Sepsis 2020

Cite this article as:
Emma Lim. Sepsis 2020, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32392

Where do we start?

Fever and suspected sepsis is our bread and butter. This post will take you through a whirlwind 2020 sepsis update. We’ll cover what sepsis is, how to recognize deterioration and the recent management updates in light of the new 2020 International Surviving Sepsis Campaign Guidelines1.

For me, it is all about “What keeps me up at night?” and there are two things I worry about. The first is missing cases of suspected sepsis.  Think back to all those hot, miserable children you sent home over your career and the heart sink you feel when someone says, “Remember that child you sent home yesterday?”.  My second worry is making bad choices; making mistakes about how much fluid to give or which antibiotics to choose or when to start inotropes.

What is sepsis?

Let’s start at the beginning. How do you get sepsis? A bacterial or viral infection causes a systemic, inflammatory response syndrome (SIRS). We are used to seeing children who have a fever and a fast heart rate or respiratory rate and a raised white cell count, for example with bronchiolitis. A certain proportion of those children will go on to get sepsis but not a lot.

Spotting sepsis in the paediatric ED is like a game of Where’s Wally: there are a whole lot of hot febrile children with accompanying hot cross parents. Fever is common but sepsis is rare – at a quick glance they all look like Wally, but, of course, there is actually only one real one and it takes a bit of time and patience to find him. It is the same with all those children with fever: around 55% have self-limiting viral infections, only 7-13% have serious bacterial infection (SBI)2-4 and only 1% have sepsis. The picture’s different in PICU; 10% of PICU admissions are for sepsis. The 2015 SPROUT study5 looked at 569 children in PICU with sepsis (8.2% point prevalence). 40% were caused by respiratory infections and 19% percent by bloodstream infections. A quarter (25%) of them died.

That quote “7-13% of febrile children have a serious bacterial infection” seems high. There are predefined criteria (such as pneumonia, urinary tract infection, meningitis, osteomyelitis, septic arthritis), but in a reductionist sense, sepsis is any infection that makes a child so unwell that they are admitted to hospital for more than 72 hours and need IV antibiotics. But, the need for admission is very subjective and dependent on the experience of the doctor and the parents’ level of concern.  The goal posts are constantly shifting.  Ten years ago, we would admit children with osteoarticular infections for 6 weeks of IV antibiotics. Now they can be in and out within 72 hours (with most of their course given orally). That doesn’t mean the infections have got less severe, it’s just that our treatments have changed.  And is a urinary tract infection over a year of age really a serious infection?  Most will get treated with a short course of oral antibiotics, as will children with pneumonia.  Because that’s a whole other controversy; reporting focal consolidation on a X ray is art not science and has been shown to be famously unreliable in double blind studies.  So if we remove children who have simple pneumonia, urinary tract infections in older children,  skin and soft tissue infections that do not have positive cultures, the number of true SBI is quite a lot less than the quoted 1 in 10.

Unbelievably, there is no good definition of ‘sepsis’ in paediatrics6, so we tend to use the adult Sepsis 3 definition7 which states:

“Sepsis is life threatening organ dysfunction caused by a dysregulated host immune response to infection including renal, respiratory, hepatic dysfunction or metabolic acidosis”. A small proportion of children or young people with sepsis will go into septic shock, where shock is defined as hypotension, or impaired perfusion requiring inotropes with a higher risk of death than sepsis.”

This doesn’t really help us spot sepsis early enough to prevent these children going into shock.  So far, there is no reliable way of pinpointing who these children are. However, there is some exciting news. 2020 has brought us new international evidence-based guidelines for the management of septic shock and sepsis associated organ dysfunction in children; the Surviving Sepsis Campaign.

This has been a huge piece of work by an incredible transatlantic consortium, including Mark Peters (for the horse’s mouth listen to our latest RCPCH Paediatric Sepsis Podcasts). I am going to take you through some of these recommendations, but I think everybody should read it themselves.  The consortium took 3 years and reviewed over 500 papers, but you only have to read this one paper, so go on, make your life easy!  

