Tessa Davis. Petechiae in Children – the PiC Study, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.30782
Today the Lancet has published the long-awaited results of the Petechiae in Children (PiC) study. Team DFTB got our hands on a pre-publication copy to read, summarise, and analyse for you. So let’s get to it.
This PERUKI study by Waterfield et al. is a prospective, multicentre cohort study:
Why is this study needed?
We are all somewhat terrified of children with fever and a non-blanching rash. We don’t want to miss meningococcal sepsis. Current guidelines are based on data from before the introduction of the Meningococcal B (2015) and C (1999) vaccines and consider a prevalence of 10-20% of meningococcal infection in children with fever and non-blanching rash.
Who were the patients?
The paper looked at children under 18 years old presenting to 37 Paediatric Emergency Departments in the UK over a 16 month period. Children were included if they had a fever (>38oC) and new onset of a non-blanching rash or features suggestive of meningococcal infection. Children were excluded if they had a pre-existing haematological condition or if they already had a diagnosis of Henoch-Schonlein purpura.
1513 patients were screened. 179 were excluded due to not meeting the criteria, not consenting, or a language barrier. Five that were enrolled had incomplete data leaving 1329 children were enrolled and included – the median age was 24 months, and 59% were male. Most children were vaccinated with 73% having had at least one dose of the Meningococcal B vaccine, and 77% having had at least one dose of the Meningococcal C vaccine.
What was the intervention?
There was no intervention here. Included patients were recruited at the point of meeting the criteria, using ‘recruitment prior to consent‘ and then consent was obtained soon after (usually within 24 hours). Data were collected contemporaneously: patient symptoms, blood test results, and treatment. A positive case was identified by being positive on PCR, or with a positive growth from another body sample (e.g. blood culture, or CSF). Patients were also checked for re-attendance to the hospital within 7 days. Results were also confirmed with the Public Health Agency – as meningococcal disease is a notifiable condition, this was a good method of picking up any missed cases.
What were the outcomes measured?
The primary outcome was assessing the performance of eight clinical guidelines on identifying children with invasive meningococcal disease (NICE meningitis (CG102); NICE sepsis (NG51); London; Chester; Bristol; Nottingham; Newcastle-Birmingham-Liverpool; and Glasgow).
The secondary outcomes were: performance of the eight guidelines in identifying children with other bacterial infections; and also looking at a cost comparison of each of the eight guidelines.
What were the results?
Of all 1334 children, 86% had a blood test and 45% had antibiotics. For patients admitted to hospital, the median length of stay was one night. 11 patients were admitted to PICU (2%) and two patients died (<1%).
Eight of these 11 PICU patients had N. meningitidis as did both of the patients who died. Seven patients had invasive bacterial infection (five with pneumococcal infection, one with E. Coli, and one with Group A Strep).
19 (1%) of patients in the cohort had meningococcal disease. 17 of these had N. meningitidis B, one had N. meningitidis C, and one had N. meningitidis W. Overall there were 26 patients (2%) with invasive bacterial infection (19 with meningococcal disease and 7 with an invasive bacterial infection).
346 patients (26%) did not have standard testing, and of these 19 patients (5%) had one unplanned re-attendance within seven days. However, none of these required readmission, antibiotics, or bacterial infection.
And how did the guidelines do?
All eight guidelines identified all of the 19 cases of meningococcal disease and all 26 cases of invasive bacterial infection (so the sensitivity of all of them is 100%). Specificity varied though. The NICE sepsis guideline stratified every patient as having a bacterial infection and therefore had a specificity of zero, making it the lowest specificity out of all the guidelines (closely followed by NICE meningitis guidelines with a specificity of 1%). This strategy clearly has cost implications too which is why the two NICE guidelines were also the most expensive per patient (£660.41 for the NICE sepsis guidelines).
Coming out top of the guideline ranking was the Barts Health NHS Trust guideline with a sensitivity of 100%, a specificity of 36%, and a cost of £490.29. This makes it the most accurate and also the cheapest.
Here’s the Barts Health NHS Trust guideline:
What about when we don’t follow the guidelines?
In practice, the guidelines were adhered to in 46% of the patients in the cohort. Deviation from guidelines resulted in fewer antibiotics being given. However, it also resulted in two patients being discharged with early meningococcal disease (they were subsequently treated and did not need PICU admission). Clinician decision-making increased the specificity (i.e. clinicians treated fewer people with antibiotics who didn’t have an invasive bacterial infection), but unfortunately reduced the sensitivity to 89%. Clinician decision-making did have the lowest cost per patient.
You’ve heard the facts, but how good was the paper?
As Ken Milne says…let’s get nerdy (and consider the CASP checklist for cohort studies)
Does the study address a clearly focused issue?
Yes.
Was the cohort recruited in an acceptable way?
