Post-transplant lymphoproliferative disorder in pediatric liver transplant recipients: Experience from a South African transplant center.

INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a clinically heterogeneous potentially fatal complication of pediatric liver transplantation (PLT). We determined the prevalence, complications, and associated factors for PTLD in PLT recipients from Wits Donald Gordon Medical Centre, South Africa from January 2012 to August 2019. METHODS: We performed a retrospective record review of 150 PLT recipients. RESULTS: Histologically proven PTLD occurred in 17/150 PLT recipients (11.3%). Children with PTLD were significantly younger at transplant (17.9 vs. 32.7 months, p = 0.001) with a significantly higher prevalence of obstructive etiology (17/17 vs. 81/133, p = 0.001). Fifteen (88.2%) children with PTLD were Epstein-Barr virus (EBV) seronegative at transplant. High post-transplant EBV viral load at a threshold value of 4.8 log10 DNA copies/mL (sensitivity: 80.0% [95% confidence interval {CI}, 46.7%-100.0%]; specificity: 73.1% [95% CI 42.3%-93.3%; area under the curve {AUC} 75.8%]) and low post-transplant albumin levels at a threshold value of 21.5 g/L (sensitivity: 70.6% [95% CI, 41.2%-94.1%]; specificity: 85.7% [95% CI, 60.4%-94.5%; {AUC} 74.8%]) were associated with PTLD. The prevalence of cytomegalovirus (CMV) disease was significantly higher in children who developed PTLD versus non-PTLD (12/17 vs. 18/133; p < 0.001). CMV disease and the combination of post-transplant high EBV viral load and low albumin were independently associated with an increased risk of developing PTLD. Four (23.5%) children with PTLD died, however, survival was equivalent to non-PTLD PLT (p = 0.580). CONCLUSION: The prevalence of PTLD in our cohort mirrors international cohorts, with mortality similar to non-PTLD PLT recipients.

Functional Outcomes of Congenital Scoliosis at a Mean 35-Year Follow-up Post In Situ Fusion. Revisiting Patients From the 2002 Goldberg et al Study.

BACKGROUND: The management of congenital scoliosis poses a significant challenge for treating surgeons. The aim of our study was to provide insight into the long-term clinical results of spinal fusion in congenital scoliosis. METHODS: We performed a retrospective review of the scoliosis database in our institution for the period 1976 until 2002 identifying 43 patients with congenital scoliosis who underwent spinal fusion. Patient demographics, diagnosis, levels fused, and radiographs were evaluated. Patients were evaluated for unplanned return to the operating room (UPROR) via SRS 22, EQ5D-5L, and Oswestry Disability Index (ODI). RESULTS: Of the 43 patients who fulfilled the inclusion criteria, 22 patients agreed to participate, 3 patients were known to be deceased and 18 patients were lost to follow-up or declined to participate and were excluded. The mean age of the respondents was 40.7 years (range, 30 to 47 y) with a mean follow-up from index surgery of 35 years (range, 20 to 44 y). At most recent follow-up, 12 patients (54%) underwent UPROR. The mean age at diagnosis was 3.4 years (range, birth to 11.5 y), and the mean age for first surgery was 5.8 years (range, 1 to 13 y). As regards radiologic follow-up; the mean number of levels fused was 5.2 (range, 2 to 12). Thoracic fusion was performed in 17 patients (77%). The mean T1 to T12 height at index surgery and maturity was 166 mm (range, 130 to 240 mm) and 202 mm (range, 125 to 270 mm), respectively. The mean functional scores at follow-up were SRS 22: 4.5 (range, 2.4 to 5), cumulative EQ5D-5L score 7.2 (range, 5 to 15), and ODI: 8% (range, 2 to 30%). All respondents completed high school, 10 patients (45%) completed university, and 2 patients were awarded doctorates. Currently, 17 patients (77%) are in paid employment. CONCLUSIONS: This report constitutes the largest series of patients treated by spinal arthrodesis for congenital scoliosis followed into maturity. We demonstrate the thorax continues to grow after index fusion, patient-reported outcomes were satisfactory with superior educational and employment rates and unplanned return to theatre is rare in adult life. LEVEL OF EVIDENCE: Therapeutic Level IV.

Healthcare disparity and its associations with cytomegalovirus disease in pediatric liver transplant recipients in South Africa.