Spotting sepsis

Recommendation number one. In children who present acutely well, “we suggest implementing systematic screening for timely recognition.”

Take note of the word suggest. This means there is some, but not definitive, evidence. We all recognise systematic screening for sepsis is a huge problem for paediatricians. Most children with a fever have a self-limiting viral infection, and many of these children will have fever, tachycardia and tachypnoea. But most do not have sepsis.  However, if we use the UK-based NICE high-risk ‘Red Flag’ criteria, these children are all flagged as potentially having sepsis. They over-trigger, shown by a 2020 paper by Ruud Nijman which showed that 41% of all febrile children in PED present with warning signs of sepsis3. If you look at this paper in some detail, 50% of children aged 1-2 years triggered the NICE red high-risk category for tachycardia alone. This mirrors data from a local audit from the Great North Children’s Hospital Emergency Department, conducted between April and June of 2017. Of 868 patients, 5% had serious bacterial infections, but 50% triggered NICE high-risk criteria. Sam Romaine from Alderhey Children’s Hospital, and part of Enitan Carrol’s group, looked at 12,241 patients and again, 55% triggered NICE high risk criteria8. For a full critical review of Ruud’s paper, take a look at our Searching for Sepsis post.

The NICE high risk criteria have a very high sensitivity but limited specificity, which means although they ‘over-trigger’, if a child doesn’t have any red flags then they are potentially ‘good to go’, helping inform safe discharge.

Is there a better score?

For a long time, adults have used the Q-SOFA score, a quick sepsis related organ failure assessment. Typically, this adult score has performed poorly in children. Enitan Carroll’s group have looked at a modified Q-SOFA score called the LQ-SOFA score (L for Liverpool), modified to predict critical care admission rather than sepsis. Critical care admission is a more common outcome than sepsis, particularly relevant because this helps us understand which children are at risk of deterioration. The modified score, is made up of four simple, straightforward criteria, including capillary refill, AVPU (that’s Alert, Verbal, only to Pain or Unresponsive), heart rate and respiratory rate, purposefully not including blood pressure, making this quick and easy to use as a screening tool. But what did they find? Carroll’s group compared five different scores that could help us predict sepsis or deterioration: lactate, CRP, adult Q-SOFA, NICE and LQ-SOFA. Lactate performed the least well, CRP and Q-SOFA a little bit better, NICE high-risk criteria better again, but best of all was the LQ-SOFA score. 

This work suggests that there are more sensitive tools out there, but these need to be combined with some way of de-escalating children who trigger because most of these children have a SIRS response from a self-limiting viral infection and not sepsis. De-escalation is usually done by ‘a senior review,’ with the intention of differentiating the hot and bothered child who has a viral infection from early sepsis.

Listen to parents

There are many examples of systematic screening protocols, the best being electronic scores. But they are not perfect.  Most importantly, the good ones listen to parents. Parental concern or health professional concern is particularly important for children with complex medical conditions: neurodisability, recurrent chest infections, those with indwelling lines or fed by gastrostomy. These children often don’t have typical signs and symptoms that health care professionals associate with infections or sepsis, often presenting with nothing more than their parents saying that they’re not well or not quite themselves. These children can be hypothermic (due to hypothalamic dysfunction) and run ‘cold’ so when they get an infection, their temperature may goes up to ‘normal’ (37 degrees), not triggering at all. The presenting signs can be very, very subtle like not tolerating their feed, or vomiting, or they may just be miserable and unhappy. This is why any escalation tool or score must in some way include parental concern. The NICE sepsis guidelines from 2017 tells us to pay particular attention to ‘concerns expressed by parents, families or carers’, for example, changes from usual behaviour.’  We must not underestimate the expertise of parents and we should incorporate them into the team of people caring for their children.

Doctors can be wary of parental concern but if we look at a systematic review of family-initiated escalation of care for the deteriorating patients in hospital, we can see that this wariness is unfounded.  Gill et al 20169 looked at a systematic review of ten articles (all descriptive studies) over ten years evaluating response systems for patients and families; five described a triaged response; five reported systems for families to directly activate the rapid response team. There were a total of 426 family-initiated calls, range 0.17 to 11 per month, with no deaths reported. All calls were deemed to be appropriate and three calls resulted in intensive care unit admissions.”