Research without prior consent was used to avoid recruitment delaying any treatment plans. However consent was obtained as soon as possible after inclusion in the study (usually within 24 hours).
Was exposure accurately measured to minimise bias?
Yes. Objective measurements were used for a blood test and PCR results. Risk factors for meningococcal disease are subjective and were based on contemporaneous clinical assessment – but this is what we do in practice so is a good reflection.
Was the outcome accurately measured to minimise bias?
Yes. Note, however, that two patients with meningococcal disease were not included – one was not enrolled and the other was deemed by local staff to be inappropriate for inclusion.
Have the authors identified all-important confounding factors?
Yes.
Was the follow up of the subjects complete and accurate?
Yes, and also results were also checked with the Public Health Agency which would have allowed pick up of any missed meningococcal positive results.
What are the results?
There is a 1% prevalence of meningococcal disease in a mainly immunised population of children with fever and a non-blanching rash. The Barts Health NHS Trust guideline was the most accurate out of all the guidelines and with the lowest cost per patient.
Do you believe the results?
Yes.
Can the results be applied to a local population?
Yes. However, they would not be transferrable to populations with lower rates of vaccine uptake or a higher disease prevalence. The data was not shared on whether those with meningococcal disease were unimmunised or not, and therefore it would be prudent to be more cautious if your patient is not vaccinated.
Do the results fit with the other evidence available?
Previous data was from prior to the meningococcal vaccination so this is the first and largest study since then.
What did the authors conclude and what can we take away from this study?
Since the advent of a vaccination programme and increased vaccine uptake, the rates of meningococcal disease are lower. Although previous data suggested 10-20% of children with fever and a non-blanching rash had meningococcal disease, in fact this study shows that only 1% had meningococcal disease.
Using a cautious guideline like NICE results in a lower specificity and higher cost. Tailored guidelines can increase the specificity and reduce the cost per patient without compromising on 100% sensitivity. The Barts Health NHS Trust guideline was the top performing guideline.
And finally, a comment from the authors themselves:
From Tom Waterfield:
“The Petechiae in Children study represents the best available evidence regarding the assessment and management of febrile children with non-blanching rashes in the UK and clearly demonstrates that a lighter touch, tailored approach, is favourable to a test/treat all approach as currently advised by NICE. Moving to a tailored approach will reduce the need for invasive procedures, improve antimicrobial stewardship and save money.
In vaccinated populations where the prevalence of invasive meningococcal disease is low the presence of Petechiae alone should no longer be viewed as a red flag and should not be used to justify immediate treatment with broad spectrum antibiotics. The emphasis and teaching should shift away from worrying about all non-blanching rashes with greater emphasis on the importance of identifying purpuric rashes as they confer the greatest risk of invasive meningococcal disease.
Finally the PiC study demonstrates the importance of well designed prospective research studies in identifying risk factors for sepsis. Traditional approaches utilising retrospective reporting of symptoms from convenience samples of children with sepsis results in an over estimation the risks. This in turn leads to the development of overly aggressive clinical practice guidelines that are poorly adhered to. “
Note from Tessa: I am an employee of Barts Health but was not involved in the PiC study or in writing the Barts Health NHS Trust guideline.
Searching for sepsis
Anna Peters. Searching for sepsis, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.31160
The child with “fever” is one of the most common paediatric presentations to the emergency department. Most of these children are managed conservatively with parental reassurance and discharged home with a safety net identifying red flags. However, failing to identify those with “sepsis” has devastating consequences. How often do we get it wrong or worry about getting it wrong? We’d all love an evidence-based clear cut path for flagging and managing febrile children at risk of sepsis. Currently the approach in the UK is predicated on the NICE SEPSIS (NG 51) screening system which has anecdotally performed poorly with concerns it is poorly specific (i.e lots of false positives). Nijman and colleagues aimed to objectively assess the impact of the NICE Sepsis screening approach in children.
Nijman RG, Jorgensen R, Levin M, Herberg J and Maconochie IK. Management of Children With Fever at Risk for Paediatric Sepsis: A Prospective Study in Paediatric Emergency Care. Frontiers in Pediatric Care 2020; 8:548154. doi: 10.3389/fped.2020.548154
The lead authors looked at the various warning signs of serious infections in febrile children presenting to PED. Their aim was to then determine these children’s risk of having sepsis and to evaluate their subsequent management.
Who did they study?
Over 5000 children (5156 to be exact) aged 1 month to 16 years old presenting with fever over a period of 9 months from June 2014–March 2015 in a single PED at St Mary’s Hospital, UK were analysed. Febrile children with no warning signs of sepsis were then excluded from the final cohort. The second largest group excluded from the final cohort was children with a complex medical history (n=119). The decision to exclude this particular cohort is important given that ‘complex medical patients’ are more likely to have sepsis. The authors make the valid point that this group has features very different from the intended cohort, such as having different management plans in the context of fever. After these exclusions, plus a few further exclusions (lack of consent, lack of complete data or excluded because the child didn’t have any warning signs) the final cohort was of 1551 children.
