Identifying early symptoms associated with a diagnosis of childhood, adolescent and young adult cancers: a population-based nested case-control study.

BACKGROUND: Childhood, teenage and young adult (CTYA, 0-24 years) cancers are rare and diverse, making timely diagnosis challenging. We aim to explore symptoms and symptom combinations associated with a subsequent cancer diagnosis and to establish their timeframe. METHODS: Using the QResearch Database, we carried out a matched nested case-control study. Associations between pre-specified symptoms encountered in primary care and a subsequent diagnosis of any cancer were explored using conditional logistic regression. Median diagnostic intervals were used to split symptoms into "late" and "early" timeframes to identify relevant early symptoms. RESULTS: 3186 cases and 50,576 controls were identified from a cohort of 3,424,771 CTYA. We identified 12 novel associations, of which hemiparesis [OR 90.9 (95%CI 24.7-335.1), PPV = 1.6%], testicular swelling [OR 186.7 (95%CI 86.1-404.8), PPV = 2.4%] and organomegaly [OR 221.6 (95%CI 28.3-1735.9), PPV = 5.4%] had significant positive predictive values (PPV). Limb pain, a known marker of serious illness in children, was a recurrent early symptom across cancer subtypes. Similar clinical presentations were observed across childhood and TYA cancers. DISCUSSION: Using the largest cohort to date, we provide novel information on the time-varying predictive utility of symptoms in the diagnosis of CTYA cancers. Our findings will help to raise clinical and public awareness of symptoms, stratify those at higher-risk and ultimately aid earlier diagnosis.

Presentation of B-cell lymphoma in childhood and adolescence: a systematic review and meta-analysis.

BACKGROUND: The diagnosis of B-cell lymphoma, one of the commonest cancers seen in childhood and adolescence, is challenging. There is a crucial need to identify and delineate the prevalence of associated symptoms in order to improve early diagnosis. AIMS: To identify clinical presentations associated with childhood and adolescent B-cell lymphomas and estimate symptom prevalence. METHODS: A systematic review of observational studies and meta-analysis of proportions was carried out. Medline and EMBASE were systematically searched, with no language restrictions, from inception to 1st August 2022. Observational studies with at least 10 participants, exploring clinical presentations of any childhood and adolescent lymphoma, were selected. Proportions from each study were inputted to determine the weighted average (pooled) proportion, through random-effects meta-analysis. RESULTS: Studies reported on symptoms, signs and presentation sites at diagnosis of 12,207 children and adolescents up to the age of 20. Hodgkin's lymphoma most frequently presented with adenopathy in the head-and-neck region (79% [95% CI 58%-91%]), whilst non-Hodgkin's lymphoma presented abdominally (55% [95% CI 43%-68%]). Symptoms associated with lymphoma included cervical lymphadenopathy (48% [95% CI 20%-77%]), peripheral lymphadenopathy (51% [95% CI 37%-66%]), B-symptoms (40% [95% CI 34%-44%]), fever (43% [95% CI 34%-54%]), abdominal mass (46% [95% CI 29%-64%]), weight loss (53% [95% CI 39%-66%]), head-and-neck mass (21% [95% CI 6%-47%]), organomegaly (29% [95% CI 23%-37%]), night sweats (19% [95% CI 10%-32%]), abdominal pain (28% [95% CI 15%-47%]), bone pain (17% [95% CI 10%-28%]) and abnormal neurology (11% [95% CI 3%-28%]). CONCLUSION: This systematic review and meta-analysis of proportions provides insight into the heterogeneous clinical presentations of B-cell lymphoma in childhood and adolescence and provides estimates of symptom prevalence. This information is likely to increase public and clinical awareness of lymphoma presentations and aid earlier diagnosis. This review further highlights the lack of studies exploring childhood and adolescent lymphoma presentations in primary care, where patients are likely to present at the earliest stages of their disease.

Neuraminidase inhibitors for preventing and treating influenza in children.

