ISOM 2023 Research Panel 5: Interventions- Vaccines and prevention, medical and surgical treatment, and impact of COVID-19 pandemic.

OBJECTIVES: To identify and synthesize key research advances from the literature published between 2019 and 2023 on the advances in preventative measures, and medical and surgical treatment of uncomplicated otitis media (OM) including the impact of the COVID-19 pandemic on OM management. DATA SOURCES: Medline (PubMed), Embase, and the Cochrane Library. REVIEW METHODS: All relevant original articles published in English between June 2019 and February 2023 were identified. Studies related to guideline adherence, impact of treatment on immune response and/or microbiology, tympanoplasty, Eustachian tube balloon dilatation, mastoidectomy procedures, and those focusing on children with Down's syndrome or cleft palate were excluded. MAIN FINDINGS: Of the 9280 unique records screened, 64 were eligible for inclusion; 23 studies related to medical treatment, 20 to vaccines, 13 to surgical treatment, 6 to prevention (excl. vaccines) and 2 to the impact of COVID-19 on OM management. The level of evidence was judged 2 in 11 studies (17.2 %) and 3 or 4 in the remaining 53 studies (82.8 %) mainly due to the observational design, study limitations or low sample sizes. Some important advances in OM management have been made in recent years. Video discharge instructions detailing the identification and management of pain and fever for parents of children with acute otitis media (AOM) was more effective than paper instructions in reducing symptomatology; compared to placebo, levofloxacin solution was more effective for treating chronic suppurative otitis media, whereas AOM recurrences during two years of follow-up did not differ between children with recurrent AOM who received tympanostomy tube (TT) insertion or medical management. Further, novel pneumococcal conjugate vaccines (PCV) schedules for preventing OM in Aboriginal children appeared ineffective, and a protein-based pneumococcal vaccine had no added value over PCV13 for preventing AOM in native American infants. During the COVID-19 pandemic, a decline in OM and TT case volumes and complications was observed. IMPLICATION FOR PRACTICE AND FUTURE RESEARCH: Whether the observed impact of the COVID-19 pandemic on OM management extends to the post-pandemic era is uncertain. Furthermore, the impact of the pandemic on the conduct of urgently needed prospective methodologically rigorous interventional studies aimed at improving OM prevention and treatment remains to be elucidated since the current report consisted of studies predominantly conducted in the pre-pandemic era.

Genomic epidemiology and antibiotic susceptibility profiling of uropathogenic Escherichia coli among children in the United States.

Escherichia coli is the most common cause of urinary tract infections (UTIs) in children, and yet the underlying mechanisms of virulence and antibiotic resistance and the overall population structure of the species is poorly understood within this age group. To investigate whether uropathogenic E. coli (UPEC) from children who developed pyelonephritis carried specific genetic markers, we generated whole-genome sequence data for 96 isolates from children with UTIs. This included 57 isolates from children with either radiologically confirmed pyelonephritis or cystitis and 27 isolates belonging to the well-known multidrug-resistant sequence type ST131, selected to investigate their population structure and antibiotic resistance characteristics. We observed a UPEC population structure that is similar to those reported in adults. In comparison with prior investigations, we found that the full pap operon was more common among UPEC from pediatric cases of pyelonephritis. Further, in contrast with recent reports that the P-fimbriae adhesin-encoding papGII allele is substantially more prevalent in invasive UPEC from adults, we found papGII was common to both invasive and non-invasive UPEC from children. Among the set of ST131 isolates from children with UTIs, we found antibiotic resistance was correlated with known genetic markers of resistance, as in adults. Unexpectedly, we observed that fimH30, an allele of the fimbrial gene fimH often used as a proxy to type ST131 isolates into the most drug-resistant subclade C, was carried by some of the subclade A and subclade B isolates, suggesting that the fimH30 allele could confer a selective advantage for UPEC. IMPORTANCE Urinary tract infections (UTIs), which are most often caused by Escherichia coli, are not well studied in children. Here, we examine genetic characteristics that differentiate UTI-causing bacteria in children that either remain localized to the bladder or are involved in more serious kidney infections. We also examine patterns of antibiotic resistance among strains from children that are part of E. coli sequence type 131, a group of bacteria that commonly cause UTIs and are known to have high levels of drug resistance. This work provides new insight into the virulence and antibiotic resistance characteristics of the bacteria that cause UTIs in children.

Accuracy of NGAL as a Biomarker for Urinary Tract Infection in Young Febrile Children: An Individual Patient Data Meta-Analysis.

