Association Between Nasopharyngeal Colonization and Clinical Outcome in Children With Acute Otitis Media.

BACKGROUND: Young children with acute otitis media (AOM) frequently exhibit nasopharyngeal colonization with either Streptococcus pneumoniae, Haemophilus influenzae or both pathogens. We aimed to determine if antibiotics could be spared or shortened in those without nasopharyngeal colonization with either pathogen. METHODS: In 2 separate randomized clinical trials in children aged 6-23 months with stringently-diagnosed AOM, we performed bacterial cultures on nasopharyngeal specimens collected at the time of diagnosis. In the first trial, we compared the efficacy of amoxicillin/clavulanate (amox/clav) administered for 10 days vs. that of placebo, and in the second trial, we compared the efficacy of amox/clav administered for 10 days vs. 5 days. In each trial, we classified children as being colonized with both S. pneumoniae and H. influenzae, S. pneumoniae alone, H. influenzae alone, or neither pathogen, and as experiencing either clinical success or clinical failure at the end-of-therapy visit, based on previously reported a priori criteria. RESULTS: We evaluated 796 children. Among children randomized to amox/clav, those colonized with either S. pneumoniae or H. influenzae or both were approximately twice as likely to experience clinical failure as children not colonized with either pathogen (odds ratio: 1.8; confidence intervals: 1.2-2.9). In contrast, among children randomized to placebo, clinical failure at the end-of-therapy visit was not associated with nasopharyngeal culture results at the time of diagnosis. CONCLUSIONS: Children colonized with either S. pneumoniae or H. influenzae or both have a greater chance of treatment failure than children colonized with neither pathogen.

Randomized Trial of Tocilizumab in the Treatment of Refractory Adult Polymyositis and Dermatomyositis.

OBJECTIVE: To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double-blind, placebo-controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM). METHODS: Thirty-six subjects with probable or definite DM/PM were enrolled in a 6-month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis-associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)-8 score of less than 136/150. If the MMT-8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid-sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes. RESULTS: There was no significant difference (P = 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid-sparing effect were also not significantly different between arms. CONCLUSION: Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24-week phase 2B study.

Corticosteroids to prevent kidney scarring in children with a febrile urinary tract infection: a randomized trial.

BACKGROUND: To evaluate the efficacy of adjuvant systemic corticosteroids in reducing kidney scarring. A previous study suggested that use of adjuvant systemic corticosteroids reduces kidney scarring in children radiologically confirmed to have extensive pyelonephritis. Efficacy of corticosteroids for children with febrile urinary tract infection (UTI) has not been studied. METHODS: Children aged 2 months to 6 years with their first febrile UTI were randomized to corticosteroids or placebo for 3 days (both arms received antimicrobial therapy); kidney scarring was assessed using 99mTc-dimercaptosuccinic acid kidney scan 5-24 months after the initial UTI. RESULTS: We randomized 546 children of which 385 had a UTI and 254 had outcome kidney scans (instead of the 320 planned). Rates of kidney scarring were 9.8% (12/123) and 16.8% (22/131) in the corticosteroid and placebo groups, respectively (p = 0.16), corresponding to an absolute risk reduction of 5.9% (95% confidence interval: - 2.2, 14.1). CONCLUSION: While children randomized to adjuvant corticosteroids tended to develop fewer kidney scars than children who were randomized to receive placebo, a statistically significant difference was not achieved. However, the study was limited by not reaching its intended sample size. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov , NCT01391793, Registered 7/12/2011 Graphical abstract.

Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media.

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (P = 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (P = 0.04) and of AOM treatment failure were 12% and 16% (P = 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit ß-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.).

Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children.