I believe there is evidence that parents only escalate when they need to.  As one of our parents of a child with a complex medical condition said;

Please listen to us when we say something is not right, we can see subtle changes in children, in our children, in their health and behaviour. That may not be apparent to the casual observer or even health professionals like yourselves and children like them cannot speak for themselves. Therefore, as parents, we have to ensure that we advocate for them in the strongest possible terms. We do not think we are better than the team, nor are we full of our own importance. But we are simply trying to give a voice to our children as they don’t have one of their own.”

What do you do next?

The Surviving Sepsis campaign developed a management algorithm for children, and while it is useful, there’s a lot of information, for many different teams in a small space. Firstly, when you look closely, the lower half (in black) is actually all about management in a Paediatric Intensive Care (PICU) setting -treatment of refractory shock and advanced haemodynamic monitoring. For paediatric emergency physicians, there is a lot that has to happen first! Let’s break it down.

The first thing that the international guidelines asks us to do is get intravenous or intraosseous access. Please only have three tries at getting intravenous access and if this isn’t successful, go straight to intraosseous access. It’s a great safe route and can be much easier to get than intravenous especially in children with complex medical conditions whom may be difficult to cannulate. Although it may feel like using an IO in an awake child will be traumatic , flushing with 0.5mg/kg of 2% lignocaine before you infuse fluids, antibiotics and other drugs, will reduce the pain.

Test, tests, tests

Recommendation number two. Get a blood culture.

This should always be your next priority, as long as it does not delay treatment. Let’s just think for a moment about blood cultures. Blood cultures are old technology. They were developed in the 1950s and have not really changed since. Traditionally, blood cultures are read at 48 hours but often don’t give any definitive answer. The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS)10 was a prospective, multi-centre, cohort study of 2844 children under 18  with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 hospitals across Europe and incredibly in 50% of patients the causative organism remained unidentified! Alasdair Munroe explains more in his blood culture post.

What we really want is a point of care test, a test that takes less than 60 minutes, that can quickly differentiate between viral and bacterial infections at the child’s bedside11. Andreola et al12 (and more recent studies by Ruud Nijman again) looked at febrile children and infants in Emergency Departments and this is what they found:

White cell counts, we know, are not helpful. A raised white cell count has poor sensitivity and specificity, so while CRP is better and PCT better still there is room for improvement.  All these tests have problems with sensitivity which means there is still going to be a worrying number of falsely negative tests.  We know this, for example, in children with diseases that progress quickly like meningococcaemia or sepsis who can have normal inflammatory markers early on.

However, new tests are on the horizon. The PERFORM/IRIS group published a diagnostic test using a two-transcript host RNA signature that can discriminate between bacterial and viral infections in febrile children (Herberg, JAMA 2016), using gene arrays to demonstrate up or down regulation of protein expression. Sensitivity in the validation group was 100% and specificity 96.4%13.  

But we don’t just want to know if a child has a bacterial or viral infection, we really want a clinical predictor of severity that could tell us which children are going to get very ill.  We have a few tests, but they’re not very specific. We often look at blood gases, looking for a metabolic acidosis. But that is very broad. What about a lactate >2mmol/l? The international guidelines did not recommend the use of lactate as the evidence is lacking, although it can give an idea of the trend and whether a child is getting better or worse and is generally considered to be best practice and is already standard in adult sepsis. But this is in direct contrast to a study by Elliot Long and team published earlier this year14 looking at predictors of organ dysfunction in over 6000 children presenting to the ED with fever. A lactate of 4 or higher was one of the best performing ED predictor of new organ dysfunction, the need for inotropic support and the need for mechanical ventilation. Take a look at Deirdre Philbin’s DFTB review of the study.

More new tests are coming.  For example, interleukin 6 and 10 may be able to predict which children with febrile neutropenia have serious infections and mid regional pro-adrenoedullin (MR pro-ADM) may be a promising biomarker to predict sepsis and septic shock15. So, watch this space!