OBJECTIVE: To compare the accuracy of urine neutrophil gelatinase-associated lipocalin (NGAL) and leukocyte esterase (LE) for the diagnosis of urinary tract infection (UTI) in children. STUDY DESIGN: We performed a systematic review and individual patient data meta-analysis of studies that examined urine NGAL as a marker of UTI in children <18 years of age. We created a standardized definition of UTI and applied it to all included children. We compared sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) of NGAL with LE. RESULTS: We included individual patient data from 3 studies for a total of 845 children. Included children had a mean age of 0.9 years (SD, 0.6 years). Using a cutoff of 32.7 ng/mL, NGAL had a sensitivity of 90.3% (95% CI: 83.2%-95.0%) and specificity of 93.7% (95% CI: 91.7%-95.4%) for the diagnosis of UTI. LE, using a cutoff of ≧ trace had a sensitivity of 81.1% (95% CI: 72.5%-87.9%) and specificity of 97.0% (95% CI: 95.4%-98.1%). The AUC for NGAL was 0.95 (95% CI: 0.92-0.98). The AUC for LE was 0.90 (95% CI: 0.86-0.93). CONCLUSION: In young, febrile children, urinary NGAL is more sensitive for the diagnosis of UTI than LE but is slightly less specific.

Cost-Effectiveness of Management Strategies in Recurrent Acute Otitis Media.

OBJECTIVE: To evaluate the cost-effectiveness of tympanostomy tube placementvs nonsurgical medical management, with the option of tympanostomy tube placement in the event of treatment failure, in children with recurrent acute otitis media (AOM). STUDY DESIGN: A Markov decision model compared management strategies in children ages 6-35 months, using patient-level data from a recently completed, multicenter, randomized clinical trial of tympanostomy tube placement vs medical management. The model ran over a 2-year time horizon using a societal perspective. Probabilities, including risk of AOM symptoms, were derived from prospectively collected patient diaries. Costs and quality-of-life measures were derived from the literature. We performed one-way and probabilistic sensitivity analyses, and secondary analyses in predetermined low- and high-risk subgroups. The primary outcome was incremental cost per quality-adjusted life-year gained. RESULTS: Tympanostomy tubes cost $989 more per child than medical management. Children managed with tympanostomy tubes gained 0.69 more quality-adjusted life-days than children managed medically, corresponding to $520 855 per quality-adjusted life-year gained. Results were sensitive to the costs of oral antibiotics, missed work, special childcare, the societal cost of antibiotic resistance, and the quality of life associated with AOM. In probabilistic sensitivity analyses, medical management was favored in 66% of model iterations at a willingness-to-pay threshold of $100 000/quality-adjusted life-year. Medical management was preferred in secondary analyses of low- and high-risk subgroups. CONCLUSIONS: For young children with recurrent AOM, the additional cost associated with tympanostomy tube placement outweighs the small improvement in quality of life. Medical management for these children is an economically reasonable strategy. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02567825.

Second primary malignancies in patients with haematological cancers treated with lenalidomide: a systematic review and meta-analysis.

BACKGROUND: Lenalidomide has been standard therapy for multiple myeloma and other haematological malignancies for more than a decade. Previous meta-analyses identified an association between lenalidomide and second primary malignancies (SPM) in patients with multiple myeloma. However, newer randomised controlled trials using lenalidomide for other indications have not reported an increased incidence of SPM. The aim of this study was to investigate the risk of developing SPM with lenalidomide use in all disease settings. METHODS: We did a systematic review of randomised controlled trials that reported SPM in patients treated with lenalidomide. PubMed, Embase, CENTRAL, Europe PubMed Central, and ClinicalTrials.gov were searched from Jan 1, 2004, to March 18, 2022. Randomised controlled trials with at least one lenalidomide group and one non-lenalidomide group were selected, regardless of the disease setting. Studies with a median follow-up of less than 12 months were excluded. Summary data were extracted by two reviewers (KS and KL) independently and verified by a third reviewer (JF). We then conducted a meta-analysis to assess the risk ratio (RR) of SPM with lenalidomide use across various disease subtypes using a random-effects model. We chose random effects for the primary analysis because of anticipated heterogeneity between different diseases, but we used fixed effects for stratified meta-analysis of multiple myeloma studies. Risk of bias was assessed with the PROTECT tool. The study was registered with PROSPERO, CRD42021257508. FINDINGS: Our search yielded 9078 studies, and 38 trials that included 14 058 patients were eligible for meta-analysis after screening, 18 of which were in multiple myeloma. The RR across all malignancies was 1·16 (95% CI 0·96-1·39). However, there was heterogeneity across indications (p=0·020). The RR when lenalidomide was used for multiple myeloma was 1·42 (1·09-1·84). There was no increase in SPM in lymphoma or chronic lymphocytic leukaemia (0·90 [0·76-1·08]) and myelodysplastic syndrome (0·96 [0·23-3·97]) trials. In the setting of multiple myeloma, lenalidomide increased both solid and haematological SPM, both in the no-transplantation and post-transplantation settings. From the 38 trials, 21 (55%) had low risk of bias, 12 (32%) had unclear risk of bias, and five (13%) had high risk of bias. INTERPRETATION: Based on the current data, lenalidomide-induced SPM seem to occur exclusively in patients with multiple myeloma. Thus, lenalidomide can be used for other indications without the major concern of a therapy-related neoplasm. In the multiple myeloma setting, lenalidomide is an effective drug, but patients should be monitored both for haematological and solid tumour SPM. This monitoring includes patients that have not received autologous haematopoietic stem-cell transplantation. Further investigations are needed to improve understanding on why lenalidomide only promotes SPM in patients with multiple myeloma. FUNDING: None.