BACKGROUND: During epidemic years, influenza attack rates in children exceed 40%. Options for prevention and treatment include the neuraminidase inhibitors: zanamivir and oseltamivir. OBJECTIVES: To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza infection in children. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005); MEDLINE (1966 to April 2005); EMBASE (January 1980 to December 2004); the on-line GlaxoSmithKline Clinical Trials Register; the on-line Roche Clinical Trial Protocol Registry and Clinical Trial Results Database (August 2005); and reference lists of articles. We also scrutinised web sites of European and US regulatory bodies and contacted manufacturers and authors. SELECTION CRITERIA: Double-blind, randomised, controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs in children less than 12 years of age. Additional safety and tolerability data from other sources were also included. DATA COLLECTION AND ANALYSIS: Four authors applied the inclusion criteria to the retrieved studies, assessed trial quality and extracted data. Data were analysed separately for oseltamivir and zanamivir. MAIN RESULTS: Three trials involving 1500 children with a clinical case definition of influenza were included, of whom 977 had laboratory-confirmed influenza. Overall, trial quality was good. Oseltamivir reduced the median duration of illness by 26% (36 hours) in healthy children with laboratory-confirmed influenza (P value less than 0.0001). The reduction was only 7.7% (10 hours) in 'at risk' (asthmatic) children, and this did not reach statistical significance (P value = 0.54). Zanamivir reduced the median duration of illness by 24% (1.25 days) in healthy children with laboratory-confirmed influenza (P value less than 0.001). No data in 'at risk' children were available. Only oseltamivir produced a significant reduction in the complications of influenza (particularly otitis media), although there was a trend to benefit for zanamivir. We identified one randomised, controlled trial of oseltamivir for the prevention of influenza transmission in households, reporting data from 222 paediatric contacts. Where index cases had laboratory-confirmed influenza, a protective efficacy of 55% was observed, but this did not reach statistical significance (P value = 0.089). The adverse events profile of zanamivir was no worse than placebo, but vomiting was more common in children treated with oseltamivir. AUTHORS' CONCLUSIONS: Neuraminidase inhibitors are effective in shortening illness duration in healthy children with influenza, but efficacy in 'at risk' children remains to be proven. Oseltamivir is also effective in reducing the incidence of secondary complications, and may be effective for influenza prophylaxis.

Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review.

BACKGROUND: We aimed to assess evidence of efficacy and effectiveness of live attenuated and inactivated influenza vaccines in children up to 16 years of age. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE Biological Abstracts, and Science Citation Index to June, 2004, in any language, and contacted vaccine manufacturers and authors of relevant studies to identify additional data. We included randomised, cohort, and case-control studies comparing efficacy of vaccines against influenza (reduction in laboratory-confirmed cases), effectiveness of vaccines against influenza-like illness (reduction in symptomatic cases), or both, with placebo or no intervention. We analysed the following outcomes: influenza, influenza-like illness, admissions, school absences, complications, and secondary transmission. FINDINGS: We included 14 randomised controlled trials, eight cohort studies, one case-control study, and one randomised controlled trial of intraepidemic use of the vaccines. Live attenuated influenza vaccines had 79% efficacy and 38% effectiveness in children older than 2 years compared with placebo or no immunisation. Inactivated vaccines had lower efficacy (65%) than live attenuated vaccines, and in children aged 2 years or younger they had similar effects to placebo. Effectiveness of inactivated vaccines was about 28% in children older than 2 years. Vaccines were effective in reducing long school absences (relative risk 0.14 [95% CI 0.07-0.27]). Studies assessing the effects of vaccines against secondary cases, lower-respiratory tract disease, acute otitis media, and hospital stay suggested no difference with placebo or standard care, but lacked statistical power. INTERPRETATION: Influenza vaccines (especially two-dose live attenuated vaccines) are efficacious in children older than 2 years. Efficacy and effectiveness of the vaccines differed strikingly. Only two small studies assessed the effects of influenza vaccines on hospital admissions and no studies assessed reductions in mortality, serious complications, and community transmission of influenza. If influenza immunisation in children is to be recommended as public-health policy, large-scale studies assessing such important outcomes and undertaking direct comparisons of vaccines are urgently needed.

