Influenza vaccination in the organ transplant recipient: review and summary recommendations.

Influenza virus causes a spectrum of illness in transplant recipients with a high rate of lower respiratory disease. Seasonal influenza vaccination is an important public health measure recommended for transplant recipients and their close contacts. Vaccine has been shown to be safe and generally well tolerated in both adult and pediatric transplant recipients. However, responses to vaccine are variable and are dependent on various factors including time from transplantation and specific immunosuppressive medication. Seasonal influenza vaccine has demonstrated safety and no conclusive evidence exists for a link between vaccination and allograft dysfunction. Annually updated trivalent inactivated influenza vaccines have been available and routinely used for several decades, although newer influenza vaccination formulations including high-dose vaccine, adjuvanted vaccine, quadrivalent inactivated vaccine and vaccine by intradermal delivery system are now available or will be available in the near future. Safety and immunogenicity data of these new formulations in transplant recipients requires investigation. In this document, we review the current state of knowledge on influenza vaccines in transplant recipients and make recommendations on the use of vaccine in both adult and pediatric organ transplant recipients.

Exploring beyond viral load testing for EBV lymphoproliferation: role of serum IL-6 and IgE assays as adjunctive tests.

We examined serum IL-6 and IgE assays as adjuncts to VL monitoring for PTLD. Paediatric solid organ transplant recipients were followed with VL monitoring. VL, IL-6, and IgE assays were compared between PTLD cases and non-cases at <3, 3-6 and >6 months after transplantation. Median IL-6 levels in PTLD cases were 15.5 (2.0-87.1) and 23.3 (2.1-276) pg/mL compared with 3.25 (0.92-114) and 3.5 (0.75-199.25) pg/mL in non-cases at 3-6 and >6 months, respectively (p = 0.006 and p = 0.005). At >6 months, IL-6 levels correlated with VL and PTLD occurrence (Spearman's coefficients = 0.40; p = 0.001 and 0.32; p = 0.003) in univariate analyses. No benefit was derived from performance of IgE levels. The sensitivity and specificity of high VL as a test of PTLD were 76.3% and 92.5%, while the negative predictive value and PPV of VL were 94.9% and 68.4%, respectively. Combining elevated IL-6 with high VL increased the PPV and specificity to 80% and 96.2%, respectively, and improved the receiver operating characteristic curve. Serum IL-6 levels can improve the clinician's ability to identify PTLD, among patients with elevated EBV viral loads.

The utility of plasma polymerase chain reaction for human herpes virus-6 among pediatric bone marrow transplant recipients: results of a pilot study.

We evaluated the utility of plasma polymerase chain reaction (PCR) for surveillance of human herpes virus 6 (HHV-6) infection among pediatric bone marrow transplant (BMT) recipients. We used a prospective, non-interventional design involving a study group and controls. BMT recipients and healthy controls were evaluated. BMT subjects had HHV-6 PCR done biweekly for 12 weeks post transplantation, while a single PCR test was done on controls. For the PCR assay, EDTA blood was collected and DNA extracted from whole blood and cell-free plasma using standard procedures. The PCR was first performed on DNA from whole blood and if a positive result was obtained, the test was repeated on the DNA from the plasma. Thirty BMT recipients (13 autologous and 17 allogeneic) were enrolled, on whom a total of 156 PCR tests were performed, while six tests were done on six healthy controls. The median age of BMT subjects was 6.2 years (range 0.5-17.5 years). The median age of the control subjects was 6.6 years (range 2-10 years). Among asymptomatic BMT patients who had PCR surveillance, the positivity rate was 3.3% (1/30) on whole blood and 0% (0/30) on plasma. None of the six healthy subjects had a positive PCR test on whole blood. During the period of the surveillance study, 14 patients had diagnostic evaluations for HHV-6 disease because of clinical symptoms. Two of these patients were diagnosed with disease associated with HHV-6 (graft failure and encephalitis) and had positive PCR tests on whole blood and plasma and whole blood and cerebrospinal fluid, respectively. We conclude that despite the fact that HHV-6 seropositivity rates are high among children, the frequency of HHV-6 plasma PCR positivity is low in pediatric BMT subjects who are asymptomatic for HHV-6 disease. Given that a positive test on plasma is consistent with active infection, this increases the utility of the PCR test as a diagnostic aid in evaluating syndromes presumed to be due to HHV-6 in pediatric bone marrow transplant recipients.