BACKGROUND: Cytomegalovirus (CMV) infection and disease are preventable complications following pediatric liver transplantation (PLT), despite the use of prophylaxis to minimize the risk of CMV disease. We evaluated the incidence and complications of CMV disease in PLT recipients in South Africa (SA), with particular reference to potential differences in outcome between state and private sector patients. METHODS: Medical records of patients younger than 16 years of age who received liver transplants between January 1, 2012, and August 31, 2018 were analyzed. RESULTS: Records of all 150 PLT patients were retrieved. The median age at transplant was 29.2 months (95% confidence interval 15.6-58.4) and follow-up was 46.3 months (interquartile range 27.6-63.1). Sixty-six (44%) patients were high risk, 79 (52.7%) were intermediate risk, and five (3.3%) were low risk for CMV infection. Forty-three (28.9%) patients had CMV DNAemia following transplantation, and 30 (20.1%) developed CMV disease. Receipt of care in the private sector was consistently associated with a lower hazard of CMV disease (adjusted hazard ratio [aHR] ranging from 0.36 to 0.43) and a consistently lower hazard of death among recipients at high risk for CMV disease and/or those who developed CMV disease (aHR ranging from 0.28 to 0.33). CONCLUSION: Receipt of care in the private health sector was associated with a consistently lower hazard of CMV disease and death in individuals with CMV disease and/or at high risk for CMV disease. Policies aimed at creating a more equitable healthcare system in SA may mitigate the differential burden of illness associated with CMV in PLT recipients.

Factors associated with graft survival in South African adolescent renal transplant patients at CMJAH over a 20-year period (GRAFT-SAT Study).

BACKGROUND: In the developed world, studies on transition of adolescent renal transplant patients have noted high rates of rejection, non-adherence and graft loss. There is a paucity of data in developing countries and none from South Africa. METHODS: We evaluated patient and graft outcomes during adolescence (10-19 years), of patients who received a renal transplant over a 20-year period (1990-2010), at a tertiary hospital in Johannesburg. Cox proportional hazards models and Kaplan-Meier curves were used to analyse graft and patient survival. RESULTS: A total of 213 kidney transplants were done in 162 patients during the study period, 165 transplants occurred during the adolescent period. Factors associated with graft failure on multivariate analysis included non-white race, transplant during the adolescent period ([aHR] 3.94; 95% [CI], 2.25-6.91), non-compliance with follow-up (aHR 3.89; 95% CI, 1.76-8.60) and receipt of a DD graft (aHR 2.10; 95% CI, 1.27-3.48). Patient survival rates at 1-, 3-, 5- and 10-years were 98.8%, 97.6%, 95.1% and 93.9% respectively. CONCLUSION: High rates of graft rejection and loss occurred in South African renal transplant recipients in the adolescent period, especially in those retained in paediatric care. Establishment of transition clinics may improve the graft outcomes of this vulnerable group and warrant further research.

Vitamin D levels in Irish children with fractures: A prospective case-control study with 5 year follow-up.

INTRODUCTION: Twenty-five-hydroxy-vitamin D3 (25-OH-vit D) is a prohormone that is essential for normal calcium homeostasis and bone metabolism. Understanding its role is an important component of the proper care of the pediatric orthopaedic patient. The aim of this study was to determine whether children in Ireland with fractures have increased prevalence of 25-OH-Vit D deficiency compared with age matched controls and to ascertain the relationship between a low 25-OH-vit D level and the incidence of fractures in Irish children. We hypothesised that children presenting to our centre following a fracture would have significantly lower 25-OH-vit D. METHODS: A prospective case-control study at a large urban tertiary referral academic hospital located in Dublin, Ireland was completed over a 14 month period from June 2014 to August 2015. A total of 116 subjects, distributed as cases (n = 58) and controls (n = 58) were included in this study. Whole blood (10 ml) was taken in two serum bottles from each patient. Serum 25-hydroxy-vitamin D3 levels were measured. An age matched control group was generated from other children attending the hospital, who also had vitamin D levels measured for different clinical reasons. We followed up both the fracture and control group for the next 5 years to assess the repeat fracture rate. RESULTS: Fifty-eight patients with a fracture requiring operative intervention, were included in the study. Statistical analysis was performed comparing to 58 age and sex-matched controls. The mean vitamin D level for the fracture group was 63.2 nmol/L (SD = 27.3), which was higher than the mean of the controls (62.5 nmol/L) (SD = 21.3) (p = 0.86), but this difference was found not to be statistically significant in unadjusted analysis. There was no statistically significant difference in the number of patients classified with low serum Vitamin D levels (<50 nmolL), with the fracture group consisting of 22 (37.9%) patients, and the control group of 17 patients (29.3%) (p = 0.33) with a level below 50 nmol/L. At five-year follow-up, 11 of the 58 patients (18.9%) in the fracture group went on to have a further fracture compared with eight patients (13.7%) from the control group. Out of these 11 from the fracture group five (45.45%) had been found to have a low serum 25-OH-Vit D level five years previously. Out of the eight controls that presented with a fracture within the five-year period, 3 (37.5%) had had a low vitamin D level at the origin of this study. CONCLUSION: The results of this study show that children presenting to our institution with low energy fractures have a prevalence of 38% 25-hydroxy-vitamin D deficiency. This study included children from age 1 to 16 primarily Caucasian encompassing all fracture types resulting from accidental trauma. Our findings suggest that in an Irish pediatric population vitamin D status may impact fracture risk with more than one-third being deficient in this review.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers in South Africa: A Longitudinal Cohort Study.

