Unrecognized prolonged viral replication in the pathogenesis of human RSV infection.

BACKGROUND: Respiratory symptoms in RSV persist long after the virus is no longer detected by culture. Current concepts of RSV pathogenesis explain this by RSV inducing a long-lasting pathogenic immune cascade. We alternatively hypothesized that prolonged unrecognized RSV replication may be responsible and studied this possibility directly in a human wild-type RSV experimental infection model. OBJECTIVE: The objective of the current report was to define the duration of true human RSV replication by studying it directly in immunocompetent adults experimentally infected with a clinical strain of RSV utilizing this previously established safe and reproducible model. STUDY DESIGN: 35 healthy adult volunteers were inoculated with RSV-A (Memphis-37, a low11 passage clinical strain virus, manufactured from a hospitalized bronchiolitic infant) and evaluated over 12 days. Viral load by culture, parallel quantitative PCR (genomic, message) and RSV-specific IgA, were measured twice daily from serially collected nasal washes. RESULTS: After inoculation, 77% (27/35) of volunteers became RSV infected. As expected, culture-detectable RSV ceased abruptly by the 5-6 t h 15 infection day. However, infected volunteers demonstrated prolonged RSV presence by both genomic and message PCR. RSV-specific IgA rose within respiratory secretions of infected volunteers during same time frame. CONCLUSIONS: RSV replication appears to continue in humans far longer than previously thought. The rise in nasal RSV-specific IgA shortly after infection likely neutralizes culture detectable virus producing misleadingly short durations of infection. Prolonged viral replication helps explain RSV's extended disease manifestations and increases the potential utility of antivirals.

Molecular detection and quantification of pertussis and correlation with clinical outcomes in children.

Pertussis is an under-recognized serious infection. Conventional cultures are insensitive and of limited utility after antibiotic exposure. We corroborated the utility of real-time polymerase chain reaction (PCR) as a diagnostic tool in pertussis and investigated its role as a prognostic tool by evaluating its benefit in the quantification of pertussis bacterial load. All pertussis-positive PCR tests (n = 104) submitted over 5 years were collected for retrospective study. PCR cycle threshold was compared to quantitative culture in 43. Compared to PCR, the sensitivity of culture was 41%. Our PCR assay reliably quantified bacterial load and was quantitatively reproducible. Higher bacterial load correlated with longer duration of hospitalization (P = 0.0003), and multivariate logistic regression models demonstrated this association to be independent. The study confirmed PCR as a superior diagnostic tool in pertussis. PCR quantification of bacterial load at initial diagnosis predicts later clinical disease severity, suggesting a potential benefit of PCR as a prognostic tool in pertussis.

Quantitative effects of palivizumab and donor-derived T cells on chronic respiratory syncytial virus infection, lung disease, and fusion glycoprotein amino acid sequences in a patient before and after bone marrow transplantation.

A patient with respiratory syncytial virus (RSV) infection and severe combined immunodeficiency was studied during a 3-month period of bone marrow transplantation and palivizumab infusion. No RSV isolates with palivizumab escape mutations were identified. Donor lymphocytes, including CD8 cells, appeared to markedly reduce the RSV load but increased the pulmonary symptoms. Immunosuppressive therapy ameliorated lung disease but allowed the RSV load to rebound.

Respiratory virus infections in pediatric hematopoietic stem cell transplantation.

Respiratory virus infections (RVI) have become an increasingly appreciated problem in the hematopoietic stem cell transplant (HSCT) population. A retrospective analysis of 274 patients undergoing 281 HSCT at St. Jude Children's Research Hospital from January 1994 through December 1997 was performed. Medical and clinical laboratory records were reviewed beginning at the onset of conditioning through the year following each HSCT, and the analysis was done for the first RVI only. Thirty-two (11%) of 281 HSCT cases developed a RVI during the first year post-HSCT. The most frequent cause of RVI was human parainfluenza virus type 3. Univariate analysis was performed to determine the association between risk factors and the cumulative incidence of RVI. Respiratory viruses are frequent causes of infections in the first year post-HSCT in the pediatric population. Only allogeneic transplant and the degree of acute or chronic graft versus host disease were found to be statistically significant risk factors for RVI.