Antibiotics

Recommendation number three. Start broad-spectrum antibiotics.

Moving on from tests to treatment, we now want to look at recommendation number three, when to start broad-spectrum antibiotics. There is a change in timing here.

In children with septic shock, antimicrobial therapy should be started as soon as possible and within one hour of recognition of sepsis.”  But, in children with suspected sepsis (i.e. organ dysfunction, but not shock), most of the children we see, guidelines suggest starting antimicrobial treatment as soon as possible after evaluation – you have 3 hours not 1 hour16.

This is important, because it gives you a chance to do tests and decide whether the child in front of you has sepsis or just a SIRS response due to a viral infection. This has bigger implications than just saving hospital beds, because we know timely initial empirical antibiotics will save lives, but unnecessary antibiotic use for all children with fevers increases antibiotic side effects, antibiotic resistance and cost.

Antibiotic choice

There are other recommendations around antibiotics. Importantly, the new consensus recommends a broad-spectrum antibiotic therapy with one single drug in normal children, such as  cefotaxime or ceftriaxone or, if they are allergic, meropenem.

As a quick aside, let’s think about penicillin allergy.

It’s important to get a history and to understand what a ‘real’ penicillin allergy is. We see a lot of children who present with a vague story of having been given a couple of doses of penicillin many years ago, who developed a rash and have been labelled as ‘penicillin allergic’.  But doing that in the heat of the moment can be tricky.

Zagursky believes “Avoidance of cephalosporins, when they are the drug of choice in a penicillin-allergic individual, results in significant morbidity that outweighs the low risk of anaphylaxis. We conclude that there is ample evidence to allow the safe use of cephalosporins in patients with isolated confirmed penicillin or amoxicillin allergy”17

Studies have found the risk of crossover between penicillin/cephalosporin reactions is <1%, so using cephalosporins as a first line is safe.  If the child also has cephalosporin sensitivity, they may need a carbapenem like meropenem.  Later, please think about referring these children to your local allergy service for penicillin or cephalosporin de-labelling, which entails having an antibiotic challenge under controlled, safe circumstances.

Moving on… antibiotics in immunocompromised children

The guidelines suggest using empiric multi-drug therapy in children with immunocompromise and those at high risk for multi-drug resistant pathogens. In this case, you might choose piperacillin-tazobactam and, if shock is present, amikacin. You can add teicoplanin if you suspect a line infection, with rigors when flushing the line, or a line site infection, with redness around their exit site, or signs of any soft tissue cellulitis.

The recommendations also cover antimicrobial stewardship. Once the pathogen and sensitivities are available, the guidelines recommend narrowing antimicrobial therapy coverage. This means narrowing down the antibiotic to something specific to the clinical presentation, site of infection, or risk factors.  Ask yourself these questions:

  • Is the child is showing clinical improvement?
  • Can they have their antibiotics at home? (via a paediatric out-patient antibiotic service)
  • Can they switch to oral antibiotics?
  • Can they stop their antibiotics?  If you don’t find any bugs, and the child is well, then the guidelines recommend stopping antimicrobial therapy.

Remember to phone a friend

Infectious disease teams or microbiologists; you never need to make decisions alone. The guidelines recommended daily assessment with clinical laboratory assessment for de-escalation of antimicrobial therapy. Assessment includes a review of the ongoing indication for antibiotics after the first 48 hours and should be guided by results from microbiology, signs of clinical improvement and evidence of reducing inflammatory markers, such as a halving of CRP, or if the child’s fever has settled for more than 24 hours.

Fluids

Moving on from antibiotics to fluids. The Surviving Sepsis Campaign has another paediatric management algorithm for fluid and vasoactive drugs. It’s also quite busy, incorporating the results of the FEAST study18.  It’s split into two, a green side and a blue side. The green side is for children who live in healthcare systems without intensive care, while the blue side is healthcare systems with paediatric intensive care. The change boils down to being more cautious with fluids.  The guidelines recommend 10-20 ml/kg boluses. I suggest giving 10 ml/kg and then reassessing for signs of fluid overload with hepatomegaly and listening for basal crackles suggesting pulmonary oedema, repeating a second or third bolus as needed.  I use 10 ml/kg because it’s the same in sepsis, in neonates and in trauma.

