PEDIATRICS Vol. 118 No. 6 December 2006, pp. e1822-e1830 (doi:10.1542/peds.2005-2673)
ARTICLE |
Brief Hospitalization and Pulse Oximetry for Predicting Amoxicillin Treatment Failure in Children with Severe Pneumonia
a Department of General and Community Pediatrics, Children's National Medical Center, Washington, DC
b Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, Massachusetts
c Clinical Epidemiology Unit, Indira Gandhi Medical Center, Nagpur, India
d Center for International Health, Boston University, Boston, Massachusetts
e Respiratory Department, Children's Hospital 1, Ho Chi Min City, Vietnam
f Paediatrics Department, Nelson R. Mandela School of Medicine, University of Kwazulu-Natal, Durban
g Department of Clinical Medicine, Tropical Disease Research Centre, Ndola, Zambia
h Department of Pediatrics, Children's Hospital, Islamabad, Pakistan
i Department of Pediatrics, Javeriana University School of Medicine, Bogotá, Columbia
j Pediatrics Department, Hospital Angeles Lomas, Mexico City, Mexico
k World Health Organization, Geneva, Switzerland
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. In settings with limited assessment tools, we sought to determine whether early clinical signs and symptoms and blood oxygen saturation would predict amoxicillin treatment failure in children with severe pneumonia (as defined by the World Health Organization).
METHODS. Data were from a previously reported, multinational trial of orally administered amoxicillin versus injectable penicillin for the treatment of World Health Organization–defined severe pneumonia in children 3 to 59 months of age. We assessed all 857 participants assigned randomly to the experimental amoxicillin arm. Six multivariate logistic regression models were created and evaluated for their ability to predict failure after 48 hours of therapy. Regression models included vital signs, symptoms, and laboratory data collected at baseline and after 12 or 24 hours of observation. Oxygen saturation data were included in 3 models.
RESULTS. Clinical treatment failure occurred for 18% of children. Younger age, increased initial respiratory rate, and baseline hypoxia predicted treatment failure in all models. Data available after 24 hours improved the ability to predict failure compared with data available at baseline or 12 hours. The inclusion of oximetry data improved the predictive ability at baseline, 12 hours, and 24 hours. The ability to predict failure after 12 hours of observation with oximetry data was similar to the predictive ability after 24 hours without pulse oximetry data.
CONCLUSIONS. Assessment of clinical parameters at presentation and after 24 hours improved the ability to predict clinical failure of oral amoxicillin therapy, compared with assessment at presentation alone or at presentation and after only 12 hours, for children with World Health Organization–defined severe pneumonia.
Key Words: amoxicillin • pneumonia • hospitalization • oximetry • child
Abbreviations: ARI—acute respiratory infection • LCI—lower chest wall indrawing • RSV—respiratory syncytial virus • WHO—World Health Organization • CI—confidence interval
Acute respiratory infection (ARI) is one of the leading causes of death throughout the world for children <5 years of age and is responsible for an estimated 1.9 million childhood deaths each year.1 In contrast to the situation in industrialized nations, childhood pneumonia in developing countries is caused commonly by bacteria and not viruses.2,3 Bacterial infection is associated with higher ARI mortality rates than viral infection.2,4 Accordingly, clinical trials have suggested that antimicrobial therapy may reduce ARI-associated mortality rates by one half in developing nations.2 Because of the difficulties associated with diagnosing bacterial pneumonia in the developing world,2,3,5 the World Health Organization (WHO) has based case management solely on clinical signs for the initiation of empiric antibiotic therapy.4,6
For children who have cough or difficulty breathing, the WHO ARI case management guidelines require only an assessment of the respiratory rate and the presence of visible and audible signs of respiratory distress. The presence of rapid breathing (
60 breaths per minute for children <2 months of age and 50 breaths per minute for children 2 months of age) confers a diagnosis of nonsevere pneumonia, which is treated with orally administered cotrimazole or amoxicillin at home. Lower chest wall indrawing (LCI) as an additional sign signifies severe pneumonia, which is treated with intramuscularly administered benzylpenicillin or ampicillin and hospitalization for at least 48 hours. A child whose disease improves from severe pneumonia to nonsevere pneumonia or well status after 48 hours of therapy is sent home with orally administered antibiotics, whereas a child whose condition remains unchanged or worsens remains hospitalized and receives expanded antibiotic coverage.3 The WHO management definitions of pneumonia do not rely on the typical diagnostic methods used in developed countries, such as bacterial culture or radiography, and inevitably include more cases of nonpneumonia respiratory disorders, such as reactive airway disease and viral bronchiolitis. Nevertheless, because of the high incidence and severity of disease associated with bacterial pneumonia in developing nations, use of empiric antibiotic therapy based on these guidelines has been estimated to reduce mortality rates in the developing world by 27%.7