From April to September 2020, we investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in a cohort of 396 healthcare workers (HCWs) from 5 departments at Chris Hani Baragwanath Hospital, South Africa. Overall, 34.6% of HCWs had polymerase chain reaction-confirmed SARS-CoV-2 infection (132.1 [95% confidence interval, 111.8-156.2] infections per 1000 person-months); an additional 27 infections were identified by serology. HCWs in the internal medicine department had the highest rate of infection (61.7%). Among polymerase chain reaction-confirmed cases, 10.4% remained asymptomatic, 30.4% were presymptomatic, and 59.3% were symptomatic.

The Etiology of Pneumonia From Analysis of Lung Aspirate and Pleural Fluid Samples: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: An improved understanding of childhood pneumonia etiology is required to inform prevention and treatment strategies. Lung aspiration is the gold standard specimen for pneumonia diagnostics. We report findings from analyses of lung and pleural aspirates collected in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS: The PERCH study enrolled children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia in 7 countries in Africa and Asia. Percutaneous transthoracic lung aspiration (LA) and pleural fluid (PF) aspiration was performed on a sample of pneumonia cases with radiological consolidation and/or PF in 4 countries. Venous blood and nasopharyngeal/oropharyngeal swabs were collected from all cases. Multiplex quantitative polymerase chain reaction (PCR) and routine microbiologic culture were applied to clinical specimens. RESULTS: Of 44 LAs performed within 3 days of admission on 622 eligible cases, 13 (30%) had a pathogen identified by either culture (5/44) or by PCR (11/29). A pathogen was identified in 12/14 (86%) PF specimens tested by either culture (9/14) or PCR (9/11). Bacterial pathogens were identified more frequently than viruses. All but 1 of the cases with a virus identified were coinfected with bacterial pathogens. Streptococcus pneumoniae (9/44 [20%]) and Staphylococcus aureus (7/14 [50%]) were the predominant pathogens identified in LA and PF, respectively. CONCLUSIONS: Bacterial pathogens predominated in this selected subgroup of PERCH participants drawn from those with radiological consolidation or PF, with S. pneumoniae and S. aureus the leading pathogens identified.

Establishing a Virtual Clinic for Developmental Dysplasia of the Hip: A Prospective Study.

BACKGROUND: The aim was to describe the introduction and operation of a virtual developmental dysplasia of the hip (DDH) clinic. Our secondary objectives were to provide an overview of DDH referral reasons, treatment outcomes, and adverse events associated with it. METHODS: A prospective observational study involving all patients referred to the virtual DDH clinic was conducted. The clinic consultant delivered with 2 DDH clinical nurse specialists (CNS). The outcomes following virtual review include further virtual review, CNS review, consultant review or discharge. Treatment options include surveillance, brace therapy, or surgery. Efficiency and cost analysis were assessed. RESULTS: Over the 3.5-year study period, 1002 patients were reviewed, of which 743 (74.2%) were female. The median age at time of referral was 7 months, (interquartile range of 5 to 11) with a median time to treatment decision of 9 days. Median waiting times from referral to treatment decision was reduced by over 70%. There were 639 virtual reviews, 186 CNS reviews, and 144 consultant reviews. The direct discharge rate was 24%. One hundred one patients (10%) had dislocated or subluxed hips at initial visit while 26.3% had radiographically normal hips. Over the study period 704 face to face (F2F) visits were avoided. Cost reductions of €170 were achieved per patient, with €588,804 achieved in total. Eighteen parents (1.8%) opted for F2F instead of virtual review. There were no unscheduled rereferrals or recorded adverse events. CONCLUSION: We report the outcomes of the first prospective virtual DDH clinic. This clinic has demonstrated efficiency and cost-effectiveness, without reported adverse outcomes to date. It is an option to provide consultant delivered DDH care, while reducing F2F consults. LEVEL OF EVIDENCE: Level III.

