Neonatal adenovirus infection: four patients and review of the literature.

Four newborns with adenovirus infection are described, and the profile of neonatal adenovirus disease is outlined based on the cases of these newborns and nine previously described. Characteristic historical features included prolonged rupture of membranes, maternal illness, vaginal delivery, and onset of illness within the first 10 days of life. Clinical findings included lethargy, fever or hypothermia, anorexia, apnea, hepatomegaly, bleeding, and progressive pneumonia. Thrombocytopenia, coagulopathy, and hepatitis were typical laboratory manifestations. Illness was severe and generally unremitting; only two survivors have been reported. Pathologic changes were prominent in lung, liver, and brain. Virus isolates, predominantly serotypes 3, 7, 21, and 30 were obtained from multiple sites and organs. Epidemiologic evidence suggests that viral acquisition from the mother, perhaps via the birth canal, is a major mode of transmission. Neonatal adenovirus infection, which is frequently disseminated and generally fatal, should be considered in the differential diagnosis of neonatal sepsis and pneumonia.

Identification of trophoblastic giant cells as the initial principal target of early gestational murine enterovirus infection.

Theiler's murine encephalomyelitis virus (TMEV), a murine enterovirus, infects the majority of murine placentae and fetuses following inoculation in early gestation and infects most placentae but almost no fetuses in late gestation. The sequence of infection of TMEV following early gestation inoculation was studied. Mice were inoculated with TMEV on day 6 or 7 of pregnancy and sacrificed at intervals between 1 h and 4 days later. Culture of placenta-embryo units identified infection at 2, 3, and 4 days post-inoculation. In situ hybridization revealed TMEV RNA primarily in giant cells around the yolk cavity and in giant cells situated between the decidua and spongiotrophoblast layers of the placenta. Occasional decidual cells located near giant cells were also hybridization-positive. The giant cells were immunohistochemically identified as fetally derived trophoblast cells. Giant cells are the earliest predominant target of TMEV infection following early gestation inoculation and appear to be an integral part of the pathogenesis of gestational murine enterovirus infection.

Characterization of the placental barrier to murine enterovirus infection.

We performed studies to characterize the mechanisms responsible for development during gestation of a placental barrier to Theiler's murine encephalomyelitis virus (TMEV) in a murine model of gestational enterovirus infection. Electron microscopy of placentae infected in early gestation revealed TMEV-induced changes in the decidua, giant cell, spongiotrophoblast, and labyrinth layers; in contrast, placentae infected in middle and late pregnancy demonstrated degenerative changes in the decidua, giant cell, and spongiotrophoblast layers but not in the labyrinth. Immunohistochemistry and in situ hybridization of placentae infected in early or late gestation demonstrated accumulation of monocytes/macrophages in infected, histologically damaged labyrinths, but no infiltration of immune cells into infected but histologically normal placental regions. Silver staining of placentae from dams inoculated in late gestation with inert gold beads the size of TMEV virions revealed beads within the decidua, giant cell, and spongiotrophoblast layers, but restriction of beads from labyrinths, similar to the usual distribution of TMEV in placentae infected in late pregnancy. These experiments suggest that anatomical relationships, and not systemic immune response, appear to be a major contributor to the murine placental barrier to TMEV.

Protection of murine gestational tissues from picornavirus infection in the preimplantation period.

Mice were inoculated with Theiler's murine encephalomyelitis virus (TMEV) on gestational days 1-3 (pre-implantation) or days 4-5 (peri- or post-implantation) or with control cell lysate (days 1-5). Dams were subsequently sacrificed between days 11-14 of gestation, and placentae and fetuses were harvested. Few placentae from dams inoculated with virus on days 1-3 were positive by virus culture (2 per cent) or in situ hybridization (6 per cent), and no fetuses were positive by either technique. In contrast, most placentae from dams inoculated with virus on days 4-5 were virus-positive by culture (96 per cent) or in situ hybridization (100 per cent), and a moderate number of fetuses were also positive (30 per cent by culture, 19 per cent by in situ hybridization). Necrosis was present more frequently in placentae from mice inoculated with virus on days 4-5 (55 per cent) than in placentae from dams inoculated with virus on days 1-3 (19 per cent) or with control cell lysate (18 per cent). Viral infection, mononuclear inflammation and cell necrosis were identified in the heart and great vessels of TMEV-infected fetuses. These results indicate that gestational tissues are largely protected from viral infection before implantation. After implantation, gestational tissues are more readily infected and damaged by maternal picornavirus infection.