Respiratory syncytial virus infections in the pediatric intensive care unit: clinical characteristics and risk factors for adverse outcomes.

OBJECTIVES: To describe the clinical characteristics of infants admitted to a pediatric intensive care unit (PICU) with respiratory syncytial virus (RSV) infection, including the prevalence of indications for RSV passive antibody prophylaxis (as currently recommended by the American Academy of Pediatrics), and to identify risk factors that predict adverse outcomes among this population. DESIGN: Retrospective medical record review. SETTING: Tertiary care PICU. PATIENTS: Children <2 yrs of age admitted to PICU for the management of RSV disease during the 1994-95, 1995-96, and 1996-97 RSV seasons. MEASUREMENTS AND MAIN RESULTS: The medical records of 89 infants were reviewed. Of these, 55% were born before 36-wks gestation, 14% had chronic lung disease that required medical therapy within the previous 6 months, and 30% met at least one indication for RSV passive antibody prophylaxis. Seven infants had congenital heart disease, five had upper airway abnormalities, and six had various noncardiac congenital malformations. Logistic regression was used to determine which characteristics were associated with prolonged durations (>75th percentile) of mechanical ventilation, PICU stay, and hospital stay. Prolonged mechanical ventilation was associated with congenital heart disease (p = 0.014), chronic lung disease (p = 0.007), and noncardiac congenital malformations (p = 0.022). Only congenital heart disease was associated with prolonged PICU stay (p = 0.004) or prolonged hospital stay (p = 0.006). All of the infants with airway abnormalities had prolonged ventilator days, PICU days, and hospital days. Currently recommended indications for RSV passive antibody prophylaxis were not predictive of prolonged ventilation, PICU stay, or hospital stay. CONCLUSIONS: A minority of infants admitted to our PICU for severe RSV disease meet currently recommended indications for RSV passive antibody prophylaxis. Risk factors that predict prolonged durations of ventilation, PICU stay, or hospital stay among this population include congenital heart disease, chronic lung disease, upper airway abnormalities, and noncardiac congenital malformations.

Adenovirus 7a: a community-acquired outbreak in a children's hospital.

BACKGROUND: Adenoviruses produce many illnesses in children, particularly respiratory and gastrointestinal disease. The most common adenoviral respiratory infections in children are caused by types 1, 2, 3 and 5. Adenoviruses spread rapidly in closed environments often causing epidemic disease. Serotype 7a has been responsible for outbreaks of respiratory disease in children living in close proximity with one another. This report describes a large community-acquired adenovirus 7a epidemic in hospitalized children. METHODS: Evaluation of all patients with cultures positive for adenovirus from a children's hospital-based virology laboratory during a recognized adenovirus outbreak. All such adenovirus isolates were typed, and patients with adenovirus 7a are described by review of medical records. RESULTS: Between March 1 and July 26, 1997, 47 children admitted to the hospital were identified as infected with adenovirus. Of these 47 patients 26 (55%) were infected with adenovirus 7a. Twenty-four (92%) infections were community-acquired. The age range was 11 days to 10 years with a median of 9.5 months. Twenty-two patients (84%) had respiratory symptoms, and 21 (8%) had fever, making these the most common symptoms. The mean durations of fever and hospitalization were 5.5 and 7 days, respectively. One of 26 patients died. CONCLUSIONS: Adenovirus 7a can cause large community epidemics affecting children. The disease produced by adenovirus 7a in children is almost exclusively of the respiratory tract, and in some individuals it may be very severe and possibly fatal.

Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation - a compassionate use experience.