The Predictive Performance of a Pneumonia Severity Score in Human Immunodeficiency Virus-negative Children Presenting to Hospital in 7 Low- and Middle-income Countries.

BACKGROUND: In 2015, pneumonia remained the leading cause of mortality in children aged 1-59 months. METHODS: Data from 1802 human immunodeficiency virus (HIV)-negative children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic. RESULTS: Predictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs). CONCLUSIONS: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.

Are Virtual Fracture Clinics During the COVID-19 Pandemic a Potential Alternative for Delivering Fracture Care? A Systematic Review.

BACKGROUND: Virtual fracture clinics are an alternative to the traditional model of fracture care. Since their introduction in 2011, they have become increasingly used in the United Kingdom and Ireland. The coronavirus disease 2019 (COVID-19) health crisis has driven institutions to examine such innovative solutions to manage patient care. The current controversies include quantifying safety outcomes, such as potential delayed or missed injuries, inadequate treatment, and medicolegal claims. Questions also exist regarding the potential for cost reductions and efficiencies that may be achieved. Physical distancing has limited the number of face-to-face consultations, so this review was conducted to determine if virtual fracture clinics can provide an acceptable alternative in these challenging times. QUESTIONS/PURPOSES: The aim of this systematic review was to describe (1) adverse outcomes, (2) cost reductions, and (3) efficiencies associated with the virtual fracture clinic model. METHODS: A systematic review of the PubMed, MEDLINE, and Embase databases was conducted from database inception to March 2020. The keywords "virtual" or "telemedicine" or "telehealth" or "remote" or "electronic" AND "fracture" or "trauma" or "triage" AND "clinic" or "consultation" were entered, using the preferred reporting items for systematic reviews and meta-analyses. Inclusion criteria included adults and children treated for injuries by a virtual clinic model at the initial review. Eligible injuries included injuries deemed to not need surgical intervention, and those able to be treated remotely using defined protocols. Exclusion criteria consisted of patients reviewed by telemedicine using video links or in person at the initial review. Initially, 1065 articles were identified, with 665 excluded as they did not relate to virtual fracture clinics. In all, 400 articles were screened for eligibility, and 27 full-text reviews were conducted on 18 studies (30,512 virtual fracture clinic encounters). Three subdomains focusing on adverse outcomes, cost reductions, and efficiencies were recorded. The term adverse outcomes was used to describe any complications, further surgeries, re-referrals back to the clinic, or deviations from the protocols. Efficiency described the number of patients reviewed and discharged using the model, savings in clinic slots, reduced waiting times, or a reduction in consumption of resources such as radiographs. All studies were observational and the quality was assessed using Newcastle-Ottawa tool, which demonstrated a median score of 6 ± 1.8, indicating moderate quality. RESULTS: Six studies reported adverse outcomes in detail, with events ranging from inappropriate splinting, deviations from protocols, and one patient underwent an osteotomy for a malunion. Efficiency varied from direct discharge proportions of 18% in early studies to 100% once the virtual fracture clinic model was more established. Cost reductions compared with estimates derived from conventional fracture clinics varied from USD 53 to USD 297 and USD 39,125 to USD 305876 compared with traditional fracture clinic visits. CONCLUSIONS: Virtual fracture clinics may provide a means to treat patients remotely, using agreed-upon protocols. They have an important role in the current COVID-19 pandemic, due to the possibility to provide ongoing care in an otherwise challenging setting. More robust studies looking at this model of care will be needed to assess its long-term effects on patients, institutions, and health care systems. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Computer-aided diagnosis for World Health Organization-defined chest radiograph primary-endpoint pneumonia in children.