Picornavirus infection in early murine gestation: significance of maternal illness.

To evaluate whether maternal illness following picornavirus infection during pregnancy adversely affects placental and fetal health, mice were inoculated with the GDVII strain of Theiler's murine encephalomyelitis virus or control cell lysate during days 4-7 of gestation. Gross appearance, histopathology and viral culture, and in situ hybridization positivity of placentae and fetuses from ill GDVII-infected, healthy GDVII-infected and control mice were compared. Twenty of 34 (59 per cent) GDVII-infected dams became clinically ill. More placenta-fetus pairs from ill mice were grossly abnormal (68 per cent) than from well GDVII-infected (51 per cent;P< 0.01) or control mice (9 per cent;P< 0.001). Virus was detected by in situ hybridization in 73 per cent of placentae and 29 per cent of fetuses from sick GDVII-infected dams, and in 85 per cent of placentae and 19 per cent of fetuses from healthy GDVII-infected mice (differences not significant). Histological abnormalities consisting of necrosis or an increase in hyaline tissue in the vascular labyrinth layer were similarly frequent in placentae from ill and well GDVII-infected mice (58 per cent versus 67 per cent, P=0.5). Viral RNA, inflammation and necrosis were evident in the heart, great vessels, brain and spinal cord of GDVII-infected fetuses. Infection with GDVII in early pregnancy produces a high rate of gross placental and fetal abnormalities. The rate of gross abnormalities exceeds the incidence of fetal infection and more closely parallels the rates of infection and histopathology in the placenta, suggesting that much of the damage to placenta-fetus pairs is a consequence of placental infection. In addition, the occurrence of viral-induced maternal illness is associated with additive risk to placental and fetal health not explained by an increased rate of placental or fetal infection.

Prognosis for neonates with enterovirus hepatitis and coagulopathy.

BACKGROUND: Neonatal enterovirus hepatitis and coagulopathy (EHC) can be a severe, life-threatening infection. However, the case-fatality rate of EHC and the prognosis for survivors are not well-defined. METHODS: A search of a hospital medical records database and the investigator's files for the period 1983 to 2000 was performed. Patients with onset of enterovirus-associated illness at age < or = 30 days and either (1) aspartate aminotransferase or alanine aminotransferase > 3 times the upper limit of normal or (2) platelet count < 100 000 plus an abnormal coagulation profile were included. RESULTS: Sixteen cases were identified. Symptoms began at a mean of 3.8 days (range, 1 to 7 days). Frequent clinical and laboratory findings included jaundice, lethargy, anorexia, hepatomegaly, thrombocytopenia, clotting time prolongation, elevated transaminase and bilirubin values and decreased fibrinogen and albumin concentrations. Five patients had myocarditis and 4 had encephalitis. Hemorrhagic complications occurred in 10 (intracranial hemorrhage in 5). Five (31%) patients died. Features discriminating patients who died from survivors were concomitant myocarditis (5 of 5 vs. 0 of 11, P < 0.001), encephalitis (3 of 5 vs. 1 of 11, P = 0.06), prothrombin time > 30 s (4 of 5 vs. 1 of 9, P = 0.02) and intracranial hemorrhage (4 of 5 vs. 1 of 8, P = 0.03). Follow-up of 6 survivors revealed normalization of liver function and platelet counts, satisfactory growth and absence of significant medical problems. CONCLUSIONS: The case-fatality rate of 31% is evidence of the potentially devastating nature of EHC. Concomitant EHC and myocarditis are especially serious, but the prognosis for children who survive neonatal EHC is generally excellent.

Profile of enterovirus disease in the first two weeks of life.