BACKGROUND: Limiting the duration of antimicrobial treatment constitutes a potential strategy to reduce the risk of antimicrobial resistance among children with acute otitis media. METHODS: We assigned 520 children, 6 to 23 months of age, with acute otitis media to receive amoxicillin-clavulanate either for a standard duration of 10 days or for a reduced duration of 5 days followed by placebo for 5 days. We measured rates of clinical response (in a systematic fashion, on the basis of signs and symptomatic response), recurrence, and nasopharyngeal colonization, and we analyzed episode outcomes using a noninferiority approach. Symptom scores ranged from 0 to 14, with higher numbers indicating more severe symptoms. RESULTS: Children who were treated with amoxicillin-clavulanate for 5 days were more likely than those who were treated for 10 days to have clinical failure (77 of 229 children [34%] vs. 39 of 238 [16%]; difference, 17 percentage points [based on unrounded data]; 95% confidence interval, 9 to 25). The mean symptom scores over the period from day 6 to day 14 were 1.61 in the 5-day group and 1.34 in the 10-day group (P=0.07); the mean scores at the day-12-to-14 assessment were 1.89 versus 1.20 (P=0.001). The percentage of children whose symptom scores decreased more than 50% (indicating less severe symptoms) from baseline to the end of treatment was lower in the 5-day group than in the 10-day group (181 of 227 children [80%] vs. 211 of 233 [91%], P=0.003). We found no significant between-group differences in rates of recurrence, adverse events, or nasopharyngeal colonization with penicillin-nonsusceptible pathogens. Clinical-failure rates were greater among children who had been exposed to three or more children for 10 or more hours per week than among those with less exposure (P=0.02) and were also greater among children with infection in both ears than among those with infection in one ear (P<0.001). CONCLUSIONS: Among children 6 to 23 months of age with acute otitis media, reduced-duration antimicrobial treatment resulted in less favorable outcomes than standard-duration treatment; in addition, neither the rate of adverse events nor the rate of emergence of antimicrobial resistance was lower with the shorter regimen. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Research Resources; ClinicalTrials.gov number, NCT01511107 .).

Toward an Improved Scale for Assessing Symptom Severity in Children With Acute Otitis Media.

The objective of the present study was to determine whether changes in the previously developed 7-item Acute Otitis Media Severity of Symptoms scale could improve its responsiveness and its longitudinal construct validity. The items "diminished activity" and "diminished appetite" had low or borderline levels of responsiveness and longitudinal construct validity. Dropping these items seems to be potentially advantageous.

Determination of the minimal important difference for the acute otitis media severity of symptom scale.

BACKGROUND: We previously developed and validated the acute otitis media severity of symptom (AOM-SOS) scale for rating symptoms of AOM in young children. In this report, we sought to estimate the minimal important difference (MID) for change in AOM-SOS scores. METHODS: In a group of children 6-24 months of age with AOM enrolled in a recently reported placebo-controlled clinical trial of antibiotic efficacy, we compared changes in AOM-SOS scores with parental assessments of change over a 24-hour period. Mean absolute and mean relative change in scores in children reportedly exhibiting only a small degree of improvement were considered in arriving at an estimated MID. We then compared the proportions of children in the antibiotic and placebo groups, respectively, whose AOM-SOS scores changed more than the estimated MID at various time points after enrollment. RESULTS: Data were available for 277 children. Children whose parents reported only a small degree of improvement 24 hours after enrollment had a mean decrease in AOM-SOS score of 3.8, or 55%, from baseline. We found the relative decrease more telling than the absolute decrease. The proportions of children in the antibiotic and placebo groups, respectively, whose AOM-SOS scores had decreased <55% on Day 7 were 12.3 and 23.8% (P=0.02), and during Days 4-7 were 28 and 40% (P=0.046). CONCLUSIONS: We estimated the MID for change in AOM-SOS scores in young children and described use of the MID as an added metric in interpreting results from a clinical trial of antibiotic efficacy.

Subject-centered free-response ROC (FROC) analysis.

PURPOSE: To develop an approach of estimating subject-centered free-response receiver operating characteristic (FROC) curve for providing patient-centered inferences regarding detection-localization characteristics of a diagnostic system. METHODS: The authors examine properties of the conventional, target-centered, FROC curve and demonstrate that in scenarios where the diagnostic performance correlates with the total number of targets on a subject, it may lead to inadequate inferences from the perspective of possible benefits to a patient. Following solutions to patient-centered approaches in other applications, the authors define a subject-centered FROC curve and develop its formulation as a covariate-adjusted FROC curve. The authors also conduct a numerical study illustrating the relative properties of the conventional and subject-centered approach and provide an example. RESULTS: A simple-to-implement approach for estimating the subject-centered FROC curve and its overall index can be formulated as a type of stratified FROC analysis. The authors demonstrate that when diagnostic performance is associated with the number of targets, the diagnostic system with apparently superior target-centered characteristics (conventional approach) can be actually inferior from the subject-centered perspective. The authors show that under some clinically reasonable conditions the magnitude of disagreement in results could be substantial. An example from an actual observer performance study illustrates the natural setting where the developed approach would be relevant and lead to conclusions that are contradictory to those obtained from conventional analysis. CONCLUSIONS: The authors developed a subject-centered FROC curve and its overall index provides tools for inferences that may be relevant from a perspective of potential benefits to a patient.