BACKGROUND: The chest radiograph is the most common imaging modality to assess childhood pneumonia. It has been used in epidemiological and vaccine efficacy/effectiveness studies on childhood pneumonia. OBJECTIVE: To develop computer-aided diagnosis (CAD4Kids) for chest radiography in children and to evaluate its accuracy in identifying World Health Organization (WHO)-defined chest radiograph primary-endpoint pneumonia compared to a consensus interpretation. MATERIALS AND METHODS: Chest radiographs were independently evaluated by three radiologists based on WHO criteria. Automatic lung field segmentation was followed by manual inspection and correction, training, feature extraction and classification. Radiographs were filtered with Gaussian derivatives on multiple scales, extracting texture features to classify each pixel in the lung region. To obtain an image score, the 95th percentile score of the pixels was used. Training and testing were done in 10-fold cross validation. RESULTS: The radiologist majority consensus reading of 858 interpretable chest radiographs included 333 (39%) categorised as primary-endpoint pneumonia, 208 (24%) as other infiltrate only and 317 (37%) as no primary-endpoint pneumonia or other infiltrate. Compared to the reference radiologist consensus reading, CAD4Kids had an area under the receiver operator characteristic (ROC) curve of 0.850 (95% confidence interval [CI] 0.823-0.876), with a sensitivity of 76% and specificity of 80% for identifying primary-endpoint pneumonia on chest radiograph. Furthermore, the ROC curve was 0.810 (95% CI 0.772-0.846) for CAD4Kids identifying primary-endpoint pneumonia compared to other infiltrate only. CONCLUSION: Further development of the CAD4Kids software and validation in multicentre studies are important for future research on computer-aided diagnosis and artificial intelligence in paediatric radiology.

Molecular Subtyping of Human Rhinovirus in Children from Three Sub-Saharan African Countries.

The pathogenesis of human rhinovirus (HRV) during severe respiratory disease remains undefined; thus, we aimed to explore the relationship between the HRV molecular subtyping results obtained during severe and asymptomatic childhood infections. Nasopharyngeal/oropharyngeal swabs from children (1 to 59 months of age) hospitalized with pneumonia and from age-frequency-matched controls were collected between August 2011 and August 2013. Swabs were tested for respiratory pathogens, including HRV, using quantitative real-time PCR assays. HRV-positive samples were sequenced for phylogenetic analysis by targeting the 5' noncoding region (5'NCR). Our data showed that there were no differences in the prevalence of HRV detection among cases and controls (21% versus 20%, P = 0.693); however, among children 13 to 59 months old, HRV detection was more often case associated (21% versus 16%; P = 0.009), with the results mainly driven by HRV-C (12% versus 7%; P = 0.001). Overall, there were no differences in the results of molecular subtyping of the HRV species prevalence among cases (for HRV-A, 48%; for HRV-B, 7%; for HRV-C, 45%) and controls (for HRV-A, 45%; for HRV-B, 10%; for HRV-C, 45% [P = 0.496]). Those with pneumonia and HRV-C were older (12.1 versus 9.4 months, P = 0.033) and more likely to present with wheeze (35% versus 25%, P = 0.031) than those with HRV-A cases. Thus, the rate of HRV detection was high, with similar degrees of genetic diversity among cases and controls, confounding the interpretation of the presence of HRV in nasopharyngeal samples for attribution of a causal role in the pathogenesis of severe pneumonia in infants. However, among children 13 to 59 months of age, HRV detection, in particular, HRV-C detection, was associated with case status, especially among children with wheezing disease.

The Incremental Value of Repeated Induced Sputum and Gastric Aspirate Samples for the Diagnosis of Pulmonary Tuberculosis in Young Children With Acute Community-Acquired Pneumonia.

BACKGROUND.: Mycobacterium tuberculosis (Mtb) contributes to the pathogenesis of childhood acute community-acquired pneumonia in settings with a high tuberculosis burden. The incremental value of a repeated induced sputum (IS) sample, compared with a single IS or gastric aspirate (GA) sample, is not well known. METHODS.: Two IS samples were obtained for Mtb culture from children enrolled as cases in the Pneumonia Etiology Research for Child Health (PERCH) study in South Africa. Nonstudy attending physicians requested GA if pulmonary tuberculosis was clinically suspected. We compared the Mtb yield of 2 IS samples to that of 1 IS sample and GA samples. RESULTS: . Twenty-seven (3.0%) culture-confirmed pulmonary tuberculosis cases were identified among 906 children investigated with IS and GA samples for Mtb. Results from 2 IS samples were available for 719 children (79.4%). Of 12 culture-confirmed pulmonary tuberculosis cases identified among children with ≥2 IS samples, 4 (33.3%) were negative at the first IS sample. In head-to-head comparisons among children with both GA and IS samples collected, the yield of 1 GA sample (8 of 427; 1.9%) was similar to that of 1 IS sample (5 of 427, 1.2%), and the yield of 2 GA samples (10 of 300; 3.3%) was similar to that of 2 IS samples (5 of 300; 1.7%). IS samples identified 8 (42.1%) of the 19 culture-confirmed pulmonary tuberculosis cases that were identified through submission of IS and GA samples. CONCLUSIONS.: A single IS sample underestimated the presence of Mtb in children hospitalized with severe or very severe pneumonia. Detection of Mtb is enhanced by combining 2 IS with GA sample collections in young children with acute severe pneumonia.