If the child needs more volume, give them more volume; you can repeat 10ml/kg boluses up to 40 ml/kg or more as needed just use smaller aliquots.  Remember there may still be children who need big volumes of fluid early on, and we have PICU readily available and the technology to support children’s circulation and ventilation and ‘dry them out’ later.  There isn’t enough evidence to fluid restrict children with sepsis in the ‘resource rich’ world just yet but trials are ongoing. The Squeeze Canadian Critical Care Group19 has started a study, so watch this space for results.

Which fluids should you choose?

Please use crystalloids not colloids. And although historically we have used 0.9% saline, it is better to choose balanced or buffered solutions such as Ringer’s lactate or Plasmalyte. Too much saline can cause hyperchloremic acidosis.   

Inotropes

There has been a real sea change in our approach with inotropes. As we’re being more cautious with fluid resuscitation, we need to start giving inotropes earlier. After giving 40 to 60 ml/kg have your inotrope lined up ready to go.  There is good evidence that the drug of choice should be adrenaline20.  You can give adrenaline via a peripheral intravenous cannula or an intra osseous cannula safely if you don’t have central access. There have also been studies in adults that showed that peripheral adrenaline is also safe, especially when given for less than four hours or in a diluted dose.

Safety netting

Most of the febrile children we see will be discharged; safe discharge is a big priority because that’s what the majority of hot bothered children need: good advice and home care.  Winters (2017)21 looked at 33,000 children who were discharged from Emergency Departments with abnormal vital signs. 27,000 (80%) of them were discharged with normal vital signs, with only one case of potentially preventable permanent disability (a child who presented with tummy pains and came back with torsion of the testes, unlucky). 5,500 children (16%) were discharged with abnormal vital signs; there were no permanent disability or deaths from this group. So, you can send children home with fevers safely. But, the proviso to this is they need good safety netting on discharge, including both verbal and written information. This is one of the NICE recommendations. Our discharge safety netting leaflet22, which (gives some straightforward, practical information about giving anti-pyretic medication like paracetamol and ibuprofen), works like a ‘parent’s PEWS’ chart. It allows parents to see if their child is OK to stay at home or if they’re at some risk and should contact the GP, go to a walk in centre or call 111-advice line if they haven’t got better in 48 hours.  If the child is on the ‘high risk’ side, we want to see them back in the Paediatric Emergency Department.

In summary…

So, in summary, please screen for sepsis, we should all be doing it. I don’t know the best systems to help you but, ideally, you should have electronic observations, protocols and local guidelines.  Be aware that in the ED the incidence of sepsis is rare and that recent surviving sepsis campaign guidance suggests you can safely observe while you make a decision on treatment. Give antibiotics within 60 minutes in septic shock, but in sepsis with no shock you have three hours. If you are treating use fluid cautiously, with 10-20 ml/kg boluses and frequent reassessments.  Start adrenaline early if appropriate, and this can be given safely, peripherally.  Finally, safety netting is essential.

Thank you very much for reading this right through to the end! If you want to hear more, please have a listen to our Paediatric Sepsis podcast, hosted by the RCPCH.