On use of partial area under the ROC curve for evaluation of diagnostic performance.

Evaluation of diagnostic performance is a necessary component of new developments in many fields including medical diagnostics and decision making. The methodology for statistical analysis of diagnostic performance continues to develop, offering new analytical tools for conventional inferences and solutions for novel and increasingly more practically relevant questions. In this paper, we focus on the partial area under the Receiver Operating Characteristic (ROC) curve or pAUC. This summary index is considered to be more practically relevant than the area under the entire ROC curve (AUC), but because of several perceived limitations, it is not used as often. To improve interpretation, results for pAUC analysis are frequently reported using a rescaled index such as the standardized partial AUC proposed by McClish (1989). We derive two important properties of the relationship between the 'standardized' pAUC and the defined range of interest, which could facilitate a wider and more appropriate use of this important summary index. First, we mathematically prove that the 'standardized' pAUC increases with increasing range of interest for practically common ROC curves. Second, using comprehensive numerical investigations, we demonstrate that, contrary to common belief, the uncertainty about the estimated standardized pAUC can either decrease or increase with an increasing range of interest. Our results indicate that the partial AUC could frequently offer advantages in terms of statistical uncertainty of the estimation. In addition, selection of a wider range of interest will likely lead to an increased estimate even for standardized pAUC.

Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.

OBJECTIVE: To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients. METHODS: Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ≥20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8. RESULTS: Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial. CONCLUSION: Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design.

Identifying children with vesicoureteral reflux: a comparison of 2 approaches.

PURPOSE: Various screening approaches have been proposed to identify the subgroup of children with urinary tract infection who have vesicoureteral reflux. However, few studies have compared the sensitivity of screening approaches in a representative population of young children. We compared the sensitivities of the top-down ((99m)technetium dimercaptosuccinic acid renal scan to screen) and biomarker based (C-reactive protein level at presentation) approaches in identifying children with vesicoureteral reflux. MATERIALS AND METHODS: We calculated the sensitivity of the 2 screening approaches in detecting vesicoureteral reflux and subsequently high grade (III or greater) vesicoureteral reflux in children. RESULTS: The top-down and C-reactive protein based approaches missed 33% and 29% of cases of high grade vesicoureteral reflux, respectively. CONCLUSIONS: The sensitivity of the top-down approach for detecting high grade vesicoureteral reflux was lower than previously reported. Further study of novel methods to identify children at risk for renal scarring is warranted.

Development of an algorithm for the diagnosis of otitis media.

BACKGROUND: The relative importance of signs and symptoms in the diagnosis of otitis media has not been adequately evaluated. This has led to a large degree of variation in the criteria used to diagnose otitis media, which has resulted in inconsistencies in clinical care and discrepant research findings. METHODS: A group of experienced otoscopists examined children presenting for primary care. We investigated the signs and symptoms that these otoscopists used to distinguish acute otitis media (AOM), otitis media with effusion (OME), and no effusion. We used recursive partitioning to develop a diagnostic algorithm. To assess the algorithm, we validated it in an independent dataset. RESULTS: Bulging of the tympanic membrane (TM) was the main finding that otoscopists used to discriminate AOM from OME; information regarding the presence or absence of other signs and symptoms added little to the diagnostic process. Overall, 92% of children with AOM had a bulging TM compared with 0% of children with OME. Opacification and/or an air-fluid level was the main finding that the otoscopists used to discriminate OME from no effusion; 97% of children diagnosed with OME had an opaque TM compared with 5% of children diagnosed with no effusion. An algorithm that used bulging and opacification of the TM correctly classified 99% of ears in an independent dataset. CONCLUSIONS: Bulging of the TM was the finding that best discriminated AOM from OME. The algorithm developed here may prove to be useful in clinical care, research, and education concerning otitis media.

Otoscopic signs of otitis media.