Respiratory syncytial virus (RSV) pneumonia in BMT recipients carries a mortality rate of approximately 50-70% despite ribavirin (Virazole) treatment. In both immunocompetent and immunocompromised animal models, RSV neutralizing antibodies rapidly reduce pulmonary virus load after a single dose. RSV-IGIV (RespiGam) is an IgG immune globulin with high concentrations of RSV neutralizing antibody (>19 200 MU/ml). From June 1991 to February 1996, a compassionate-use protocol using RSV-IGIV for treatment of RSV infections was conducted. Eleven children at multiple centers, mean age 3.3 years (4 months to 9 years), were undergoing BMT and met the protocol criteria. They received a single 1500 mg/kg dose of RSV-IGIV infused over 12 h at a median of 5 days (1-37 days) after RSV symptom onset. Ten of these patients received prior or concurrent aerosolized ribavirin. Serum RSV neutralizing titers were measured in five patients and showed a 3- to 30-fold increase 24 h after RSV-IGIV infusion. Adverse events were mild. One of 11 (9.1%) patients died from their RSV illness (91% RSV survival). In comparison to previously published reports, RSV-IGIV treatment of RSV pneumonia in BMT patients may increase survival above that in such patients treated with ribavirin alone. Bone Marrow Transplantation (2000) 25, 161-165.

Nasal quantity of respiratory syncytical virus correlates with disease severity in hospitalized infants.

OBJECTIVE: To evaluate the relationship between nasal quantity of respiratory syncytial virus (RSV) and disease severity in hospitalized infants without underlying cardiopulmonary disease or immunodeficiency. METHODS: Nasal aspirates were obtained from hospitalized infants <24 months of age with recently identified RSV infection and evaluated for RSV quantity by a standard plaque assay on HEp-2 cell monolayers. Subjects were classified as having "severe" disease if they required mechanical ventilation at the time of sample collection and as having "nonsevere" disease if they did not. Linear modeling was used to determine the relationship between nasal RSV quantity and various independent variables, including disease severity. RESULTS: Nasal aspirates from 39 patients were evaluated. Age, gender and mean duration of time from symptom onset to sample acquisition (5 days) were similar between the severe (n = 15) and nonsevere (n = 24) groups. Significantly more infants were born at <35 weeks gestation in the severe disease group (7 of 15 vs. 3 of 24, P = 0.017), and infants born at <35 weeks gestation were significantly more likely to be of non-Caucasian ethnicity than were infants born at > or =35 weeks gestation (8 of 10 vs. 12 of 29, P = 0.035). The linear model found that higher nasal RSV quantities were associated with severe disease [mean +/- SEM, 5.06 +/- 0.34 log plaque-forming units (pfu)/ml vs. 3.91 +/- 0.35 log pfu/ml, P = 0.022], gestational age > or =35 weeks (5.44 +/- 0.27 log pfu/ml vs. 3.52 +/- 0.45 log pfu/ml, P = 0.002) and non-Caucasian ethnicity (5.16 +/- 0.30 log pfu/ml vs. 3.80 +/- 0.37 log pfu/ml, P = 0.006). CONCLUSIONS: Nasal RSV quantity correlates with disease severity in hospitalized infants with recently identified RSV infection.

Multidrug-resistant tuberculosis meningitis: clinical problems and concentrations of second-line antituberculous medications.