Biomarkers for febrile urinary tract infection in children.

BACKGROUND: The sensitivity and specificity of the leukocyte esterase test for the diagnosis of urinary tract infection (UTI) are suboptimal. Recent studies have identified markers that appear to more accurately differentiate children with and without UTI. The objective of this study was to determine the accuracy of these markers, which included CCL3, IL-8, CXCL1, TNF-alpha, IL-6, IFN-gamma, IL-17, IL-9, IL-2, and NGAL, in the diagnosis of UTI. METHODS: This was a prospective cross-sectional study to compare inflammatory proteins between urine samples from febrile children with a UTI, matched febrile controls without a UTI, and asymptomatic healthy controls. RESULTS: We included 192 children (75 with febrile UTI, 69 febrile controls, and 48 asymptomatic healthy controls). Urinary proteins that best discriminated between febrile children with and without UTI were NGAL, a protein that exerts a local bacteriostatic role in the urinary tract through iron chelation; CCL3, a chemokine involved in leukocyte recruitment; and IL-8, a cytokine involved in neutrophil recruitment. Levels of these proteins were generally undetectable in asymptomatic healthy children. CONCLUSIONS: NGAL, CCL3, and IL-8 may be useful in the early diagnosis of UTI. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01391793) A higher resolution version of the Graphical abstract is available as Supplementary information.

Constipation on abdominal radiograph as potential risk factor for recurrent urinary tract infection development.

BACKGROUND: To compare clinical history and measurements of fecal load on abdominal radiography (AR) in the prediction of urinary tract infection (UTI) recurrence in children. METHODS: We combined data from two multicenter longitudinal studies in which children less than 6 years of age with a first or second UTI were followed for recurrence of UTI. Two radiologists reviewed the scout abdominal radiographs of initial voiding cystourethrograms obtained at enrollment from children at two participating sites and measured stool visible in various parts of the colon. We examined how well clinical variables (e.g., voiding and bowel history, use of laxatives at enrollment) and measurements of fecal load predicted recurrence of UTI within 12 months of enrollment. RESULTS: One hundred and ninety-two children were included. On univariate analyses, age, vesicoureteral reflux (VUR), cecal diameter, rectal diameter, and total stool length on AR were associated with recurrence of UTI. After controlling for age, the odds of recurrent UTI in children with VUR at baseline was 3.85 (95% CI: 1.62, 9.14) higher than in children without VUR. Recurrent UTI was 2.57 (95% CI: 1.01, 6.55) times more likely in children with cecal diameter > 3.10 cm than children with lower cecal diameters; time to first recurrent UTI was shorter in children with elevated cecal diameters (p = 0.0023). CONCLUSIONS: Cecal diameter on abdominal radiographs predicts UTI recurrence in children with a previous UTI. However, its accuracy is suboptimal to serve as a screening test. Accordingly, its routine use for this indication is not supported. If cecal diameter on an AR ordered for another indication is > 3.10 cm, then management of constipation could be considered.

Neutrophil gelatinase-associated lipocalin for urinary tract infection and pyelonephritis: a systematic review.