Varicella-zoster infection in pediatric solid-organ transplant recipients: a hospital-based study in the prevaricella vaccine era.

We reviewed 58 cases of varicella-zoster infection that occurred between 1988 and 1998 in 47 pediatric solid-organ transplant recipients. The median age of patients at the time of admission with varicella-zoster infection was 8.0 yr (range 1-17 yr). The median interval between transplantation (Tx) and varicella-zoster virus (VZV) infection was 1.6 yr (range 0.06-9.3 yr). Varicella infection occurred at a rate of one case for every seven transplant recipients. Among the 58 cases of VZV infection, 53% were varicella while 47% were herpes-zoster. Varicella infection occurred despite treatment with varicella-zoster immune globulin (VZIG) in 17 of 31 cases of varicella infection. However, the disease was generally mild with severe disease occurring in only two patients. One patient (1.7%) died as a result of bacterial sepsis. There was no significant relationship between VZV infection and specific immune suppressants. Episodes of rejection were more likely to be temporally associated with the occurence of herpes zoster than with varicella infection (p = 0.02). The data generated provide useful background information in our population in the prevaricella vaccine era.

Medical decision analysis in infectious diseases.

Medical decision analysis (MDA) has played an important role in assisting infectious disease physicians make decisions associated with varying levels of complexity. Clinicians are often uncomfortable with some aspects of MDA, particularly when utilities are used as outcome measures. However, as the present paper outlines, MDA may use other outcome variables, including costs and disease complications. In this context, this explicit, reproducible analytic framework is an important tool in the area of infectious diseases, and is frequently applied to many situations, including cost effectiveness analyses, studies involving assessment of risks versus benefits of preventive and treatment strategies, and other situations. The objective of this paper is to assist infectious diseases clinicians to understand better the role of MDA in clinical practice. In this regard, the principles of MDA are reviewed and a common clinical example is used for illustrative purposes.

Antibiotic prescribing by pediatricians for respiratory tract infection in children.

To examine antimicrobial prescribing rates for viral respiratory tract infections by primary care pediatricians in the greater Toronto area, charts were reviewed for the week of 17-21 February 1997 at 61 pediatricians' offices. Antibiotics were considered appropriate if the diagnosis was compatible with bacterial infection. A total of 3,585 patient visits were reviewed. The common cold was the most common respiratory tract syndrome leading to an office visit (1,317 visits). The overall rate of appropriate antibiotic prescribing was 89.5%. There was no significant difference in prescribing when physicians were compared by year of graduation from medical school, sex, or location of training. Diagnostic codes (ICD-9 [International Classification of Diseases, 9th edition] codes) did not match the chart diagnosis in 41% of cases. Toronto primary care pediatricians appear to have a lower rate of inappropriate antibiotic prescribing than do primary care physicians in other regions of Canada and the United States.

Risk factors for resistance to "first-line" antimicrobials among urinary tract isolates of Escherichia coli in children.