We studied 57 infants < or = 14 days of age referred for possible enterovirus (EV) infection to assess the accuracy of that clinical diagnosis and describe the natural history of neonatal EV infection. Twenty-nine neonates proved to have EV infection, 23 had illnesses compatible with (but not proven to be) EV infection, and 5 had alternative diagnoses: bacterial infections (2); herpes simplex virus infection (1); and metabolic disorders (2). Neonates with proved EV infection were generally full term and had uncomplicated immediate postnatal periods but high percentages of ill contacts. Neonatal symptoms and signs included fever, irritability, anorexia, lethargy, hypoperfusion, rash, jaundice and respiratory findings. Laboratory abnormalities included cerebrospinal fluid (CSF) pleocytosis, chest radiograph infiltrates, abnormal urinalyses and elevated transaminases. EVs were most commonly isolated from CSF and rectum/stool but also frequently from serum and urine. Five EV-infected patients had severe multisystem disease (pneumonitis, hepatitis, thrombocytopenia, bleeding and meningitis), requiring supportive care and lengthy hospitalizations. All survived, 2 with residual hepatic dysfunction. Markers of severe disease included: early age of illness onset (especially Day 1 of life); maternal viral symptoms at delivery; absence of fever and irritability; tachypnea; lethargy; abdominal distension; hepatomegaly; and positive serum viral culture. These data support conservative management of ill infants < or = 2 weeks of age and suggest that antiviral therapy for neonatal EV infection would be optimally targeted at infants with early onset illness, multisystem disease and/or viremia.

Antibiotic-resistant bacteria in pediatric chronic sinusitis.

BACKGROUND: Limited information exists on emerging bacterial resistance patterns in pediatric chronic sinusitis. METHODS: A retrospective review (1995 to 1998) of the aerobic microbiology of chronic sinusitis in children at a tertiary care children's hospital was conducted. One hundred nineteen children (mean age, 4.9 years) with maxillary sinusitis of >8 weeks duration and no known immunodeficiency or cystic fibrosis who underwent antral irrigation were included. RESULTS: One hundred sixty-one of 240 (67%) aerobic cultures were positive, yielding 274 isolates. Eighty-eight positive cultures were polymicrobial. The most frequent isolates were nontypable Haemophilus influenzae (24%), Streptococcus pneumoniae (19%), Moraxella catarrhalis (17%), coagulase-negative Staphylococcus (6%), alpha-streptococci (6%), diphtheroids (5%), Staphylococcus aureus (3%) and Neisseria spp. (3%). Rates of nonsusceptibility of Streptococcus pneumoniae were 64% for penicillin (24% high grade resistance), 40% for cefotaxime, 18% for clindamycin and 0% for vancomycin. Rates of nonsusceptibility of S. pneumoniae did not change significantly during the study period. Thirty-nine percent of H. influenzae isolates were beta-lactamase-positive and 44% were nonsusceptible to ampicillin (41% high grade resistance). Beta-lactamase positivity of H. influenzae decreased during the study period (P = 0.06). All M. catarrhalis isolates tested were beta-lactamase-positive. CONCLUSION: This study indicates that the aerobic pathogens in pediatric chronic sinusitis include bacteria typical of acute sinusitis as well as organisms more characteristic of chronic disease. Moreover it highlights the significant role of antibiotic-resistant aerobes, including multiply resistant S. pneumoniae, in pediatric chronic sinusitis.

Viral pneumonia in the first month of life.

We performed a 5-year review of 40 patients less than or equal to 30 days of age with viral pneumonia. Isolates included respiratory syncytial virus (55%), enteroviruses (15%), rhinoviruses (15%), adenoviruses (10%), parainfluenza virus (7.5%) and herpes simplex virus (5%). Most infants were previously healthy but had ill family members. Nine were born at less than 37 weeks of gestation. Symptoms and signs included tachypnea, decreased feeding, cough, cyanosis, lethargy, retractions, apnea, bradycardia, seizures and depressed consciousness. Seasonality and clinical features, but not radiographic patterns, suggested specific pathogens. Patients were moderately to severely ill. The median duration of hospitalization was 7 days; therapies administered included oxygen (90%), mechanical ventilation (45%), blood transfusions (25%) and supplemental oxygen after discharge (27%). The case fatality rate was 7.5%. Prematurity, ill appearance at presentation, lobar consolidation and adenovirus infection were risk factors for severe disease.

Intracellular detection of sense and antisense enteroviral RNA by in situ hybridization.

We prepared sense (S) and anti-sense (AS) 3H-labelled single-stranded RNA probes by polymerase-directed in vitro transcription of a coxsackievirus B3-derived cDNA fragment cloned in the PGEM2 plasmid vector. The probes detected, by in situ hybridization, both S and AS forms of viral RNA in the cytoplasm of coxsackievirus-infected tissue culture cells. More S (genomic and messenger) RNA was present than AS (negative and replicative intermediate) RNA. We confirmed and quantitated this observation with slot-blot hybridization of lysates of infected cells in which the ratio of detectable S to AS RNA was 40:1. The selective detection and localization of both forms of RNA in infected cells with sensitive and specific bi-directional probes advances the applicability of in situ hybridization to the study of viral pathogenesis.