Vaccines for preventing influenza in healthy children.

BACKGROUND: In children and adults the consequences of influenza are mainly absences from school and work, however the risk of complications is greatest in children and people over 65 years old. OBJECTIVES: To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children; assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness) and document adverse events associated with receiving influenza vaccines. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005); OLD MEDLINE (1966 to 1969); MEDLINE (1969 to December 2004); EMBASE (1974 to December 2004); Biological Abstracts (1969 to December 2004); and Science Citation Index (1974 to December 2004). We wrote to vaccine manufacturers and a number of corresponding authors of studies in the review. SELECTION CRITERIA: Any randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years old. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: Fifty-one studies involving 263,987 children were included. Seventeen papers were translated from Russian. Fourteen RCTs and 11 cohort studies were included in the analysis of vaccine efficacy and effectiveness. From RCTs, live vaccines showed an efficacy of 79% (95% confidence interval (CI) 48% to 92%) and an effectiveness of 33% (95% CI 28% to 38%) in children older than two years compared with placebo or no intervention. Inactivated vaccines had a lower efficacy of 59% (95% CI 41% to 71%) than live vaccines but similar effectiveness: 36% (95% CI 24% to 46%). In children under two, the efficacy of inactivated vaccine was similar to placebo. Thirty-four reports containing safety outcomes were included, 22 including live vaccines, 8 inactivated vaccines and 4 both types. The most commonly presented short-term outcomes were temperature and local reactions. The variability in design of studies and presentation of data was such that meta-analysis of safety outcome data was not feasible. AUTHORS' CONCLUSIONS: Influenza vaccines are efficacious in children older than two years but little evidence is available for children under two. There was a marked difference between vaccine efficacy and effectiveness. That no safety comparisons could be carried out emphasizes the need for standardisation of methods and presentation of vaccine safety data in future studies. It was surprising to find only one study of inactivated vaccine in children under two years, given recent recommendations to vaccinate healthy children from six months old in the USA and Canada. If immunisation in children is to be recommended as public-health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required.

A children's acute respiratory illness scale (CARIFS) predicted functional severity and family burden.

OBJECTIVE: The Canadian Acute Respiratory Illness and Flu Scale (CARIFS) was developed to measure illness severity in children with acute respiratory infection. The objective of this study was to evaluate its performance in a European primary care setting. STUDY DESIGN AND SETTING: 178 children (median age 3 years) with cough and fever were recruited in UK general practice. Perceived severity of illness at recruitment was recorded by parents, doctors, and nurses. Parents also completed an illness diary, including the CARIF scale, until their child had recovered. In-depth interviews were conducted with 24 parents. RESULTS: Parents found CARIFS relatively easy and quick to complete (78% of parents returned a fully completed diary covering the duration of the illness), internal consistency was high (minimum item correlation with total score 0.22; overall Cronbach's alpha statistic 0.85), and responsiveness to improvement in health was good (observed effect size of 0.45 at 8 h). At presentation, however, neither the overall CARIFS score nor the clinical element of the score correlated with physician assessment of clinical severity. CONCLUSION: Of the three recognized domains of illness severity, CARIFS appears to be a good and valid measure of functional severity and burden of illness to the parent but it may not be a good measure of physiological severity.

Neuraminidase inhibitors for preventing and treating influenza in children.