In a recent, hospital-based trial, orally administered amoxicillin was found to be equivalent to injectable penicillin for the treatment of severe pneumonia in developing countries.8 Although this finding supports the home administration of orally administered amoxicillin, the safety of home-based therapy has yet to be established. An important concern is that therapies such as supplemental oxygen and nebulized bronchodilator therapy cannot be administered routinely in the home. In addition, continuous observation of a patient's response to therapy by trained health care workers is not possible. To guide practitioners in their use of orally administered amoxicillin, our study used data from the previously published trial to determine the incremental gain in ability to predict amoxicillin treatment failure achieved with information gathered after 12 or 24 hours of hospitalization, compared with information from a single baseline assessment, for children with severe pneumonia.8 We also evaluated whether changes in blood oxygen saturation further improved the ability to predict treatment failure.8–11
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Sample and Data
This posthoc cohort analysis was nested within the previously completed, randomized trial comparing orally administered amoxicillin with injectable penicillin for children 3 to 59 months of age with severe pneumonia and included only children assigned randomly to the amoxicillin arm.8 The trial was conducted in the pediatric departments of tertiary care facilities in 9 locations in 8 countries, namely, Colombia, Ghana, India, Mexico, Pakistan, South Africa (2 sites), Vietnam, and Zambia. Children who presented to the emergency department with a history of cough or difficulty breathing and LCI were considered for study entry. Children with LCI associated with reactive airway disease (determined on the basis of the response to 2 courses of nebulized bronchodilator therapy) were excluded. In addition, children with danger signs (inability to drink, abnormal sleepiness, central cyanosis, or convulsions) indicating very severe disease, a recent history of a very severe infectious/noninfectious disease, a chronic or congenital illness, known asthma, clinically evident HIV infection, persistent vomiting, a known penicillin allergy, or >48 hours of antibiotic therapy before presentation were excluded.
Baseline clinical assessment (history and physical examination) and laboratory (oxygen saturation and nasopharyngeal isolate respiratory syncytial virus [RSV] testing) data were obtained within 1 hour after enrollment, before the first dose of antibiotics. The children included in this analysis received their first dose of orally administered amoxicillin syrup (45 mg/kg per day, divided into 3 doses) within the first hour of enrollment. Oxygen saturation was determined through pulse oximetry in room air, when the child was calm and not crying (Nellcor N-200E pulse oximeter, with N-25 sensor; Nellcor, Hayward, CA). Study personnel were trained and certified in assessing respiratory rate, presence of LCI, and danger signs by using WHO standard ARI case management modules and a WHO training videotape.
All subjects were hospitalized for 48 hours. Vital, clinical, and danger signs and oxygen saturation data were recorded every 6 hours. Indications for providing oxygen (oxygen saturation of <90% or respiratory rate of 70 breaths per minute), antipyretics (fever of 39°C), and bronchodilator treatments (audible wheeze) were standardized across study sites. Supportive therapies were given as needed after vital signs were assessed and recorded for each time interval. Designation of treatment failure occurred only after the site principal investigator reviewed all study data to confirm failure. All variables collected were entered into a SAS-format database.8 Written informed consent was obtained from parents or legal guardians of children before enrollment. Ethical approval was obtained from every local institution and both sponsoring organizations. The study was monitored by an independent data safety monitoring board.
Coding of Treatment Outcomes
Treatment success was considered to be improvement to nonsevere pneumonia or well status (normal respiratory rate) after 48 hours of therapy in both the original trial and this analysis. Treatment failure in this analysis included children with persistent LCI after 48 hours of therapy and those with danger signs or severe hypoxia (oxygen saturation in room air of <80% at sea level and <75% at elevation). Case report forms for children with non–pneumonia-related outcomes that were classified as failure in the original trial (children who received another antibiotic, had a newly diagnosed comorbid condition, withdrew from the study voluntarily, or left against medical advice at any time after study enrollment)8 were reviewed and reclassified as treatment success or treatment failure or excluded if they did not meet 1 of the 2 definitions. Reclassification of cases was performed independently by 2 investigators, and discrepancies were resolved through discussion and consensus. Inter-rater agreement was assessed with a 
statistic.