Selected references

  1. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Weiss SL et al. Pediatr Crit Care Med. 2020 Feb;21(2):e52-e106. doi: 10.1097/PCC.0000000000002198.PMID: 32032273
  2. Craig JC et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ. 2010;340:c1594 10.1136/bmj.c1594
  3. Nijman RG et al. Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study. BMJ. 2013;346:f1706 10.1136/bmj.f1706
  4. van de Maat J et al. Antibiotic prescription for febrile children in European emergency departments: a cross-sectional, observational study. Lancet Infect Dis. 2019;19:382–91. 10.1016/S1473-3099(18)30672-8
  5. Weiss SL et al. Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med. 2015 May 15;191(10):1147-57. doi: 10.1164/rccm.201412-2323OC. Erratum in: Am J Respir Crit Care Med. 2016 Jan 15;193(2):223-4. PMID: 25734408; PMCID: PMC4451622.
  6. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis.Pediatr Crit Care Med. 2005 Jan;6(1):2-8. doi: 10.1097/01.PCC.0000149131.72248.E6. PMID: 15636651 Review
  7. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Shankar-Hari M et al. Sepsis Definitions Task Force. JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289. PMID: 26903336
  8. Romaine ST et al. Accuracy of a Modified qSOFA Score for Predicting Critical Care Admission in Febrile Children. Pediatrics. 2020 Oct;146(4):e20200782. doi: 10.1542/peds.2020-0782. PMID: 32978294; PMCID: PMC7786830.
  9. Gill FJ et al. The Impact of Implementation of Family-Initiated Escalation of Care for the Deteriorating Patient in Hospital: A Systematic Review. Worldviews Evid Based Nurs. 2016 Aug;13(4):303-13. doi: 10.1111/wvn.12168. Epub 2016 Jun 3. PMID: 27258792.
  10. Martinón-Torres F et al. EUCLIDS Consortium. Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study. Lancet Child Adolesc Health. 2018 Jun;2(6):404-414. doi: 10.1016/S2352-4642(18)30113-5. Epub 2018 Apr 28. PMID: 30169282.
  11. Herberg JA et al. IRIS Consortium. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA. 2016 Aug 23-30;316(8):835-45. doi: 10.1001/jama.2016.11236. Erratum in: JAMA. 2017 Feb 7;317(5):538. PMID: 27552617; PMCID: PMC5997174.
  12. Andreola, B et al. Procalcitonin and C-Reactive Protein as Diagnostic Markers of Severe Bacterial Infections in Febrile Infants and Children in the Emergency Department, The Pediatric Infectious Disease Journal: August 2007 – Volume 26 – Issue 8 – p 672-677. doi: 10.1097/INF.0b013e31806215e3
  13. Herberg JA et al. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA. 2016 Aug 23-30;316(8):835-45. doi: 10.1001/jama.2016.11236. Erratum in: JAMA. 2017 Feb 7;317(5):538. PMID: 27552617; PMCID: PMC5997174.
  14. Long E, Solan T, Stephens DJ, et al. Febrile children in the Emergency Department: Frequency and predictors of poor outcome. Acta Paediatr. 2020; 00: 1– 10 
  15. Xia T, Xu X, Zhao N, Luo Z, Tang Y. Comparison of the diagnostic power of cytokine patterns and procalcitonin for predicting infection among paediatric haematology/oncology patients. Clin Microbiol Infect. 2016 Dec;22(12):996-1001. doi: 10.1016/j.cmi.2016.09.013. Epub 2016 Sep 22. PMID: 27665705.
  16. Elke G et al. SepNet Critical Care Trials Group. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis – a secondary analysis of a large randomised controlled trial. Crit Care. 2018 Mar 21;22(1):79. doi: 10.1186/s13054-018-2001-5. PMID: 29562917; PMCID: PMC5863464.
  17. Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. 2018 Jan-Feb;6(1):72-81.e1. doi: 10.1016/j.jaip.2017.08.027. Epub 2017 Oct 7. PMID: 29017833.
  18. Maitland K et al. FEAST Trial Group. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483-95. doi: 10.1056/NEJMoa1101549. Epub 2011 May 26. PMID: 21615299.
  19. Parker, M.J., Thabane, L., Fox-Robichaud, A. et al. A trial to determine whether septic shock-reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy versus usual care (SQUEEZE): study protocol for a pilot randomized controlled trial. Trials 17, 556 (2016). https://doi.org/10.1186/s13063-016-1689-2
  20. Ramaswamy KN, Singhi S, Jayashree M, Bansal A, Nallasamy K. Double-Blind Randomized Clinical Trial Comparing Dopamine and Epinephrine in Pediatric Fluid-Refractory Hypotensive Septic Shock. Pediatr Crit Care Med. 2016 Nov;17(11):e502-e512. doi: 10.1097/PCC.0000000000000954. PMID: 27673385.
  21. Winter J, Waxman MJ, Waterman G, Ata A, Frisch A, Collins KP, King C. Pediatric Patients Discharged from the Emergency Department with Abnormal Vital Signs. West J Emerg Med. 2017 Aug;18(5):878-883. doi: 10.5811/westjem.2017.5.33000. Epub 2017 Jul 19. PMID: 28874940; PMCID: PMC5576624.
  22. Lim E, Mistry RD, Battersby A, Dockerty K, Koshy A, Chopra MN, Carey MC, Latour JM. “How to Recognize if Your Child Is Seriously Ill” During COVID-19 Lockdown: An Evaluation of Parents’ Confidence and Health-Seeking Behaviors. Front Pediatr. 2020 Nov 17;8:580323. doi: 10.3389/fped.2020.580323. PMID: 33313025; PMCID: PMC7707121.