BACKGROUND: Lack of agreed-upon diagnostic criteria for acute otitis media (AOM) has led to inconsistencies in clinical care, misleading research results, and misguided educational efforts. The objective of this study was to examine findings that expert otoscopists use when diagnosing AOM. METHODS: A group of experienced otoscopists examined 783 children presenting for primary care. In addition, endoscopic still images of the tympanic membranes (TMs) were obtained. A random sample of 135 of these images was sent for review to a group of 7 independent physicians who were expert otoscopists. We examined the findings that both groups of observers used to distinguish between AOM, otitis media with effusion (OME), and no effusion. RESULTS: Among both groups of observers, bulging of the TM was the finding judged best to differentiate AOM from OME: 96% of ears and 93% of ear image evaluations assigned a diagnosis of AOM by members of the 2 groups were reported as showing bulging of the TM, compared with 0% and 3%, respectively, of ears and ear image evaluations assigned a diagnosis of OME. Opacification of the TM was the finding that best differentiated OME from no effusion. CONCLUSIONS: We describe findings that are used by experienced otoscopists to diagnose AOM and OME. The findings point to the advisability under most circumstances of restricting antimicrobial treatment for AOM to children who have TM bulging, and they call into question clinical trials of the treatment of AOM in which TM bulging has not been a required element for participation.

Localized detection and classification of abnormalities on FFDM and tomosynthesis examinations rated under an FROC paradigm.

OBJECTIVE: The purpose of our study was to assess diagnostic performance when retrospectively interpreting full-field digital mammography (FFDM) and breast tomosynthesis examinations under a free-response receiver operating characteristic (FROC) paradigm. MATERIALS AND METHODS: We performed FROC analysis of a previously reported study in which eight experienced radiologists interpreted 125 examinations, including 35 with verified cancers. The FROC paradigm involves detecting, locating, and rating each suspected abnormality. Radiologists reviewed and rated both FFDM alone and a combined display mode of FFDM and digital breast tomosynthesis (DBT) (combined). Observer performance levels were assessed and compared with respect to the fraction of correctly identified abnormalities, the number of reported location-specific findings (both true and false), and their associated ratings. The analysis accounts for the number and locations of findings and the location-based ratings using a summary performance index (Λ), which is the FROC analog of the area between the receiver operating characteristic curve and the diagonal (chance) line. RESULTS: Under the FROC paradigm, each reader detected more true abnormalities associated with cancer, or a higher true-positive fraction, under the combined mode. In an analysis focused on both the number of findings and associated location-based ratings, each of the radiologists performed better under the combined mode compared with FFDM alone, with increases in Λ ranging from 5% to 34%. On average, under the combined mode radiologists achieved a 16% improvement in Λ compared with the FFDM alone mode (95% CI, 7-26%; p < 0.01). CONCLUSION: We showed that DBT-based breast imaging in combination with FFDM could result in better performance under the FROC paradigm.

Treatment of acute otitis media in children under 2 years of age.

BACKGROUND: Recommendations vary regarding immediate antimicrobial treatment versus watchful waiting for children younger than 2 years of age with acute otitis media. METHODS: We randomly assigned 291 children 6 to 23 months of age, with acute otitis media diagnosed with the use of stringent criteria, to receive amoxicillin-clavulanate or placebo for 10 days. We measured symptomatic response and rates of clinical failure. RESULTS: Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7; among children who received placebo, 28% had initial resolution of symptoms by day 2, 54% by day 4, and 74% by day 7 (P=0.14 for the overall comparison). For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, as compared with 14%, 36%, and 53% with placebo (P=0.04 for the overall comparison). Mean symptom scores over the first 7 days were lower for the children treated with amoxicillin-clavulanate than for those who received placebo (P=0.02). The rate of clinical failure--defined as the persistence of signs of acute infection on otoscopic examination--was also lower among the children treated with amoxicillin-clavulanate than among those who received placebo: 4% versus 23% at or before the visit on day 4 or 5 (P<0.001) and 16% versus 51% at or before the visit on day 10 to 12 (P<0.001). Mastoiditis developed in one child who received placebo. Diarrhea and diaper-area dermatitis were more common among children who received amoxicillin-clavulanate. There were no significant changes in either group in the rates of nasopharyngeal colonization with nonsusceptible Streptococcus pneumoniae. CONCLUSIONS: Among children 6 to 23 months of age with acute otitis media, treatment with amoxicillin-clavulanate for 10 days tended to reduce the time to resolution of symptoms and reduced the overall symptom burden and the rate of persistent signs of acute infection on otoscopic examination. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00377260.).

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.