Coding of Predictor Variables
A priori and on the basis of findings from previous studies,4,9,12–17 we selected the following as potential predictor variables: age (<6 months, 6–11 months, or 12 months); use of antibiotics within 48 hours before enrollment; immunization status (up to date or not); breastfeeding status (breastfeeding at time of enrollment, not breastfeeding, or not applicable because child was >24 months of age); dehydration at baseline; nutritional status (based on weight-for-age z score); presence of RSV; respiratory rate at baseline, at 12 hours, and at 24 hours; oxygen saturation at baseline, at 12 hours, and at 24 hours; temperature at baseline, at 12 hours, and at 24 hours; and presence of nonauscultatory audible wheeze at 12 hours and at 24 hours. Wheezing at baseline was not included in the analysis because this was a study exclusion criterion. Respiratory rate at baseline was recorded as a 3-level class variable (for children <12 months of age: very fast: 70 breaths per minute; fast: 50 breaths per minute; not fast: <50 breaths per minute; for children 12 months of age: very fast: 60 breaths per minute; fast: 40 breaths per minute; not fast: <40 breaths per minute).3 Hypoxemia at baseline was assessed on room air and was considered present if oxygen saturation was <90% at sea level or <88% at elevation (in Columbia and Mexico). Temperature, respiratory rate, and oxygen saturation were analyzed at 12 hours and at 24 hours as changes from baseline values. Variables assessed at 12 hours and 24 hours were coded as missing for children who were designated as experiencing treatment failure before the assessment time.
Statistical Analyses
The relationship of each predictor variable to oral amoxicillin treatment failure was examined in univariate analyses by using the 
2 test (discrete data) or unpaired t test (continuous data). A crude odds ratio with 95% confidence interval (CI) was calculated for the effect of each predictor on the outcome by using logistic regression modeling. All analyses were conducted with SAS 9.0 (SAS Institute, Cary, NC). Test levels for significance were P < .05.
To address our study question, 3 multivariate logistic regression models were created. The first model used data obtained at baseline only, the second used data from baseline and from 12 hours after therapy initiation, and the third used data from baseline and from 24 hours after therapy initiation. A forward stepwise selection process was used each time to choose variables to predict failure. Pulse oximetry data were excluded from these models. Three additional models were then created by allowing pulse oximetry data to enter the selection process. All variables used in the development of regression models were checked for colinearity; a Pearson correlation coefficient of >0.8 was considered highly colinear. Because the range of Pearson correlation coefficients was 0 to 0.73 for all pairings, no variable was excluded. Because of a relatively high percentage of missing values for the variables of immunization status (5%) and presence of RSV (11%), dummy variables were created in all 6 models for missing values for these 2 variables. Significance levels for entry and elimination in the stepwise procedure were set at .1.
The final regression models included study site as a random effect. Random-effects modeling was performed by using the SAS macro program Glimmix (available at: http://ftp.sas.com). The predictive abilities of the 6 models generated were compared by using receiver operating characteristic curve areas and likelihood ratios. The Hosmer-Lemeshow goodness-of-fit test was used to determine the fit of the models to the data.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Group
A total of 857 children (50.4% of 1702 patients enrolled in the study) who were assigned randomly to the amoxicillin arm of the clinical trial represented the present study sample. We identified 23 children in the trial with treatment failure for reasons other than failure to exhibit improvement or worsening pneumonia (8 children received another antibiotic, 4 had newly diagnosed comorbid conditions, 2 had newly diagnosed conditions and received another antibiotic, and 9 withdrew from the study voluntarily or left against medical advice). Two investigators (Drs Fu and Fox) independently reclassified these cases according to our definitions of treatment success and failure and agreed on 22 of 23 cases. Inter-rater agreement was high (
= 0.93; 95% CI: 0.80–1.00). Of the 23 cases in question, 3 were reclassified as treatment success, 8 were reclassified as treatment failure, and 12 were excluded from analysis because they were not classifiable with the information available (Fig 1). After reclassification, the rate of treatment failure was 18% (152 of 843 cases), which was very similar to the percentage obtained in the amoxicillin arm of the clinical trial (19%). Among all of the patients classified as experiencing treatment failure, the condition of 13% had worsened, compared with baseline, whereas that of the rest had not changed.