Unlucky dip: Rational diagnostic testing for infections

Cite this article as:
Alasdair Munro. Unlucky dip: Rational diagnostic testing for infections, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.20311

We see lots of children with suspected infections. Modern microbiology techniques have opened up a huge array of tests: some new and expensive, but we are often still reliant on good old fashion microscopy and culture.

With so many tests so readily available, we need to think hard about diagnostic stewardship. This means testing the right patients for the right reasons. We must be wary of over-diagnosis, preventing confusion, anxiety or unnecessary treatment, and making choices that represent good value. Many tests can be expensive and are often not necessary to make management decisions.

With that in mind, let’s take a look at some of the most common diagnostic tests for infections, and when we should (or shouldn’t!) be deploying them.

 

Urine dips and MC&S

Urinary tract infections (UTIs) are the most common serious bacterial infection in high-income countries. There are many departments where it is routine to set up every febrile child to get a “clean catch” urine as soon as they arrive. This is unwise, because it is VERY EASY to contaminate a urine sample from a clean catch. We have all seen children or parents putting their hands/feet/face in the bowl, and let’s be honest – if the child is sitting on the container, it’s basically directly under the body’s primary waste pipe.

Accepting a decent risk of false positives, we must aim to test only those who need the test. So when should we do it?

Fever without a source

This is the primary indication for doing a urine dip, and it is a sensible one. However, still not every child with fever and no source needs a urine dip. Older children can report urinary symptoms, and the absence of these makes a UTI much less likely. In addition, by school age, UTIs in males with normal renal tracts become very rare, so urine testing also becomes less useful.

As a framework, urine dips should be performed in the following groups with fever and no source (assuming they have no risk factors for UTIs and have no red flags):

Outside of these groups, use your clinical discretion to decide if the pre-test probability justifies the risk of a false positive – take into consideration the child’s age, gender, duration of symptoms, how unwell they appear, and obviously if they have known risk factors such as renal abnormalities or previous UTIs.

Symptoms of UTI

This seems obvious – but it’s worth stating that once urinary symptoms are present (increased frequency, dysuria) you should dip the urine to check for infection, and it may be worth sending samples for MC&S even if they are dip negative in this scenario (you can withhold treatment pending results).

It is worth taking more care for children with non-urinary symptoms, such as abdominal pain or vomiting (which is probably not predictive of UTI). Once at school age (particularly in boys) these symptoms are unlikely to be a symptom of a UTI so a higher threshold for testing should be adopted.

Some people say that all children with rigors require urine testing. Rigors are not evidenced to have any influence on the risk of UTI (or any significant risk of bacterial infection). If there is another source of the fever, urine dip is certainly not indicated on the basis of a rigor alone.

For more information on relative risks for UTIs in younger children, the supplementary materials to the UTI risk calculator study make an interesting read.

What about hot babies with bronchiolitis?

This becomes a slightly more controversial topic, and decisions require risk stratification based on the age of the child. For example, a febrile neonate with bronchiolitis might be lucky to escape the full shebang of a septic screen anyway – and a quick in/out catheter is unlikely to yield a false positive.