BACKGROUND: There are increasing concerns regarding antimicrobial resistance in Canada. Data are limited on the prevalence, patterns of resistance and risk factors associated with resistant organisms, including coliforms, in children. This study was done to address these issues as they relate to urinary tract isolates of Escherichia coli in a tertiary care pediatric centre in Ottawa. METHODS: A surveillance study was conducted from December 1992 to December 1994. Susceptibility testing of urinary tract isolates of E. coli was performed using a panel of antimicrobial agents. A case-control study was also conducted for subjects with isolates resistant to trimethoprim-sulfamethoxazole (T-S), this drug being used a representative "first-line" agent. RESULTS: A total of 1636 consecutive isolates were obtained from 967 subjects. Of the 1636 isolates, 736 (45.0%) were resistant to ampicillin, 514 (31.4%) were resistant to T-S, 363 (22.2%) were resistant to both ampicillin and T-S, and 27 (1.7%) were resistant to both ampicillin and gentamicin. In the case-control study 274 children with isolates resistant to T-S were matched with 274 children who had T-S-sensitive isolates obtained during the study period or the preceding or subsequent 6 months. Multivariate analyses indicated that subjects who had received antimicrobials for more than 4 weeks in the previous 6 months were about 23 times more likely to have isolates resistant to T-S than were subjects without this risk factor (odds ratio [OR] 23.4, 95% confidence interval [CI] 12.0-47.6). Children with genitourinary tract abnormalities were 2.4 times more likely to have resistant isolates than those without such abnormalities (95% CI 1.2-4.5). Compared with children who had no hospital admissions in the previous year, those with 1 admission in that period were more likely to have resistant isolates (OR 2.3, 95% CI 1.4-7.5), as were those with 2 or more admissions in that period (OR 3.2, 95% CI 1.1-4.8). Compared with children aged 2-6 years, children under 2 years of age were less likely to have resistant isolates (OR 0.3, 95% CI 0.2-0.8). INTERPRETATION: Selective antimicrobial pressure and multiple admissions to hospital were among the risk factors associated with antimicrobial resistance. The finding of a low but definite level of resistance to both ampicillin and gentamicin is important for the selection of empiric therapy for sepsis in neonates. The role of inexpensive first-line agents in the outpatient treatment and prevention of urinary tract infections requires re-examination, particularly in children who have recently received antimicrobial therapy.

Medical therapy of otitis media: use, abuse, efficacy, and morbidity.

OBJECTIVE: Otitis media (OM) is one of the most common paediatric disorders encountered by primary care physicians. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the principal pathogens responsible for OM. As a result of the increasing prevalence of antimicrobial resistance, the use of antimicrobial therapy in OM has come under close scrutiny. Amoxicillin remains the most appropriate option for initial empiric therapy of acute otitis media (AOM). The duration of therapy required for AOM depends on the age of the patient, the severity of disease, and the route of administration. In most cases, particularly in children older than 5 years of age, a 5-day course of antibiotic therapy should suffice. Antibiotic therapy is not required in most cases of otitis media with effusion (OME) and should be reserved for those with bilateral effusions persisting for longer than 3 months associated with significant hearing loss. Antibiotic prophylaxis for recurrent AOM should be minimized. Myringotomy with or without tympanostomy tube placement is an important therapeutic option in those with OME and recurrent AOM. Active immunization against S. pneumoniae and Influenza A is likely to play an increasingly important role in the prevention of OM.

Serum immunoreactive erythropoietin levels and associated factors amongst HIV-infected children.

OBJECTIVES: To determine the spectrum of serum immunoreactive erythropoietin (SIE) levels amongst HIV-infected children aged < 13 years in relation to the levels among healthy children as well as those with renal failure; to examine the relationship between clinical and laboratory parameters and SIE levels. DESIGN: A cross-sectional study with a descriptive non-interventional format. HIV-infected Canadian subjects were recruited through four tertiary Canadian and one Bahamian centre. Children with renal failure and healthy children were recruited from one of the Canadian centres. METHODS: Study subjects had clinical and laboratory profiles determined at baseline and at each of five follow-up periods over 1 year. SIE levels were measured by radioimmunoassay with a normal range of 12-28 IU/I. Data handling and statistical functions were performed by the Canadian HIV Trials Network. RESULTS: The study enrolled 133 HIV-infected subjects and 38 controls. Of these, 117 HIV-infected subjects, 24 healthy controls, and 11 controls with renal failure were eligible for analysis. The median age of infected subjects was 44 months, whereas that of healthy controls was 56 months, and 95 months for controls with renal failure. The median SIE levels were 14 and 11 IU/I for subjects with renal failure and healthy subjects, respectively. The median SIE level was 61 IU/I among zidovudine (ZDV)-treated subjects and 22 IU/I among ZDV-naive HIV-infected subjects. HIV-infected children almost invariably had SIE levels < 200 IU/I. The median SIE levels amongst HIV-infected subjects whose hemoglobin levels were < 100 g/l were 98 and 31 IU/I for ZDV-treated and ZDV-naive subjects, respectively (P = 0.002). This difference in median SIE levels between ZDV-treated subjects and ZDV-naive subjects was also observed among subjects whose hemoglobin levels were > 100 g/l (median, 58 and 15 IU/l, respectively; P < 0.001). Hemoglobin level was the most important predictor of log10 SIE (P < 0.01 for ZDV-treated and ZDV-naive subjects). CONCLUSIONS: SIE levels amongst HIV-infected children were affected by HIV infection, use of ZDV, and presence or absence of anemia. SIE levels amongst HIV-infected children were generally lower than 200 IU/I. This characterization of SIE levels will facilitate clinical trials of exogenous recombinant human erythropoietin in HIV-infected children with anemia.