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According to univariate analysis, age was a strong predictor of treatment failure (P < .001) (Table 1). The odds of failure for the youngest children (<6 months of age) was 3.6 times the odds of failure for the oldest children (
12 months of age). Immunizations not being up to date and antibiotic use for up to 48 hours before trial entry were both associated with twofold greater odds of treatment failure (P = .004 and P = .02, respectively). In addition, baseline fast or very fast respiratory rate and baseline hypoxia were associated with greater odds of treatment failure (P = .03 and P =.004, respectively). The apparent association of breastfeeding with treatment failure disappeared after adjustment for age (P = .54).
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Assessment of the Benefits of 12 or 24 Hours of Patient Observation for Predicting Amoxicillin Treatment Failure
In univariate analysis, at 12 hours after enrollment in the amoxicillin arm of the trial, a 1°C increase in temperature over baseline was associated with 27% increased odds of treatment failure (P = .01) (Table 1). After 24 hours of treatment, a 1°C increase in temperature was associated with 52% increased odds of failure, and an increase in respiratory rate of 5 breaths per minute was associated with 18% increased odds of failure (P < .001 for both variables) (Table 1).
We created 3 multilevel, multivariate, logistic regression models to compare the ability to predict treatment failure with (1) baseline data only, (2) data from baseline and from 12 hours after therapy initiation, or (3) data from baseline and from 24 hours after therapy initiation. These models included only variables that could be assessed with methods promoted currently by the WHO for care at the first referral level in developing countries (ie, excluding pulse oximetry data). In the model that included only baseline data, younger age and increased respiratory rate were significant predictors of treatment failure (Table 2). In the model that included data from baseline and from 12 hours after therapy initiation, younger age, high respiratory rate at baseline, and increasing respiratory rate over time were significant predictors of treatment failure. In the model that included data from baseline and from 24 hours after therapy initiation, younger age, increased respiratory rate at baseline, higher temperature at baseline, increasing respiratory rate over time, and increasing temperature over time were significant predictors of treatment failure. When we compared the 3 models' likelihood ratios, we found that treatment failure was predicted most accurately by using data from baseline and from 24 hours after therapy initiation (P < .001 for comparisons with both other models) (Table 3). There was no significant difference in predictive ability between the regression model that included baseline data alone and the model that included data from baseline and from 12 hours after therapy initiation (P = .35) (Table 3).
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Assessment of the Benefits of Pulse Oximetry Data for Predicting Amoxicillin Treatment Failure
In univariate analysis, hypoxia at baseline was associated with more than twofold increased odds of treatment failure (P = .004) (Table 1). After 12 and 24 hours of treatment, decreasing blood oxygen saturation was associated with 14% and 20% increased odds of failure, respectively (P < .001 for both variables) (Table 1). We created 3 new predictive models that allowed variables related to blood oxygen saturation to enter the selection process. The 3 models used (1) baseline data only, (2) data from baseline and from 12 hours after therapy initiation, or (3) data from baseline and from 24 hours after therapy initiation. In the logistic regression model that used baseline data alone, younger age, increased respiratory rate, and hypoxia were significant predictors of treatment failure (Table 2). This model predicted treatment failure better than did the model that used baseline data and excluded hypoxia as a possible predictor variable (P < .001) (Table 3). In the regression model that used data from baseline and from 12 hours after therapy initiation, younger age, higher respiratory rate at baseline, hypoxemia at baseline, increasing respiratory rate over time, and decreasing oxygen saturation over time were significant predictors of treatment failure (Table 2). This 12-hour model predicted treatment failure better than did the 12-hour model that excluded pulse oximetry data (P < .001) (Table 3). In the regression model that used data from baseline and from 24 hours after therapy initiation, younger age, increased respiratory rate at baseline, hypoxia at baseline, development of audible wheezing, increasing respiratory rate over time, and decreasing oxygen saturation over time were significant predictors of treatment failure (Table 2). When we compared this model with the one that included 24 hours of data without pulse oximetry information, again we found that treatment failure was predicted more accurately with pulse oximetry data than without such data (P < .001) (Table 3).