What did they do?
They first looked at the numbers of febrile children with tachycardia and tachypnea by using APLS and NICE (the National Institute of Healthcare Excellence) thresholds. Subsequently, they looked at the numbers of febrile children fulfilling sepsis criteria by using well-known sepsis screening tools (NICE traffic light guidelines, SIRS, qSOFA, Sepsis Trust UK trigger criteria).
All the data for this study (vital signs, clinical signs and symptoms, tests, working diagnosis, need for hospital admission, timeliness of interventions) were collected electronically, having been recorded prospectively for all febrile children.
What did they look for?
As a primary outcome the study determined:
Secondary outcomes included the compliance of clinicians with the paediatric sepsis 6 care bundle (PS6), what clinical interventions were and were not used from this care bundle and the timeliness of the interventions that were undertaken
What did they find?
Almost a third of children aged 1 month to 16 years who presented to the PED had fever (28% to be exact).
41% of these febrile children had one or more warning signs (our study population).
The incidence of IBI was 0.39%. Of these children, only 0.3% required PICU admission.
This meant that using the sepsis guideline recommendations, 256 children would need to be treated to catch one IBI. Another way of saying this is the number needed to treat was 256. NNT for any serious outcome was 141.
How did the sepsis guidelines fare?
The thresholds for tachycardia and tachypnoea yielded a high false positive rate.
Adding sepsis criteria to predict the presence of a serious bacterial infection (SBI), IBI or PICU admission was also unreliable, with a lot of false positives.
Lactate levels were not significantly associated with the decision to give IV fluid bolus or presence of SBI, IBI or PICU admission. There WAS, however, a significant association between lactate levels and hospital admission.
Looking at the Paediatric Sepsis 6 Interventions, although many children triggered, two-thirds (65%) of the children with PS6 warning signs had none of PS6 interventions. And when it came to the ‘golden hour? Only a third (36%) of children with IBI or PICU admission received all PS6 interventions in the ‘golden hour with only 39 children (2%) receiving a fluid bolus.
What does this all mean?
It is important to note that this study was only conducted in one single PED and in a time period that was before the NICE sepsis guidelines were formally implemented into practice. The data was collected for this study via an electronic interface. While large amounts of data can be collected rapidly there can sometimes be gaps, either due to extraction issues or brevity on the behalf of clinicians that don’t give a comprehensive picture. Data were also only taken from initial triage and not from any clinical deterioration in the ED. Given that acuity changes over time, especially in children with fever, this may have missed subsequent clinical change although is a pragmatic approach given the way that sepsis screening tools are applied in nearly all Emergency Departments.
Numbers needed to treat were exceptionally high. Despite the allure of a protocol-based screening and management pathway, the benefits of catching true sepsis early must be weighed against the possible unwanted effects of overtreating or overdiagnosing mostly well children in a potentially resource-stretched PED. The study really does highlight the difficulties we face when screening for a septic child in a generally well cohort, the ‘needle in a haystack’.
Essentially, what this study shows us is that serious infections are rare and most children who are categorised as ‘at risk of sepsis’ can in fact be managed conservatively with little intervention other than observation. It is clear that our current guidelines have very poor specificity; and while they tell us to investigate and treat lots of children, a lot of the time we as clinicians choose to rely on our clinical judgement and essentially ‘do nothing’. Observation and good clear red flagging must not be underestimated. Instead of continuing to research more and better early predictors of sepsis, such as point of care biomarkers, perhaps we should be looking at this from another angle. The focus of the lens can also be flipped; we also need more research on how it can be safe NOT to do anything too.
We’ll end with some thoughts from the authors
The Infections in Children in the Emergency Department (ICED) study is a single centre, prospective observational study. The study describes unique and carefully curated clinical data of febrile children with warning signs of sepsis, from a period prior to the implementation of the NICE sepsis guidelines.
Our results confirm what many paediatricians dealing with acutely unwell febrile children already suspected: that many febrile children have warning signs of sepsis, but that the large majority have non-life threatening infections.
Our findings will hopefully contribute to ongoing discussions about the use of sepsis screening tools in paediatric emergency medicine. Our study makes it clear that current tools lead to a high number of false positive cases, and their usefulness in routine clinical care in paediatric emergency medicine should be questioned. Escalation to senior decision makers of all children with warning signs of sepsis should be aspired, but is seldomly feasible in clinical practice and with unproven impact on reducing missed cases and optimising clinical care for the total cohort of febrile children.
Although all children with serious infections would have been detected by the various sepsis tools, it is now evident that we need better tools to more selectively identify children at the highest risk of sepsis. Future studies should explore the utility of machine learning as well as the potential of combining clinical signs and symptoms with point of care biomarkers.
Ruud Nijman