Elevated interleukin-1 receptor antagonist levels in pediatric sepsis syndrome.

OBJECTIVE: To measure plasma levels of interleukin-1 beta, interleukin-1 receptor antagonist (IL-Ira), and tumor necrosis factor alpha in children with sepsis syndrome. STUDY DESIGN: A prospective, observational study of 14 patients aged 5 months to 13 years with sepsis syndrome admitted to a pediatric intensive care unit. Cytokine levels were measured by enzyme-linked immunosorbent assay at baseline and at a 12, 24, and 48 hours and compared with the levels of 21 age-matched control subjects. RESULTS: The mean pediatric risk of mortality score was 16.1. Bacterial and viral sepsis was confirmed in five and three patients, respectively. Compared with the levels in the control subjects (mean level of IL-Ira: 654 pg/ml), the IL-Ira levels were elevated in the septic patients, with mean values of 17855 (p < 0.001), 12771 (p < 0.001), 9182 (p < 0.01), and 2296 pg/ml (p = not significant) at baseline and at 12, 24, and 48 hours, respectively. The IL-Ira level was greater than 1000-fold higher than the IL-1 beta level at all time points in 13 of 14 septic patients. CONCLUSIONS: At the time of hospital admission, circulating IL-Ira levels in a cohort of children with sepsis syndrome were at concentrations known to block IL-1 receptors. Thus additional benefit from exogenous IL-Ira therapy would be questionable. Further studies are indicated to determine whether there is a population of patients with sepsis who could benefit from administration of exogenous IL-Ira.

Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial.

OBJECTIVE: To determine the clinical benefit of oral dexamethasone in children admitted to the hospital with bronchiolitis treated with nebulized salbutamol. METHODS: Randomized, double-blind, placebo-controlled trial in the inpatient wards of a pediatric tertiary care hospital. The participants, children aged 6 weeks to 15 months, admitted with first-time wheezing, were eligible if their oxygen saturation was less than 95% on admission to the hospital and their Respiratory Distress Assessment Instrument (RDAI) score was greater than 6. Patients were excluded if they had any one of the following: an underlying disease that might affect cardiopulmonary status, asthma, recent treatment with steroids (within 2 weeks), or any history of adverse reaction to steroids. Patients were randomly assigned to receive either orally administered dexamethasone with 0.5 mg/kg as the first dose and 0.3 mg/kg for the next 2 mornings, or an equal volume of an orally administered placebo with an identical appearance. All patients received nebulized salbutamol at 0.15 mg/kg every 4 hours for the first 24 hours. The primary outcome measure was the change from baseline in the RDAI score at 24 hours. Secondary outcome measures were oxygen saturation, respiratory rate, RDAI measurement twice daily for the first 4 days, and the length of hospitalization. RESULTS: At 24 hours the mean change (SD) from baseline in the RDAI score was 1.6 (2.3) in the placebo group (n = 28) and 1.4 (2.0) in the dexamethasone group (n = 33; p = 0.74). There were no significant differences between the two groups in change in oxygen saturation, respiratory rate, and RDAI score at any assessment period. The median length of stay (95% confidence interval) for the placebo group was 48 (42, 54) hours compared with 57 (38, 76) hours in the dexamethasone group (p = 0.19). CONCLUSIONS: Oral dexamethasone therapy does not affect the clinical course of children hospitalized with bronchiolitis and therefore cannot be recommended in this clinical situation.

Cost-effectiveness of recombinant human erythropoietin versus transfusions in the treatment of zidovudine-related anemia in HIV-infected children.