BACKGROUND: The sensitivity and specificity of the leukocyte esterase test are relatively low for a screening test for urinary tract infection (UTI). More accurate tests could reduce both overtreatment and missed cases. This study aimed to determine whether neutrophil gelatinase-associated lipocalin (NGAL) can replace leukocyte esterase in the diagnosis of UTI and/or whether NGAL accurately identifies children with acute pyelonephritis. METHODS: Data sources-MEDLINE and EMBASE. We only considered published studies that evaluated the results of an index test (NGAL) against the results of urine culture (for UTI) or against the results of dimercaptosuccinic acid (for acute pyelonephritis) in children aged 0 to 18 years. Two authors independently applied the selection criteria to all citations and independently extracted the data. RESULTS: A total of 12 studies met our inclusion criteria. Four studies (920 children) included data on NGAL for UTI; eight studies (580 children) included data on NGAL for pyelonephritis. We did not pool accuracy values because the included studies used different cutoff values. For the diagnosis of UTI, urinary NGAL appeared to have better accuracy than the leukocyte esterase test in all included studies. For the diagnosis of pyelonephritis, neither plasma NGAL nor urinary NGAL had high sensitivity and/or specificity. The number of studies was the main limitation of this systematic review. CONCLUSIONS: Urinary NGAL appears promising for the diagnosis of UTI; however, larger studies are needed to validate this marker as a replacement for leukocyte esterase. The use of NGAL for diagnosing acute pyelonephritis requires further study.

Contemporary Management of Urinary Tract Infection in Children.

Urinary tract infection (UTI) is common in children, and girls are at a significantly higher risk, as compared to boys, except in early infancy. Most cases are caused by Escherichia coli Collection of an uncontaminated urine specimen is essential for accurate diagnosis. Oral antibiotic therapy for 7 to 10 days is adequate for uncomplicated cases that respond well to the treatment. A renal ultrasound examination is advised in all young children with first febrile UTI and in older children with recurrent UTI. Most children with first febrile UTI do not need a voiding cystourethrogram; it may be considered after the first UTI in children with abnormal renal and bladder ultrasound examination or a UTI caused by atypical pathogen, complex clinical course, or known renal scarring. Long-term antibiotic prophylaxis is used selectively in high-risk patients. Few patients diagnosed with vesicoureteral reflux after a UTI need surgical correction. The most consequential long-term complication of acute pyelonephritis is renal scarring, which may increase the risk of hypertension or chronic kidney disease later in life. Treatment of acute pyelonephritis with an appropriate antibiotic within 48 hours of fever onset and prevention of recurrent UTI lowers the risk of renal scarring. Pathogens causing UTI are increasingly becoming resistant to commonly used antibiotics, and their indiscriminate use in doubtful cases of UTI must be discouraged.

Procalcitonin, C-reactive protein, and erythrocyte sedimentation rate for the diagnosis of acute pyelonephritis in children.

BACKGROUND: In children with urinary tract infection (UTI), only those with pyelonephritis (and not cystitis) are at risk for developing long-term renal sequelae. If non-invasive biomarkers could accurately differentiate children with cystitis from children with pyelonephritis, treatment and follow-up could potentially be individualized. This is an update of a review first published in 2015. OBJECTIVES: The objectives of this review were to 1) determine whether procalcitonin (PCT), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) can replace the acute DMSA scan in the diagnostic evaluation of children with UTI; 2) assess the influence of patient and study characteristics on the diagnostic accuracy of these tests, and 3) compare the performance of the three tests to each other. SEARCH METHODS: We searched MEDLINE, EMBASE, DARE, Web of Science, and BIOSIS Previews through to 17th December 2019 for this review. The reference lists of all included articles and relevant systematic reviews were searched to identify additional studies not found through the electronic search. SELECTION CRITERIA: We only considered published studies that evaluated the results of an index test (PCT, CRP, ESR) against the results of an acute-phase 99Tc-dimercaptosuccinic acid (DMSA) scan (conducted within 30 days of the UTI) in children aged 0 to 18 years with a culture-confirmed episode of UTI. The following cut-off values were used for the primary analysis: 0.5 ng/mL for procalcitonin, 20 mg/L for CRP and 30 mm/hour for ESR. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria to all citations and independently abstracted data. We used the bivariate model to calculate pooled random-effects pooled sensitivity and specificity values. MAIN RESULTS: A total of 36 studies met our inclusion criteria. Twenty-five studies provided data for the primary analysis: 12 studies (1000 children) included data on PCT, 16 studies (1895 children) included data on CRP, and eight studies (1910 children) included data on ESR (some studies had data on more than one test). The summary sensitivity estimates (95% CI) for the PCT, CRP, ESR tests at the aforementioned cut-offs were 0.81 (0.67 to 0.90), 0.93 (0.86 to 0.96), and 0.83 (0.71 to 0.91), respectively. The summary specificity values for PCT, CRP, and ESR tests at these cut-offs were 0.76 (0.66 to 0.84), 0.37 (0.24 to 0.53), and 0.57 (0.41 to 0.72), respectively. AUTHORS' CONCLUSIONS: The ESR test does not appear to be sufficiently accurate to be helpful in differentiating children with cystitis from children with pyelonephritis. A low CRP value (< 20 mg/L) appears to be somewhat useful in ruling out pyelonephritis (decreasing the probability of pyelonephritis to < 20%), but unexplained heterogeneity in the data prevents us from making recommendations at this time. The procalcitonin test seems better suited for ruling in pyelonephritis, but the limited number of studies and the marked heterogeneity between studies prevents us from reaching definitive conclusions. Thus, at present, we do not find any compelling evidence to recommend the routine use of any of these tests in clinical practice.

