Keith R. Powell

Respiratory Syncytial Viral Infection in Children with Compromised Immune Function

For 10 winters, 608 children five years old or younger who were hospitalized with respiratory syncytial virus (RSV) infection were prospectively studied to evaluate the relation between their immune status and the severity of their infection. Forty-seven had been immunocompromised by chemotherapy, steroid therapy, or a primary immunodeficiency disorder. Among the immunocompromised children, those receiving chemotherapy for cancer and those with immunodeficiency disease had more severe RSV disease, with pneumonia occurring at all ages, and a higher mortality rate. Children receiving long-term steroid therapy did not appear to have more severe clinical manifestations than normal children. Viral shedding, however, was significantly greater and more prolonged in the children receiving steroid therapy, and particularly in those receiving chemotherapy or with an immunodeficiency disease. Giant-cell pneumonia was documented in one child with leukemia. Over half the immunocompromised children acquired the RSV infection nosocomially. These findings indicate that children receiving chemotherapy for cancer and those with immunodeficiency disease are at risk for complicated or fatal infections from RSV and should be considered for antiviral and other therapies as they become available. Efforts should also be made to protect compromised children if hospitalization cannot be avoided.

Practice guideline for the management of infants and children 0 to 36 months of age with fever without source

STUDY OBJECTIVE To develop guidelines for the care of infants and children from birth to 36 months of age with fever without source. PARTICIPANTS AND SETTING An expert panel of senior academic faculty with expertise in pediatrics and infectious diseases or emergency medicine. DESIGN AND INTERVENTION A comprehensive literature search was used to identify all publications pertinent to the management of the febrile child. When appropriate, meta-analysis was used to combine the results of multiple studies. One or more specific management strategies were proposed for each of the decision nodes in draft management algorithms. The draft algorithms, selected publications, and the meta-analyses were provided to the panel, which determined the final guidelines using the modified Delphi technique. RESULTS All toxic-appearing infants and children and all febrile infants less than 28 days of age should be hospitalized for parenteral antibiotic therapy. Febrile infants 28 to 90 days of age defined at low risk by specific clinical and laboratory criteria may be managed as outpatients if close follow-up is assured. Older children with fever less than 39.0 C without source need no laboratory tests or antibiotics. Children 3 to 36 months of age with fever of 39.0 C or more and whose WBC count is 15,000/mm3 or more should have a blood culture and be treated with antibiotics pending culture results. Urine cultures should be obtained from all boys 6 months of age or less and all girls 2 years of age or less who are treated with antibiotics. CONCLUSION These guidelines do not eliminate all risk or strictly confine antibiotic treatment to children likely to have occult bacteremia. Physicians may individualize therapy based on clinical circumstances or adopt a variation of these guidelines based on a different interpretation of the evidence.

Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis

During a 2-year period, 233 infants younger than 3 months were prospectively studied to determine whether physical examination, white blood cell and band count, and urinalysis could identify infants unlikely to have serious bacterial infections. Only previously healthy infants (born at term, no perinatal complications, no previous or underlying diseases, no previous antibiotic therapy) were studied. One hundred forty-four (62%) of the 233 infants were considered unlikely to have serious bacterial infections, because they did not have physical findings consistent with ear, soft tissue, or skeletal infection, had between 5000 and 15,000 white blood cells/mm3, had less than 1500 bands/mm3, and urinalysis yielded normal findings. Eighty-nine (38%) infants did not meet one or more of these criteria and were classified as being at high risk for serious bacterial infection. Only one (0.7%) of the 144 infants in the low-risk group had a serious infection, compared with 22 (25%) of the 89 infants in the high risk group (P less than 0.0001). None of the infants in the low-risk group had bacteremia, compared with nine (10%) of the 89 infants in the high-risk group (P less than 0.0005). Neither traditional risk factors, such as age, sex, and temperature, nor other signs, symptoms, or laboratory findings were adequate predictors of serious bacterial infection. We conclude that previously healthy infants younger than 3 months with an acute illness are unlikely to have serious bacterial infection if they have no findings consistent with ear, soft tissue, or skeletal infections and have normal white blood cell and band form counts and normal urine findings.

Risk of secondary bacterial infection in infants hospitalized with respiratory syncytial viral infection.