In all 3 regression models that included pulse oximetry variables, baseline hypoxia increased the odds of treatment failure twofold to fourfold, and each 1% decrease in oxygen saturation over 12 or 24 hours was associated with 
20% increased odds of treatment failure (Table 2). Variables related to pulse oximetry were such strong predictors of treatment failure that there was no difference in predictive ability between the model that used data collected after 12 hours of therapy and included pulse oximetry information and the model that used data collected after 24 hours of therapy and excluded pulse oximetry information (P = .24) (Table 3). All 6 logistic regression models fit the data well, according to the Hosmer-Lemeshow goodness-of-fit test (P = .52–.99).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Our study has 2 main findings. First, information obtained after at least 12 hours but ideally 24 hours of patient observation provides more valuable information than baseline assessments alone for predicting which children with severe pneumonia are likely to experience failure of oral amoxicillin therapy. Second, assessments of blood oxygen saturation at baseline and saturation trends over time improve the ability to predict which children will experience failure of oral therapy. Specifically, if pulse oximetry is available, then the ability to predict treatment failure with data from baseline and from 12 hours after initiation of therapy is almost identical to the predictive ability obtained with data from baseline and from 24 hours without the benefit of pulse oximetry. Having 24 hours to observe a child with access to pulse oximetry provides the best predictive ability for treatment failure.
These findings extend the observations of the recently published trial that demonstrated equivalence between injectable penicillin and orally administered amoxicillin for the treatment of severe pneumonia in children.8 The original trial established the equivalence of oral and parenteral therapy in a facility setting, without affirming the safety of home oral therapy. Our study suggests that an identifiable subset of children presenting with severe pneumonia may need to be hospitalized for optimally safe care if treated with oral therapy. Hospitalization provides patients with monitoring by trained professionals, as well as the opportunity to receive ancillary therapies as appropriate. Patient observation has been cited as one of the most common methods through which health care providers acquire information on which to base decisions.18 One fifth of all children in our study received supplemental oxygen at least once during the first 24 hours, and two fifths received bronchodilator therapy. Appropriate administration of oxygen and bronchodilators by health care workers, according to well-defined criteria, during 24 hours of hospitalization likely contributes to the high treatment success rate achieved with amoxicillin.
Our findings that demonstrate the benefits of blood oxygen saturation measurements in the prediction of amoxicillin treatment outcomes are consistent with the findings of other researchers. Studies from Indonesia, Kenya, Zambia, and the Gambia have found the risk of death with acute lower respiratory tract infection to be 1.4 to 4.6 times higher for children with hypoxia than for those without.9,19–21
In our study, low blood oxygen saturation conferred a risk of treatment failure even with adjustment for respiratory rate. This suggests that the 2 factors may not be measures of exactly the same physiologic process. A study of children in the Gambia found that high respiratory rate was a poor predictor of hypoxemia.22 Oxygen saturation trends may prove to be as helpful as clinical criteria such as respiratory rate trends for guiding pneumonia care. In one study in Papua, New Guinea, children with severe pneumonia who were given supplemental oxygen on the basis of saturation criteria had a marginally lower risk of death (P = .07) than those treated according to clinical signs.10 This might be attributable to the fact that pulse oximetry readings are more consistent and therefore more reliable than clinical assessments, which vary from clinician to clinician.23 Ideally, oximetry data could be used in conjunction with clinical guidelines to assess patient status and progress. In one study, blood oxygen saturation of 
96.6% and WHO criteria for pneumonia (nonsevere or severe) together identified 87% of cases of radiologically evident pneumonia.11
Despite the growing literature supporting their use, pulse oximeters are not routinely available at first-referral health facilities in developing countries. The 2 greatest obstacles to their widespread use are perceived high cost and impracticality. These obstacles are not insurmountable. Pulse oximeters are less expensive to use than radiographic technology and can operate with car batteries if necessary. The machines are easy to calibrate, to use, to maintain, and to repair when broken.11,24 Because oximeters improve the ability to differentiate children with pneumonia who are more likely to fare poorly from those who are less likely, they may assist practitioners in deciding which children can be sent home with oral therapy. In this way, they may be a cost-effective addition for families and overall health care. Of course, achieving the maximal benefit of pulse oximeters involves using them to guide administration of supplemental oxygen. As new technologies such as oxygen concentrators,25 which provide oxygen inexpensively and reliably, become more available in developing nations, there will be even more inducements for widespread distribution of pulse oximeters.