BACKGROUND: During epidemic years, influenza attack rates in children exceed 40%. Options for prevention and treatment include immunisation, amantadine and rimantadine, and the neuraminidase inhibitors: zanamivir and oseltamivir. OBJECTIVES: Our objective was to assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prophylaxis of influenza infection in children. SEARCH STRATEGY: We searched the Cochrane Acute Respiratory Infections Group Specialised Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the GlaxoSmithKline Clinical Trials Register, generally from inception through to December 2002. We also screened the references of retrieved articles and scrutinised relevant web sites. We also screened references of retrieved articles and other systematic reviews, scrutinised web sites of European and US regulatory bodies, and contacted manufacturers and authors. SELECTION CRITERIA: Double-blind randomised controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs in children less than 12 years of age. Additional safety and tolerability data from other sources were also included. DATA COLLECTION AND ANALYSIS: Four reviewers applied the inclusion criteria to the retrieved studies, assessed trial quality and extracted data. Data were analysed separately for oseltamivir and zanamivir. MAIN RESULTS: We identified three randomised controlled trials reporting data from 1500 children with a clinical case definition of influenza, of whom 798 had laboratory confirmed influenza infection. Two were trials of oseltamivir (in healthy children and in children with asthma) and one was a trial of zanamivir (in healthy children). Overall, trial quality was good. Oseltamivir reduced the median duration of illness by 26% (36 hours) in previously healthy children with laboratory confirmed influenza (p < 0.0001) and by 17% (21 hours) in the intention-to-treat population (p = 0.0002). Zanamivir reduced the median duration of illness by 24% (1.25 days) in previously healthy children with laboratory confirmed influenza (p < 0.001) and by 10% (0.5 days) in the intention-to-treat population (p = 0.011). Both drugs also significantly reduced the time to return to normal activity. Only oseltamivir produced a significant reduction in the complications of influenza (particularly otitis media), although there was a trend to benefit for zanamivir. No data on the use of zanamivir in 'at risk' children were available. The reduction in time to resolution of illness in 'at risk' children (with asthma) treated with oseltamivir was not statistically significant. Although we identified three trials of neuraminidase inhibitors in the prevention of influenza in families (including children), Roche and GlaxoSmithKline were not willing to break-out data for paediatric populations, and so no data were eligible for inclusion in the review. The adverse events profile of zanamivir was no worse than placebo and we found no reports of zanamivir-induced bronchospasm in children. Vomiting was more common in children treated with oseltamivir (p = 0.008), but study withdrawals were similar (<2%) between oseltamivir and placebo. REVIEWER'S CONCLUSIONS: Neuraminidase inhibitors were effective in shortening illness duration and hastening return to normal activity in previously healthy children with a clinical or laboratory diagnosis of influenza. Oseltamivir was effective in reducing the incidence of secondary complications. Efficacy in 'at risk' children remains to be proven. The drugs are safe, but oseltamivir can cause vomiting.

Why do children hospitalised with pneumonia not receive antibiotics in primary care?

BACKGROUND: Although antibiotics are recommended for the primary care management of community-acquired pneumonia, a recent UK study reported that most children admitted to hospital had not received antibiotics. OBJECTIVE: To describe primary care antibiotic use for children subsequently hospitalised with community-acquired pneumonia. DESIGN/METHODS: A case series of 280 children <5 years old hospitalised with pneumonia in Auckland, New Zealand. Pneumonia was defined as an acute illness with cough or respiratory distress, the presence of tachypnoea or indrawing and an abnormal chest radiograph. Receipt of antibiotics was determined by parental report and medical record review. RESULTS: Fewer than half (108, 39%) of the children had received an antibiotic before hospital admission. For 60 children (21%) there had been no opportunity to prescribe because the illness evolved rapidly, resulting in early hospital admission. For the remaining 112 children (40%) an opportunity to receive antibiotics was missed. The parent failed to obtain the antibiotic prescribed for 23 children (21% of 112), but in 24 children (21%) pneumonia was diagnosed but no antibiotic prescribed and in a further 28 children (25%) the diagnosis was not made despite parental report of symptoms suggesting pneumonia. Missed opportunities to prescribe were not associated with increased overall severity of symptoms at hospital presentation but were associated with an increased risk of: focal chest radiological abnormalities (rate ratio (RR)=2.14; 95% CI 1.49 to 2.83), peripheral leucocytosis >15×10(9)/l (RR=2.29; 95% CI 1.61 to 2.98) and bacteraemia (RR=6.68, 95% CI 1.08 to 58.44). CONCLUSIONS: Young children with community-acquired pneumonia may not receive an antibiotic before hospital admission because the illness evolves rapidly or the prescribed medicine is not given by parents. However, missed opportunities for appropriate antibiotic prescribing by health professionals in primary care appear to be common.