Because infants hospitalized with respiratory syncytial virus (RSV) infection frequently receive antibiotics, our study was undertaken to determine what the actual risk of secondary bacterial infections in patients with RSV infection is and what effect antibiotic treatment might have on the course of illness. In a 9-year prospective study of 1706 children hospitalized with acute respiratory illnesses, 565 children had documented RSV infections. A subsequent bacterial infection rarely developed in those with RSV lower respiratory tract disease. The rate of subsequent bacterial infection was 1.2% in the total group of children infected with RSV, and 0.6% in the 352 children who received no antibiotics. A significantly greater proportion (4.5%) of subsequent bacterial infections occurred in infants who received parenteral antibiotics (p = 0.01), and especially in a subgroup who received parenteral antibiotics for 5 or more days (11%, p less than 0.001). We conclude that the risk of secondary bacterial infection appears to be low for most infants with RSV infection. In a few infants given parenteral broad-spectrum antibiotics the risk may be greater, but whether this is related to the antibiotic therapy or to other risk factors is not clear.

Prevention of bacteremia attributed to luminal colonization of tunneled central venous catheters with vancomycin-susceptible organisms.

Forty-five children with oncologic or hematologic disorders requiring tunneled central venous catheters (TCVC) for the administration of immunosuppressive therapy were randomized to receive either 10 U/mL heparin (H) (24 patients) or a solution of 10 U/mL H and 25 micrograms/mL vancomycin (H-V) (21 patients) for all catheter flushes. Episodes of fever or suspected sepsis were evaluated to determine whether the addition of vancomycin to the flush solution would alter the incidence of symptomatic bacteremia attributed to luminal colonization of TCVC with vancomycin-susceptible bacteria. Patients were enrolled for 247 +/- 150 days, accounting for a total of 11,095 days of catheter use. Bacteremia attributed to luminal colonization with vancomycin-susceptible organisms occurred in five patients (six infections) receiving H alone compared with zero patients receiving H-V (P = .035). The time to the first episode of bacteremia with vancomycin-susceptible organisms, analyzed by Kaplan-Meier survival curves, was significantly longer in patients receiving H-V (P = .04). There were no differences in the incidence of other infections including bacteremia attributed to luminal colonization with vancomycin-resistant organisms, other bacteremias (including those arising from the catheter exit site), exit-site cellulitis, or fungal infections. No organisms resistant to vancomycin were identified. Vancomycin could not be detected in the peripheral blood of patients receiving vancomycin in the flush solution. No vancomycin-related toxicities were noted. We conclude that the use of an H-V flush solution in immunocompromised patients with TCVC can decrease the frequency of bacteremia attributed to luminal colonization with vancomycin-susceptible bacteria.

Epidemiology of neonatal enterovirus infection

During a typical enterovirus season in Rochester, New York, none of 666 neonates or 629 mothers were found to be excreting nonpolio enteroviruses within 1 day of delivery. No enteroviruses were isolated from weekly cultures of the 23 infants who died or remained hospitalized during the first month of life. After discharge, culture specimens were obtained in 586 infants at one to four weekly home visits until 1 month of age. The incidence of acquisition of nonpolio enterovirus infection was 12.8%, and the overall prevalence of enterovirus excretion was 5.3%. Risk of virus infection was associated only with lower socioeconomic status (P less than 0.0001) and lack of breast-feeding (P less than 0.0001). Four percent of all infants and 21% of infants in whom cultures for enterovirus were positive were readmitted to the hospital in the first month of life; 79% of infants with positive enterovirus cultures were asymptomatic. We conclude that enterovirus infection during the first month of life is very common in the late summer and early fall. Most infants are asymptomatic, but the risk of hospitalization is high. Breast-feeding may be associated with protection from infection.

Prevention of central venous catheter-related coagulase-negative staphylococcal sepsis in neonates

A randomized, double-blind, controlled trial was conducted to determine whether vancomycin added to parenteral alimentation solution given via a central venous catheter would decrease the incidence of catheter-related coagulase-negative staphylococcal sepsis. Seventy infants with a central venous catheter (CVC) in place were randomly selected to receive total parenteral nutrition--either the standard solution or a solution containing 25 micrograms of vancomycin per milliliter. Catheter-related sepsis was defined as the isolation of the same bacterial species from specimens of both peripheral and CVC blood with the concentration of bacteria at least tenfold greater in the specimen obtained from the CVC. Specimens from the CVCs were cultured on removal of the catheters to determine colonization. The colonization of catheters by coagulase-negative staphylococci was reduced from 40% to 22% (p = 0.03) in the vancomycin group; catheter-related sepsis was reduced from 15% to no cases (p = 0.004). Fewer infants required CVC reinsertion in the vancomycin-treated group (p = 0.02), who also regained birth weight earlier (13.4 vs 17.1 days (p = 0.014)). Adverse effects of vancomycin infusion were not observed. We conclude that vancomycin added to the solution used for total parenteral nutrition effectively reduces catheter-related sepsis in the neonatal intensive care unit and offers other potential benefits such as the need for fewer catheters and earlier weight gain. However, we do not recommend widespread implementation of this technique until there are data regarding the emergence of vancomycin-resistant organisms.

Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenance plus replacement fluid therapy

We hypothesized that plasma arginine vasopressin (AVP) concentrations in children with meningitis are appropriate for the childrens degree of hypovolemia, even though the concentrations were higher than expected for the serum osmolality. A randomized study was conducted to compare the effect on plasma AVP concentrations of giving maintenance fluid requirements plus replacement of any deficit versus restricting fluids to two thirds of maintenance requirements for 24 hours. Plasma AVP concentrations and serum osmolality were measured before fluid therapy was begun and again after 24 hours. Nineteen children, 2 months to 17 years of age, were studied; 13 had bacterial meningitis (12 with Haemophilus influenzae type b). Ten children (seven with bacterial meningitis) received a mean of 1.42 times the calculated maintenance fluid requirements, and nine (six with bacterial meningitis) were restricted to a mean of 0.65 times maintenance. Children in the maintenance group also received significantly more sodium (mean = 6.3 mEq/kg/24 hr) than children in the fluid-restricted group (mean = 2.0 mEq/kg/24 hr). The two groups were comparable for plasma AVP concentration and serum osmolality before fluid therapy was begun. The plasma AVP concentration was significantly lower after 24 hours of maintenance plus replacement fluids than after fluid restriction (p = 0.005), and the change in AVP concentration correlated with the amount of sodium given (p less than 0.02). This study supports the hypothesis that serum AVP concentrations are elevated in patients with meningitis because of hypovolemia and become normal when sufficient sodium is given to facilitate reabsorption of water by the proximal tubule of the kidney. Patients with meningitis can be given maintenance plus replacement fluids but should be monitored for the development of the syndrome of inappropriate secretion of antidiuretic hormone.

Intramuscular versus oral antibiotic therapy for the prevention of meningitis and other bacterial sequelae in young, febrile children at risk for occult bacteremia

Because studies of the treatment of children with occult bacteremia have yielded conflicting results, we compared ceftriaxone with amoxicillin for therapy. Inclusion criteria were age 3 to 36 months, temperature > or = 39 degrees C, an acute febrile illness with no focal findings or with otitis media (6/10 centers), and culture of blood. Subjects were randomly assigned to receive either ceftriaxone, 50 mg/kg intramuscularly, or amoxicillin, 20 mg/kg/dose orally for six doses. Of 6733 patients enrolled, 195 had bacteremia and 192 were evaluable: 164 Streptococcus pneumoniae, 9 Haemophilus influenzae type b, 7 Salmonella, 2 Neisseria meningitidis, and 10 other. After treatment, three patients receiving amoxicillin had the same organism isolated from their blood (two H. influenzae type b, one Salmonella) and two from the spinal fluid (two H. influenzae type b), compared with none given ceftriaxone. Probable or definite infections occurred in three children treated with ceftriaxone and six given amoxicillin (adjusted odds ratio 0.43, 95% confidence interval 0.08 to 1.82, p = 0.31). The five children with definite bacterial infections (three meningitis, one pneumonia, one sepsis) received amoxicillin (adjusted odds ratio 0.00, 95% confidence interval 0.00 to 0.52, p = 0.02). Fever persisted less often with ceftriaxone (adjusted odds ratio 0.52, 95% confidence interval 0.28 to 0.94, p = 0.04). Although the difference in total infections was not significant, ceftriaxone eradicated bacteremia, prevented significantly more definite focal bacterial complications, and was associated with less persistent fever.

The use of systemic fluoroquinolones

The only indications for which a fluoroquinolone (ie, ciprofloxacin) is licensed by the US Food and Drug Administration for use in patients younger than 18 years are complicated urinary tract infections, pyelonephritis, and postexposure treatment for inhalation anthrax. Nonetheless, approximately 520 000 prescriptions for fluoroquinolones were written in the United States for patients younger than 18 years in 2002; 13 800 were written for infants and children 2 to 6 years of age, and 2750 were written for infants younger than 2 years. Clinical trials of fluoroquinolones in pediatric patients with various diagnoses have been published and are reviewed. Fluoroquinolones cause arthrotoxicity in juvenile animals and have been associated with reversible musculoskeletal events in both children and adults. Other adverse events associated with fluoroquinolones include central nervous system disorders, photosensitivity, disorders of glucose homeostasis, prolongation of QT interval with rare cases of torsade de pointes (often lethal ventricular arrhythmia in patients with long QT syndrome), hepatic dysfunction, and rashes. The increased use of fluoroquinolones in adults has resulted in increased bacterial resistance to this class of antibacterial agents. This report provides specific guidelines for the systemic use of fluoroquinolones in children. Fluoroquinolone use should be restricted to situations in which there is no safe and effective alternative to treat an infection caused by multidrug-resistant bacteria or to provide oral therapy when parenteral therapy is not feasible and no other effective oral agent is available.