The objectives of this study were to compare the costs and benefits of recombinant human erythropoietin (r-HuEPO) relative to repeated transfusions in the treatment of zidovudine (AZT)-related anemia among HIV-infected children. The study was based on a tertiary care Canadian Pediatric Hospital Model. A decision analytic structure was used for the evaluation of cost-effectiveness. The decision tree involved two options. In option A:r-HuEPO, subjects receive r-HuEPO three times weekly at home for 1 year, whereas in B:no r-HuEPO, transfusions are given on a monthly basis in a medical short-stay unit over a 1-year period. Probabilities of various outcomes and downstream events were obtained from a literature review. The analysis was conducted from the perspective of the health-care system and utilized standard cost-effectiveness methodology. The results indicated that for every child receiving r-HuEPO, the total cost is Can $11,245 for 1 year compared with $3,130 per year for those in B:no r-HuEPO. The incremental cost effectiveness of A:r-HuEPO relative to B:no r-HuEPO is $1,373 per transfusion episode averted. The order of magnitude of the results was not significantly affected by changes in any of the assumptions used for the cost estimates or baseline probability values.

Relationship between parental occupation and children's oropharyngeal colonization with Neisseria meningitidis.

We explored, during an outbreak of meningococcal disease, whether children of parents with workplace exposure to children were at increased risk of oropharyngeal colonization with Neisseria meningitidis. In comparison with children of parents without workplace exposure to children, the risk of colonization was not increased (odds ratio = 1.62; 95% confidence interval, 0.56 to 4.72). Therefore a parent's occupation does not appear to increase the risk of their children's colonization with N. meningitidis.

Cephalhematomas revisited. When should a diagnostic tap be performed?

The purpose of this article is to review the most appropriate method for investigating cephalhematomas for possible infection and to clarify the indications for diagnostic aspiration. MEDLINE searches were conducted for the period from 1972 to 1993, and all English-language reports were obtained. A summary of the findings from the reports identified was supplemented by a patient report. Eleven articles reporting 13 infected cephalhematomas were identified in the literature from 1972 to 1993. Escherichia coli was isolated from approximately 50% of the cephalhematomas that were aspirated. Most patients presented with obvious clinical signs of scalp infection, sepsis, meningitis, and/or osteomyelitis. Plain radiographs, bone scans, and enhanced CT scans were limited in their ability to determine if a cephalhematoma was infected unless associated osteomyelitis existed. Aspiration is the diagnostic procedure of choice for cephalhematomas suspected of being infected, as indicated by an increase in size, development of erythema, development of fluctuance, relapse of systemic infection, or a delay in the resolution of clinical symptoms of infection.

Standardizing the assessment of diarrhea in clinical trials: results of an interobserver agreement study.

Interobserver agreement was determined between nurses and parents using a standard method of assessing diarrheal stools. The study population consisted of patients less than three years of age hospitalized at The Hospital for Sick Children, Toronto, Canada. Stool samples were independently categorized by observer pairs within minutes of being obtained from children with and without diarrhea as: watery--liquid, no solid elements; loose--liquid with solid elements; pasty--like a paste; formed--normal solid. Watery and loose stools were regarded as abnormal and indicative of diarrhea. Teaching sessions were conducted for nursing shifts, while parents were instructed prior to each observation. In the nurses' agreement study, each stool specimen was examined by the nurse providing care to the patient from whom the stool was obtained and a nurse not looking after the patient. Parents' assessments were also compared with nurses' assessments. Finally, parents' assessments were compared with each other. In the first group, agreement beyond chance for presence or absence of diarrhea measured by kappa was 0.78 (95% confidence intervals (CI) 0.55-1.0). The observed agreement on 148 pairs of observations between parents and nurses was 75% (kappa = 0.5; 95% CI 0.36-0.64). Between-parent agreement on 30 other paired observations was 77% (kappa = 0.54; 95% CI 0.24-0.84). Teaching parents about the four categories is a potentially useful adjunct for assessment of diarrheal stools in children.

Cow's milk versus soy-based formula in mild and moderate diarrhea: a randomized, controlled trial.