Fungal mastoiditis in immunocompromised children.

The immunocompromised host is subject to a variety of opportunistic infections. Mycotic infections, including invasive fungal sinusitis, are a dreaded complication in immune deficient children. Fungal mastoiditis has rarely been described in this population. Our experience with 2 cases of fungal mastoiditis in immunocompromised children is reviewed. Case histories describing aggressive medical management with and without surgical intervention and a review of the literature are presented.

Persistent rhinosinusitis in children after endoscopic sinus surgery.

The efficacy of endoscopic sinus surgery (ESS) in children is insufficiently addressed in the medical literature. We report a cohort of 14 children (mean age 7.7 years, median age 5.1 years) seen at our multidisciplinary clinic for refractory rhinosinusitis during a 30-month period who continued to have rhinosinusitis despite previous ESS. Prior ESS procedures were performed by 11 surgeons in 3 states. The first ESS was performed when the children were a mean age of 4.6 years, and in 10 of 14, it was performed when they were younger than 4.8 years. This cohort required a disproportionately high rate of subsequent surgical intervention, 50%, versus a 9% surgical rate in the remaining clinic population (P = 0.0002). Osteomeatal scarring was the single most difficult surgical complication. Significant morbidity, in the form of persistent disease, is encountered after ESS in young children. Although chronic rhinosinusitis after ESS, to a certain degree, can still be managed by medical therapy, judicial use of ESS, especially in the very young, is recommended.

Clinical practice guidelines for the management of chronic sinusitis in children.

Chronic sinusitis in children is a common and vexing disease for clinicians and the public. There are insufficient data in the literature to develop an evidence-based clinical guideline. Experience in managing pediatric chronic sinusitis has been gained through a multidisciplinary clinic at our institution during the past 3 years. A panel of experts was formed, and with the guidance of a guideline methodologist, the development of a rigorous outcome-based guideline was undertaken. Symptom-improvement and recurrence estimates for a variety of medical and surgical treatments were assessed. Wide probability estimates were made by the panelists in most cases. Although we refrained from making specific recommendations, we developed a ranked series of practical treatment options taking into account side effects and costs.

Incidence of nonbacterial intraamniotic infections in abnormal pregnancies.

Amniotic fluids from 41 abnormal and 47 control pregnancies were examined for viruses, Chlamydia trachomatis, Ureaplasma urealyticum and Mycoplasma hominis. Abnormal pregnancies included those with fetal abnormalities, maternal complications, suspected chorioamnionitis and premature labor. Two percent of cultures were positive, including cytomegalovirus from one case of fetal growth retardation and U urealyticum from two patients with chorioamnionitis and from two controls. The abnormal pregnancies studied generally were not associated with nonbacterial intraamniotic infections.

Posaconazole as salvage therapy for zygomycosis.

Zygomycosis, an infection that is associated with significant morbidity and mortality, is becoming common in immunocompromised patients. Posaconazole is a new extended-spectrum azole antifungal that has demonstrated in vitro and in vivo activity against zygomycetes. This report provides the results from the first 24 patients with active zygomycosis who were enrolled in two open-label, nonrandomized, multicentered compassionate trials that evaluated oral posaconazole as salvage therapy for invasive fungal infections. Posaconazole was usually given as an oral suspension of 200 mg four times a day or 400 mg twice a day. Eleven (46%) of the infections were rhinocerebral. Duration of posaconazole therapy ranged from 8 to 1,004 days (mean, 292 days; median, 182 days). Rates of successful treatment (complete cure and partial response) were 79% in 19 subjects with zygomycosis refractory to standard therapy and 80% in 5 subjects with intolerance to standard therapy. Overall, 19 of 24 subjects (79%) survived infection. Survival was also associated with surgical resection of affected tissue and stabilization or improvement of the subjects' underlying illnesses. Failures either had worsening of underlying illnesses or requested all therapy withdrawn; none of the failures received more than 31 days of posaconazole. Posaconazole oral solution was well tolerated and was discontinued in only one subject due to a drug rash. Posaconazole appears promising as an oral therapy for zygomycosis in patients who receive required surgery and control their underlying illness.