Why children die: avoidable factors associated with child deaths.

AIM: To describe the avoidable factors associated with child deaths identified by a confidential enquiry. METHOD: In the Centre for Maternal and Child Enquiries confidential enquiry, a sample (13%) of cases was subjected to case note review by multidisciplinary panels attempting to identify avoidable factors associated with the deaths. Cases were selected blindly but in equal numbers from predetermined age bands and participating regions. The anonymised records were reviewed in regions remote to where the child lived and died. Panel composition, conduct and reporting were standardised. RESULTS: 119 of 126 cases reviewed by enquiry panels had sufficient information to determine avoidable factors. These cases were comparable with the whole dataset in terms of sex and causes of death. 31 (26%) of 119 had avoidable factors that were predominantly related to individuals or agencies with a direct responsibility to the child. 51 (43%) of 119 were defined as potentially avoidable. In all, 130 factors were considered in relation to these 82 cases, and 64% of the factors were healthcare related. Avoidable factors were more likely where life-limiting illness was not present. Recurring avoidable factors included failure to recognise serious illness at the point of presentation and death occurring in children who had been lost to follow-up. CONCLUSION: Child Death Overview Panels now have the responsibility to review child deaths using similar methods but relying upon data forms rather than the case record. Analysis of contributory factors on a national scale has the potential to improve understanding of why children die and indicate strategies to reduce child mortality.

Deriving temperature and age appropriate heart rate centiles for children with acute infections.

OBJECTIVES: To describe the reference range for heart rate in children aged 3 months-10 years presenting to primary care with self-limiting infections. DESIGN: Cross-sectional study of children presenting to primary care with suspected acute infection. Heart rate was measured using a pulse oximeter and axillary temperature using an electronic thermometer. Centile charts of heart rates expected at given temperatures for children with self-limiting infections were calculated. SETTING: Ten general practice surgeries and two out-of-hours centres in England. PARTICIPANTS: 1933 children presenting with suspected acute infections were recruited from in-hours general practice surgeries (1050 or 54.3%) or out-of-hours centres (883 or 45.7%). After excluding children who subsequently attended hospital and those without a final diagnosis of acute infection, 1589 children were used to create the centile charts of whom (859 or 54.1%) had upper respiratory tract infections and (215 or 13.5%) non-specific viral illness. MAIN OUTCOME MEASURES: Median, 75th, 90th and 97th centiles of heart rate at each temperature level. RESULTS: Heart rate increased by 9.9-14.1 bpm with each 1 degrees C increment in temperature. The 50th, 75th, 90th and 97th centiles of heart rate at each temperature level are presented graphically. CONCLUSIONS: Age-specific centile charts of heart rates expected at different temperatures should be used by clinicians in the initial assessment of children with acute infections. The charts will identify children who have a heart rate higher than expected for a given temperature and facilitate the interpretation of changes in heart rate on reassessment. Further research on the predictive value of the centile charts is needed to optimise their diagnostic utility.

How well do vital signs identify children with serious infections in paediatric emergency care?

OBJECTIVES: To determine whether vital signs identify children with serious infections, and to compare their diagnostic value with that of the Manchester triage score (MTS) and National Institute for Health and Clinical Excellence (NICE) traffic light system of clinical risk factors. DESIGN: Prospective cohort of children presenting with suspected acute infection. We recorded vital signs, level of consciousness, activity level, respiratory distress, hydration and MTS category. SETTING: Paediatric assessment unit at a teaching hospital in England. PARTICIPANTS: 700 children (median age 3 years), of whom 357 (51.0%) were referred from primary care, 198 (28.3%) self-referrals and 116 (16.6%) emergency ambulance transfers. Just over half (383 or 54.7%) were admitted. MAIN OUTCOME MEASURES: Severity of infection categorised as serious, intermediate, minor or not infection. RESULTS: Children with serious or intermediate infections (n = 313) were significantly more likely than those with minor or no infection (n = 387) to have a temperature >or=39 degrees C, tachycardia, saturations 2 seconds. Having one or more of temperature >or=39 degrees C, saturations