We determined the efficacy of a soy-based formula compared with a cow's milk formula in infant refeeding after acute diarrhea in a randomized controlled double-blind clinical trial. Infants 2-12 months of age with diarrhea of less than one week's duration and mild or moderate dehydration admitted to a pediatric hospital or in the practice of a participating primary care pediatrician were investigated. Seventy-six patients were enrolled and 73 completed the study; 39 infants received a soy-based formula (Isomil) and 34 received a cow's milk formula (SMA). Hospitalized patients were rehydrated with an oral glucose-electrolyte solution or an iv dextrose-sodium solution. Outpatients received oral glucose-electrolyte solution. In all patients, the study formula was commenced ad libitum during the first 24 h as determined by the attending pediatrician. The primary outcome measure was duration of diarrhea, defined as time to first normal stool, when subsequent stools were normal for a 24-h period. In addition, a predetermined secondary outcome was proportion of treatment failures, defined as the need to reinstitute clear fluids because of emesis, refusal to accept study formula, need for iv fluids due to negative fluid balance or diarrhea persisting beyond 7 days after enrollment. Total duration of diarrhea was significantly longer (p = 0.03) in those receiving cow's milk (mean +/- SD 6.6 +/- 4.2 days) than in those receiving soy-based formula (4.5 +/- 3.6 days). Volume of formula intake and weight gain at 14 days were not different in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of intrapartum penicillin prophylaxis in preventing early-onset group B streptococcal infection: results of a meta-analysis.

OBJECTIVE: To determine the effectiveness of intrapartum penicillin prophylaxis in preventing early-onset group B streptococcal (GBS) infection in neonates of women whose birth canals are colonized by group B streptococci. DATA SOURCES: Articles published between 1966 and 1992 identified from MEDLINE, EMBASE, the Science Citation Index and the Oxford Perinatal Database; the bibliographies of primary studies, textbooks and review articles and published abstracts from major conferences and symposia. DATA SELECTION: Studies were selected if four criteria were met: (a) the target population was intrapartum women and neonates, (b) the intervention was penicillin prophylaxis, (c) invasive early-onset GBS infection was an outcome measure, and (d) the studies were controlled trials or cohort studies. Seven primary studies were identified, four of which were randomized controlled trials. DATA EXTRACTION: Explicit methodologic criteria were used by two of the authors to assess independently the study quality; one of the reviewers was blind as to author, institution and journal. The baseline characteristics of the population, intervention and outcome were summarized twice and checked for accuracy by two of the authors. DATA SYNTHESIS: Five of the studies showed a trend toward a beneficial effect of penicillin prophylaxis, and two showed a statistically significant effect. The pooled odds ratio indicated a 30-fold reduction (95% confidence interval 0.0013 to 0.17) in the incidence of early-onset GBS infection with intrapartum penicillin prophylaxis. Subgroup analyses did not change these results. The magnitude of improvement observed did not differ between women with prenatal risk factors (premature rupture of the membranes and premature labour) and those without these risk factors. CONCLUSIONS: There is accumulative evidence that intrapartum penicillin prophylaxis is effective in preventing early-onset GBS infection. Such therapy is beneficial to women whose birth canals are colonized with group B streptococci. Further studies are needed to determine the optimum timing and method of detecting vaginal colonization during pregnancy.

Pneumocystis prophylaxis for all, some, or no HIV-infected infants less than one year of age: A decision analysis approach.

Pneumocystis carinii pneumonia (PCP) is associated with significant mortality and morbidity among infants infected with human immunodeficiency virus (HIV). The preferred prophylaxis strategy for such infants is a subject of debate. Medical decision analysis was used to determine the preferred strategy for primary PCP prophylaxis among asymptomatic HIV-infected infants less than one year of age, and to determine the thresholds at which different variables influence decision making. Utility measures (health state preference values) were used to determine whether prophylaxis should be given to all, some or no infants. In this regard, some infants would receive prophylaxis if baseline CD4 counts are fewer than 1500 cells/mm(3). The results suggest that the preferred option is to give prophylaxis to all asymptomatic HIV-infected infants despite CD4 counts, if the risk of PCP is equal to or greater than 25%. However, if the risk of PCP is less than 25%, prophylaxis is recommended for those infants with CD4 counts of fewer than 1500 cells/mm(3). The results complement current guidelines regarding PCP prophylaxis for HIV-infected infants.