OBJECTIVE: [corrected] To describe a case of culture-proven multidrug-resistant tuberculous (MDR-TB) meningitis, in which the patient survived long enough for clinicians to adjust antituberculous therapy to second-line therapeutic agents. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENT: Twenty-one-month-old girl with MDR-TB meningitis. INTERVENTIONS: Initial standard treatment failed. Subsequent treatment with second-line therapeutic agents including ciprofloxacin, cycloserine, ethambutol, ethionamide, and rifabutin were given for approximately two years. Concentrations of these drugs were measured in serum and cerebrospinal fluid in the presence and absence of meningeal inflammation. MAIN OUTCOME MEASURES/RESULTS: The patient survived for approximately two years after initiation of second-line anti-TB therapy. During this treatment, she developed a ventriculo-peritoneal shunt tunnel tract infection secondary to MDR-TB. CONCLUSIONS: All TB meningitis isolates for which the source case antibiotic susceptibility pattern is not known should be cultured and susceptibility tested using rapid broth techniques. Measurement and subsequent adjustment of therapeutic drug concentrations may optimize therapy with second-line anti-TB drugs in TB meningitis. Better pediatric formulations and pharmacokinetic data for second-line and anti-TB therapeutic agents are needed.

Changes in mandibular length before, during, and after successful orthopedic correction of Class II malocclusions, using a functional appliance.

Forty-seven girls were successfully treated with a functional appliance (FA). To be included in this study, the rate of increase in mandibular length during treatment had to be greater than twice the mean rate for a subgroup of 20 of these patients evaluated during a pre-FA observation period. The mean mandibular growth rate was 6 mm per year while the FA was activated. In the ensuing months, cephalograms were taken at intervals coinciding with five post-FA phases, including complete edgewise treatment and retention. During the post-FA phase of initial edgewise treatment, the mandibular growth rate was dramatically reduced when compared with 47 controls matched for age, sex, and initial SN:GoGn angle. Selected individual cases are presented to illustrate the great variability in growth responses that were obtained. This study found highly significant increases in mandibular length still present 2 years after treatment, diminished but still significant gains after 3 years, and no significant difference after 4 years.

Orthopedic and orthodontic effects resulting from the use of a functional appliance with different amounts of protrusive activation.

A functional appliance worn full-time was given to 50 consecutively treated girls aged 8 1/2 to 14 years. These patients were divided into three groups: in 14 patients, protrusive activation was maintained at 1 mm; in another 14 patients, it was maintained at 3 mm; and in 22 patients, there was an initial, large single advancement averaging 5 to 6 mm. These amounts of protrusion were checked and maintained every 2 months. Analysis of the data, using control patients matched for age and sex, indicated that there was no difference in either orthopedic or orthodontic variables between the 3 mm continuous-advancement group and the single large-advancement group. The 1 mm continuous-advancement group showed a diminished but still statistically significant response. Assuming linearity, it was calculated that, had the 1 mm activation group been treated long enough to have obtained the mandibular orthopedic effects of the other two groups, the orthodontic changes also would have been comparable.

Maxillary incisor intrusion and facial growth.

A palate and first molar anchorage appliance is used to intrude upper incisors, and the effects on dental and skeletal variables are examined in 25 growing females and 25 matched controls. On average, the mandible was unaffected for the entire treated sample, but those with the largest reduction in overbite showed more increase in mandibular length than expected.

A study in human subjects using a new device designed to mimic the protrusive functional appliances used previously in monkeys.

A new appliance is described that mimics in function the protrusive jaw-positioning devices used previously in monkeys. The appliance consists of maxillary and mandibular posterior biteplates separated by a sharp vertical interface perpendicular to the occlusal plane. Function of the appliance was evaluated in 35 consecutively treated patients and compared against matched controls. The patients, who ranged in age from 9 to 14 years, accepted the appliance readily and wore it 24 hours each day, even while eating. Although cephalometrics was the primary assessment tool, tomograms and/or transcranial x-ray films and models were also obtained. The rate of mandibular length increase, measured from articulare, was comparable to or better than that found in monkeys using similar devices. The dentoalveolar effects were also similar to those found in monkeys, including anterior migration of the mandibular dentition and posterior movement of the maxillary dentition. The mandibular molars moved forward 4.8 mm of which 73% was determined to have come from increased anterior movement of the mandible. Subtracting normal growth, the net mandibular length increase was 2.2 mm during the 9.4-month average treatment interval.