Urinary tract infections in children.

Urinary tract infections (UTIs) in children are among the most common bacterial infections in childhood. They are equally common in boys and girls during the first year of life and become more common in girls after the first year of life. Dividing UTIs into three categories; febrile upper UTI (acute pyelonephritis), lower UTI (cystitis), and asymptomatic bacteriuria, is useful for numerous reasons, mainly because it helps to understand the pathophysiology of the infection. A single episode of febrile UTI is often caused by a virulent Escherichia coli strain, whereas recurrent infections and asymptomatic bacteriuria commonly result from urinary tract malformations or bladder disturbances. Treatment of an upper UTI needs to be broad and last for 10 days, a lower UTI only needs to be treated for 3 days, often with a narrow-spectrum antibiotic, and asymptomatic bacteriuria is best left untreated. Investigations of atypical and recurrent episodes of febrile UTI should focus on urinary tract abnormalities, whereas in cases of cystitis and asymptomatic bacteriuria the focus should be on bladder function.

Host and Bacterial Markers that Differ in Children with Cystitis and Pyelonephritis.

OBJECTIVE: To determine whether treatment for urinary tract infections in children could be individualized using biomarkers for acute pyelonephritis. STUDY DESIGN: We enrolled 61 children with febrile urinary tract infections, collected blood and urine samples, and performed a renal scan within 2 weeks of diagnosis to identify those with pyelonephritis. Renal scans were interpreted centrally by 2 experts. We measured inflammatory proteins in blood and urine using LUMINEX or an enzyme-linked immunosorbent assay. We evaluated serum RNA expression using RNA sequencing in a subset of children. Finally, for children with Escherichia coli isolated from urine cultures, we performed a polymerase chain reaction for 4 previously identified virulence genes. RESULTS: Urinary markers that best differentiated pyelonephritis from cystitis included chemokine (C-X-C motif) ligand (CXCL)1, CXCL9, CXCL12, C-C motif chemokine ligand 2, INF γ, and IL-15. Serum procalcitonin was the best serum marker for pyelonephritis. Genes in the interferon-γ pathway were upregulated in serum of children with pyelonephritis. The presence of E coli virulence genes did not correlate with pyelonephritis. CONCLUSIONS: Immune response to pyelonephritis and cystitis differs quantitatively and qualitatively; this may be useful in differentiating these 2 conditions.

Successful Management of Chylothorax With Etilefrine: Case Report in 2 Pediatric Patients.

Chylothorax is defined as the accumulation of chyle within the pleural space. Originally described in 1917 by Pisek, it is the most common cause of pleural effusion in the neonatal period. The leading cause of chylothorax is laceration of the thoracic duct during surgery, which occurs in 0.85% to 6.6% of children undergoing cardiothoracic surgery. Few authors of reports in the literature have looked at etilefrine, a relatively unknown sympathomimetic, as an option for the medical treatment of chylothorax. In this case report, we review the clinical course of 2 infants with type III esophageal atresia who developed chylothorax after thoracic surgery and were successfully treated with intravenous etilefrine after failing initial dietary and pharmacological management.

Dimercaptosuccinic acid scan or ultrasound in screening for vesicoureteral reflux among children with urinary tract infections.

