS types, which are widely distributed among both neonates and staff of the neonatal unit, suggesting cross-contamination. Therefore, infection control measures may be valuable in the prevention of this common nosocomial septicemia.

Removal of percutaneously inserted central venous catheters in neonates is associated with the occurrence of sepsis

Background: Clinical signs of sepsis are frequently observed after removal of a percutaneously inserted central venous catheter (PCVC) in neonates admitted at our Neonatal Intensive Care Unit (NICU). To substantiate this finding and to evaluate the effect of antibiotics administered at the time of removal of a PCVC, we conducted a retrospective study among all infants with a PCVC, admitted at our NICU during 2002 and 2005.

Pneumococcal septicemia in the newborn. A report on seven cases and a review of the literature

This report summarizes the essential findings of seven cases of pneumococcal septicemia in the newborn and compares the data with those reported in the literature. It is emphasized that pneumococcal septicemia is a rare but highly lethal disease of the newborn. The clinical course strongly resembles early onset group B streptococcal disease. Epidemiological data suggest that the majority of infants are colonized near birth. Analogous to group B streptococcal sepsis, it seems rational to administer penicillin prophylaxis during labor to women with S. pneumoniae isolated from their genital tract to prevent vertical transmission and neonatal pneumococcal septicemia.