Data Management and Data Quality in PERCH, a Large International Case-Control Study of Severe Childhood Pneumonia.

The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed comprehensive quality indicator, data query, and monitoring reports. Among the approximately 9000 cases and controls, analyzable laboratory results were available for ≥96% of core specimens collected. Selected approaches to data management in PERCH may be extended to the planning and organization of international studies of similar scope and complexity.

Standardized Interpretation of Chest Radiographs in Cases of Pediatric Pneumonia From the PERCH Study.

BACKGROUND.: Chest radiographs (CXRs) are a valuable diagnostic tool in epidemiologic studies of pneumonia. The World Health Organization (WHO) methodology for the interpretation of pediatric CXRs has not been evaluated beyond its intended application as an endpoint measure for bacterial vaccine trials. METHODS.: The Pneumonia Etiology Research for Child Health (PERCH) study enrolled children aged 1-59 months hospitalized with WHO-defined severe and very severe pneumonia from 7 low- and middle-income countries. An interpretation process categorized each CXR into 1 of 5 conclusions: consolidation, other infiltrate, both consolidation and other infiltrate, normal, or uninterpretable. Two members of a 14-person reading panel, who had undertaken training and standardization in CXR interpretation, interpreted each CXR. Two members of an arbitration panel provided additional independent reviews of CXRs with discordant interpretations at the primary reading, blinded to previous reports. Further discordance was resolved with consensus discussion. RESULTS.: A total of 4172 CXRs were obtained from 4232 cases. Observed agreement for detecting consolidation (with or without other infiltrate) between primary readers was 78% (κ = 0.50) and between arbitrators was 84% (κ = 0.61); agreement for primary readers and arbitrators across 5 conclusion categories was 43.5% (κ = 0.25) and 48.5% (κ = 0.32), respectively. Disagreement was most frequent between conclusions of other infiltrate and normal for both the reading panel and the arbitration panel (32% and 30% of discordant CXRs, respectively). CONCLUSIONS.: Agreement was similar to that of previous evaluations using the WHO methodology for detecting consolidation, but poor for other infiltrates despite attempts at a rigorous standardization process.

Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites.

BACKGROUND.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. RESULTS.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. CONCLUSIONS.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Safety of Induced Sputum Collection in Children Hospitalized With Severe or Very Severe Pneumonia.

BACKGROUND.: Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. METHODS.: IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. RESULTS.: A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%-0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as "possibly related" to the procedure. CONCLUSIONS.: The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a low-risk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety.

Microscopic Analysis and Quality Assessment of Induced Sputum From Children With Pneumonia in the PERCH Study.

BACKGROUND.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. METHODS.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. RESULTS.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. CONCLUSIONS.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia.

Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study.

BACKGROUND.: Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. METHODS.: The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)-defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. RESULTS.: CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%-64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. CONCLUSIONS.: Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge.

The Diagnostic Utility of Induced Sputum Microscopy and Culture in Childhood Pneumonia.

BACKGROUND.: Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. METHODS.: We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community-acquired pneumonia in children aged 1-59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed pneumonia and children categorized as nonpneumonia (due to the absence of prespecified clinical and laboratory signs and absence of infiltrate on chest radiograph). RESULTS.: One induced sputum sample was available for analysis from 3772 (89.1%) of 4232 suspected pneumonia cases enrolled in PERCH. Of these, sputum from 2608 (69.1%) met the quality criterion of <10 squamous epithelial cells per low-power field, and 1162 (44.6%) had radiographic pneumonia. Induced sputum microscopy and culture results were not associated with radiographic pneumonia, regardless of prior antibiotic use, stratification by specific bacteria, or interpretative criteria used. CONCLUSIONS.: The findings of this study do not support the culture of induced sputum specimens as a diagnostic tool for pneumonia in young children as part of routine clinical practice.