BACKGROUND: There is considerable interest in detecting vesicoureteral reflux (VUR) because its presence, especially when severe, has been linked to an increased risk of urinary tract infections and renal scarring. Voiding cystourethrography (VCUG), also known as micturating cystourethrography, is the gold standard for the diagnosis of VUR, and the grading of its severity. Because VCUG requires bladder catheterisation and exposes children to radiation, there has been a growing interest in other screening strategies that could identify at-risk children without the risks and discomfort associated with VCUG. OBJECTIVES: The objective of this review is to evaluate the accuracy of two alternative imaging tests - the dimercaptosuccinic acid renal scan (DMSA) and renal-bladder ultrasound (RBUS) - in diagnosing VUR and high-grade VUR (Grade III-V VUR). SEARCH METHODS: We searched MEDLINE, EMBASE, BIOSIS, and the Cochrane Register of Diagnostic Test Accuracy Studies from 1985 to 31 March 2016. The reference lists of relevant review articles were searched to identify additional studies not found through the electronic search. SELECTION CRITERIA: We considered published cross-sectional or cohort studies that compared the results of the index tests (DMSA scan or RBUS) with the results of radiographic VCUG in children less than 19 years of age with a culture-confirmed urinary tract infection. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria to all citations and independently abstracted data. We used the bivariate model to calculate summary sensitivity and specificity values. MAIN RESULTS: A total of 42 studies met our inclusion criteria. Twenty studies reported data on the test performance of RBUS in detecting VUR; the summary sensitivity and specificity estimates were 0.44 (95% CI 0.34 to 0.54) and 0.78 (95% CI 0.68 to 0.86), respectively. A total of 11 studies reported data on the test performance of RBUS in detecting high-grade VUR; the summary sensitivity and specificity estimates were 0.59 (95% CI 0.45 to 0.72) and 0.79 (95% CI 0.65 to 0.87), respectively. A total of 19 studies reported data on the test performance of DMSA in detecting VUR; the summary sensitivity and specificity estimates were 0.75 (95% CI 0.67 to 0.81) and 0.48 (95% CI 0.38 to 0.57), respectively. A total of 10 studies reported data on the accuracy of DMSA in detecting high-grade VUR. The summary sensitivity and specificity estimates were 0.93 (95% CI 0.77 to 0.98) and 0.44 (95% CI 0.33 to 0.56), respectively. AUTHORS' CONCLUSIONS: Neither the renal ultrasound nor the DMSA scan is accurate enough to detect VUR (of all grades). Although a child with a negative DMSA test has an < 1% probability of having high-grade VUR, performing a screening DMSA will result in a large number of children falsely labelled as being at risk for high-grade VUR. Accordingly, the usefulness of the DMSA as a screening test for high-grade VUR should be questioned.

Utility of sedation for young children undergoing dimercaptosuccinic acid renal scans.

BACKGROUND: No studies have examined whether use of sedation during a Tc-99 m dimercaptosuccinic acid (DMSA) renal scan reduces patient discomfort. OBJECTIVE: To compare discomfort level during a DMSA scan to the discomfort level during other frequently performed uroradiologic tests, and to determine whether use of sedation during a DMSA scan modifies the level of discomfort. MATERIALS AND METHODS: We examined the discomfort level in 798 children enrolled in the Randomized Intervention for children with Vesicoureteral Reflux (RIVUR) and Careful Urinary Tract Infection Evaluation (CUTIE) studies by asking parents to rate their child's discomfort level with each procedure on a scale from 0 to 10. We compared discomfort during the DMSA scan and the DMSA image quality between centers in which sedation was used >90% of the time (sedation centers), centers in which sedation was used <10% of the time (non-sedation centers), and centers in which sedation was used on a case-by-case basis (selective centers). RESULTS: Mean discomfort level was highest for voiding cystourethrogram (6.4), followed by DMSA (4.0), followed by ultrasound (2.4; P<0.0001). Mean discomfort level during the DMSA scan was significantly higher at non-sedation centers than at selective centers (P<0.001). No difference was apparent in discomfort level during the DMSA scan between sedation centers and selective centers (P=0.12), or between the sedation centers and non-sedation centers (P=0.80). There were no differences in the proportion with uninterpretable DMSA scans according to sedation use. CONCLUSION: Selective use of sedation in children 12-36 months of age can reduce the discomfort level experienced during a DMSA scan.

Procalcitonin, C-reactive protein, and erythrocyte sedimentation rate for the diagnosis of acute pyelonephritis in children.