Our study has several limitations. To make the results of our study readily applicable to practitioners internationally, we used the WHO ARI algorithm as the basis for our definition of treatment failure. Because of the minimal resources needed to follow the guidelines, the WHO ARI algorithm is the accepted method for diagnosing pneumonia in much of the world. Use of empiric antibiotic therapy based on these guidelines has been estimated to reduce mortality rates in the developing world by 27%.7 However, the WHO definition of "pneumonia" has a significant false-positive rate and misclassified 35% of well children as having pneumonia in one study.11 Patients with ARI attributable to pathologic processes not expected to be responsive to amoxicillin were likely included as cases of antibiotic failure in our study. At the Durban and Zambia study sites, the adult seroprevalence of HIV was as high as 30%. Children from those sites who experienced failure of therapy were at greater risk of having pneumonia caused by Pneumocystis jiroveci, because amoxicillin is ineffective against that organism. Overall, 67% of the children in our study were afebrile at the time of study enrollment; some of those children with "failure" of antibiotic therapy were likely suffering from reactive airway disease rather than pneumonia, despite our baseline exclusion of children with known asthma or positive responses to bronchodilator therapy. Our study identified children infected with the 2 most common pathogens causing community-acquired pneumonia. Twenty-seven percent of the children had Streptococcus pneumoniae isolated from their nasopharynx, and 20% had Haemophilus influenzae. Negative culture results were not a risk factor for treatment failure. It is likely that a higher percentage of children in the study had bacterial lung infections, because the percentage of children with ARI symptoms and positive lung aspirate cultures ranged from 21% to 74% in other studies.2 Because of the diagnostic ambiguity inherent in using the WHO definition of "severe pneumonia" for determination of treatment failure, the conclusions of our study and the original trial may not be directly applicable to settings in which more-precise methods of diagnosing bacterial pneumonia, such as bacterial culture and radiography, are routine.
Additional study is necessary to translate our findings into simple practical guidelines for individual-level patient care in developing countries. We found incrementally increasing value of 12-hour and 24-hour patient data over baseline data alone, as well as benefits of knowing blood oxygen saturation at all time points, for predicting amoxicillin treatment failure. Future treatment guidelines will need to balance the maximization of predictive ability with practicality. Although the techniques for assessing clinical status in this trial were the same as the methods promoted by the WHO for care at first-referral health facilities, this trial was conducted in tertiary care hospitals, to ensure patient safety and study quality. The feasibility of providing observational stays and pulse oximetry for patients at first-referral health facilities in developing nations has yet to be determined.
Oral therapy may now be considered appropriate treatment for severe pneumonia in developing nations.8 Because oral therapy does not require technical skill for administration, the hospital length of stay for severe pneumonia may be reduced. However, caution must be exercised to ensure that children at risk of oral therapy failure are identified properly. Identification of children at high risk can be performed with 12 hours of patient observation if the capacity to measure blood oxygen saturation is available. If it is not, then information gathered after 24 hours of observation without pulse oximetry may be equally beneficial in predicting treatment failure.
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ACKNOWLEDGMENTS |
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This work was supported in part by the Agency for Healthcare Research and Quality (grant T32 HS00060); the Department of Child and Adolescent Health and Development, World Health Organization (Geneva, Switzerland); and the Applied Research in Child Health Project, Boston University (Boston, MA), under the US Agency for International Development cooperative agreement HRN-A-00-96-900100-00.
We are grateful to Gregory Koblentz, Robert Goldberg, and Olivier Fontaine for their careful review of the manuscript and helpful suggestions.
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FOOTNOTES |
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Accepted Jul 11, 2006.
Address correspondence to Linda Y. Fu, MD, MSc, Department of General and Community Pediatrics, George Washington University, Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010. E-mail: lfu{at}cnmc.org
We attest to the fact that we, the authors, are responsible for this research review. We have all participated in the concept and design of the manuscript, interpretation of the articles reviewed, and drafting and revising of the manuscript. We have all approved the documents submitted.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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