BACKGROUND: In children with urinary tract infection (UTI), only those with pyelonephritis (and not cystitis) are at risk for developing long-term renal sequelae. If non-invasive biomarkers could accurately differentiate children with cystitis from children with pyelonephritis, treatment and follow-up could potentially be individualized. OBJECTIVES: The objectives of this review were to 1) determine whether procalcitonin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) can replace the acute DMSA scan in the diagnostic evaluation of children with UTI; 2) assess the influence of patient and study characteristics on the diagnostic accuracy of these tests, and 3) compare the performance of the three tests to each other. SEARCH METHODS: We searched MEDLINE, EMBASE, DARE, Web of Science, and BIOSIS Previews for this review. The reference lists of all included articles and relevant systematic reviews were searched to identify additional studies not found through the electronic search. SELECTION CRITERIA: We only considered published studies that evaluated the results of an index test (procalcitonin, CRP, ESR) against the results of an acute-phase DMSA scan (conducted within 30 days of the UTI) in children aged 0 to 18 years with a culture-confirmed episode of UTI. The following cutoff values were used for the primary analysis: 0.5 ng/mL for procalcitonin, 20 mg/L for CRP and 30 mm/h for ESR. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria to all citations and independently abstracted data. We used the bivariate model to calculate pooled random-effects pooled sensitivity and specificity values. MAIN RESULTS: A total of 24 studies met our inclusion criteria. Seventeen studies provided data for the primary analysis: six studies (434 children) included data on procalcitonin, 13 studies (1638 children) included data on CRP, and six studies (1737 children) included data on ESR (some studies had data on more than one test). The summary sensitivity estimates (95% CI) for the procalcitonin, CRP, ESR tests at the aforementioned cutoffs were 0.86 (0.72 to 0.93), 0.94 (0.85 to 0.97), and 0.87 (0.77 to 0.93), respectively. The summary specificity values for procalcitonin, CRP, and ESR tests at these cutoffs were 0.74 (0.55 to 0.87), 0.39 (0.23 to 0.58), and 0.48 (0.33 to 0.64), respectively. AUTHORS' CONCLUSIONS: The ESR test does not appear to be sufficiently accurate to be helpful in differentiating children with cystitis from children with pyelonephritis. A low CRP value (< 20 mg/L) appears to be somewhat useful in ruling out pyelonephritis (decreasing the probability of pyelonephritis to < 20%), but unexplained heterogeneity in the data prevents us from making recommendations at this time. The procalcitonin test seems better suited for ruling in pyelonephritis, but the limited number of studies and the marked heterogeneity between studies prevents us from reaching definitive conclusions. Thus, at present, we do not find any compelling evidence to recommend the routine use of any of these tests in clinical practice.

Low-dose transdermal estradiol for vasomotor symptoms: a systematic review.

OBJECTIVE: This review aims to determine the effectiveness of low-dose transdermal estrogen versus placebo in postmenopausal women with moderate to severe hot flashes. METHODS: We conducted a systematic review of studies by searching Medline and EMBASE using the following inclusion criteria: double-blind, placebo-controlled, randomized controlled trials conducted in postmenopausal women with at least 7 hot flashes per day and/or at least 50 hot flashes per week. All included studies used estrogen formulations below the equivalent dose of 0.05 mg of 17ß-estradiol. RESULTS: Nine studies met all inclusion criteria. Seven of nine studies had low risk of bias, whereas two studies had high risk of bias. Low-dose transdermal estrogen in all dose ranges was more likely than placebo to decrease the daily number of hot flashes. Meta-analysis was not performed as only three of the nine studies included measures of variance; weighted means were used to summarize the data. Results were divided into three groups by decreasing estrogen dose range (0.037-0.045, 0.020-0.029, and 0.003-0.125 mg). The mean daily decrease in the number of hot flashes from baseline was 9.36, 7.91, and 7.07, respectively. The mean daily decrease in the placebo groups was 5.07. Eight of the nine studies reported P values comparing each estrogen dose to placebo; all were significant at P < 0.05. CONCLUSIONS: Although publication bias cannot be excluded, risk of bias and heterogeneity among studies are low. There is strong evidence to conclude that low-dose transdermal estrogen at any dose is more effective than placebo in decreasing the daily number of moderate to severe hot flashes.

Identification of children and adolescents at risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data.

IMPORTANCE: No studies have systematically examined the accuracy of clinical, laboratory, and imaging variables in detecting renal scarring in children and adolescents with a first urinary tract infection. OBJECTIVES: To identify independent prognostic factors for the development of renal scarring and to combine these factors in prediction models that could be useful in clinical practice. DATA SOURCES: MEDLINE and EMBASE. STUDY SELECTION: We included patients aged 0 to 18 years with a first urinary tract infection who underwent follow-up renal scanning with technetium Tc 99m succimer at least 5 months later. DATA EXTRACTION AND SYNTHESIS: We pooled individual patient data from 9 cohort studies. MAIN OUTCOMES AND MEASURES: We examined the association between predictor variables assessed at the time of the first urinary tract infection and the development of renal scarring. Renal scarring was defined by the presence of photopenia on the renal scan. We assessed the following 3 models: clinical (demographic information, fever, and etiologic organism) and ultrasonographic findings (model 1); model 1 plus serum levels of inflammatory markers (model 2); and model 2 plus voiding cystourethrogram findings (model 3). RESULTS: Of the 1280 included participants, 199 (15.5%) had renal scarring. A temperature of at least 39°C, an etiologic organism other than Escherichia coli, an abnormal ultrasonographic finding, polymorphonuclear cell count of greater than 60%, C-reactive protein level of greater than 40 mg/L, and presence of vesicoureteral reflux were all associated with the development of renal scars (P ≤ .01 for all). Although the presence of grade IV or V vesicoureteral reflux was the strongest predictor of renal scarring, this degree of reflux was present in only 4.1% of patients. The overall predictive ability of model 1 with 3 variables (temperature, ultrasonographic findings, and etiologic organism) was only 3% to 5% less than the predictive ability of models requiring a blood draw and/or a voiding cystourethrogram. Patients with a model 1 score of 2 or more (21.7% of the sample) represent a particularly high-risk group in whom the risk for renal scarring was 30.7%. At this cutoff, model 1 identified 44.9% of patients with eventual renal scarring. CONCLUSIONS AND RELEVANCE: Children and adolescents with an abnormal renal ultrasonographic finding or with a combination of high fever (≥39°C) and an etiologic organism other than E coli are at high risk for the development of renal scarring.

Pain management in young children undergoing diagnostic tympanocentesis.

OBJECTIVE: To describe the pain associated with diagnostic tympanocentesis and to gather preliminary data comparing the efficacy of 3 methods of pain reduction for tympanocentesis. METHODS: In children 6 to 36 months of age undergoing tympanocentesis for acute otitis media, the authors measured pain and distress throughout all phases of the procedure and recovery using physiological (heart rate) and behavioral measures (cry duration, Global Mood Scale score, and pain visual analog scales). They compared--in a randomized controlled trial--3 pain reduction interventions: acetaminophen, acetaminophen plus codeine, and ibuprofen plus midazolam. RESULTS: Heart rate increased throughout the procedure, peaking during needle aspiration. Children treated with acetaminophen alone had higher peak heart rates and Global Mood Scale scores during parts of the procedure. CONCLUSIONS: Acetaminophen alone may not be as effective in reducing pain-related physiological and behavioral changes as acetaminophen plus codeine or ibuprofen plus midazolam during diagnostic tympanocentesis.

Rationale and design issues of the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study.

OBJECTIVE: Our goal is to determine if antimicrobial prophylaxis with trimethoprim/sulfamethoxazole prevents recurrent urinary tract infections and renal scarring in children who are found to have vesicoureteral reflux after a first or second urinary tract infection. DESIGN, PARTICIPANTS, AND METHODS: The Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study is a double-blind, randomized, placebo-controlled trial. Six hundred children aged 2 to 72 months will be recruited from both primary and subspecialty care settings at clinical trial centers throughout North America. Children who are found to have grades I to IV vesicoureteral reflux after the index febrile or symptomatic urinary tract infection will be randomly assigned to receive daily doses of either trimethoprim/sulfamethoxazole or placebo for 2 years. Scheduled follow-up contacts include in-person study visits every 6 months and telephone interviews every 2 months. Biospecimens (urine and blood) and genetic specimens (blood) will be collected for future studies of the genetic and biochemical determinants of vesicoureteral reflux, recurrent urinary tract infection, renal insufficiency, and renal scarring. RESULTS: The primary outcome is recurrence of urinary tract infection. Secondary outcomes include time to recurrent urinary tract infection, renal scarring (assessed by dimercaptosuccinic acid scan), treatment failure, renal function, resource utilization, and development of antimicrobial resistance in stool flora. CONCLUSIONS: The RIVUR study will provide useful information to clinicians about the risks and benefits of prophylactic antibiotics for children who are diagnosed with vesicoureteral reflux after a first or second urinary tract infection. The data and specimens collected over the course of the study will allow researchers to better understand the pathophysiology of recurrent urinary tract infection and its sequelae.