The literature on this topic is a bit confusing because of varying definitions of UTI and bronchiolitis (some studies including any child with RSV detected in their nose). The most recent meta-analysis with more stringent criteria for diagnosing UTI found a rate of concomitant UTI with bronchiolitis of 0.8% – low enough that testing is not advised.

Bottom line: if an infant has a fever and a clinical diagnosis of bronchiolitis, then urine dip is not necessary in most instances – however this should be given strong consideration in infants <60d and should be performed in neonates.

 

Blood culture

For a full myth busting exercise in blood cultures, please read the recent DFTB post on this topic. Some things to bear in mind if you’re thinking of taking a blood culture:

  • You are testing for bacteraemia. If you do not suspect bacteraemia, do not send a blood culture.
  • Blood cultures are extremely low yield in uncomplicated skin/soft tissue infection and pneumonia and should be avoided.
  • You do not need to wait for a fever to take a blood culture – it has no influence on the likelihood of obtaining a positive result. If you suspect bacteraemia, take the culture now.
  • If you are going to take a blood culture, aim to inoculate at least 1ml of blood per year of the child’s age. Less than this and you increase the risk of contamination and decrease the sensitivity.

 

Wound swab

When it comes to swabbing for microscopy, culture and sensitivity (MC&S), there is a golden rule*:

Do not swab any non-sterile site that you have not already clinically diagnosed as being infected.

A skin swab, throat swab, eye swab etc. will grow bacteria 100% of the time, because these places are non-sterile. They will often grow pathogens, because many pathogens are quite happy just being colonisers a lot of the time, and actually some of them are more often found as bystanders than as trouble-makers (Pseudomonas aeruginosa is a prime example – it is very rarely pathogenic in non-sterile sites). A positive swab does not diagnose infection.

YOU have to diagnose infection; a swab will just tell you what bacteria is causing it.

I would like to give a special shout out to gastrostomies at this point – just because they are “mucky” is not a good reason to swab. If you do swab it, you will find good old Pseudomonas (it loves playing in wet stuff). Skin and soft tissue infections are red, hot and inflamed +/- a bit of pus. Yellowish clearish greenish stuff is normally just serous fluid, so don’t worry about it and don’t swab it!

The same goes for babies sticky eyes. If you swab it, it will grow bacteria, but this tells you nothing about whether they are infected. Look for inflammation, if you find it then diagnose infection, treat empirically and send a swab if you are concerned about resistant bacteria.

*there are some exceptions to the golden rule, including burns and chronic wounds in immunosuppressed patients.

 

Throat swabs

Before starting – let’s remember that you cannot diagnose a bacterial throat infection with a swab alone. If you are considering swabbing a throat for MC&S, you must have already clinically diagnosed infection.

Guidelines vary quite widely in their recommendations to swab or not swab when diagnosing tonsillitis. It is worth considering that a throat swab has a reasonable sensitivity for group A Strep, if performed correctly. Sadly – we are all dreadful at performing throat swabs in children (who are usually very good at not wanting a throat swab), and often get a good dose of tongue and palate. Not good.

A further thing to consider is that approximately half of all throat swabs positive for group A Strep just indicate carriage – you’ve found the bug, but it’s just a bystander.

This means that if you swab and haven’t found the bacteria, it might be there but you’ve missed it, and if you have found it, there’s a 50% chance it’s not causing the illness anyway…

If it’s extremely important you detect the presence of group A Strep (for example in populations high risk for rheumatic fever) then I would definitely do a swab. If it’s not (and it usually is not), then make your decision to treat or not on clinical grounds alone.

Also, remember that in children <4yrs group A Strep tonsillitis is rare and almost never causes complications, so if you’re thinking of doing a throat swab for a child in this age group you need to have a very good reason.

 

Respiratory virus testing

Respiratory tract infections are extremely common in children. There is a fair amount of controversy and disagreement about the role for respiratory virus testing. It can have several roles:

  1. Local epidemiology. Some big/university hospitals like to keep track of what’s circulating, and will often have guidelines on who and when they want these tests performed.
  2. Cohorting. In bronchiolitis season, some hospitals might fill one bay with RSV and another with Rhinovirus. This is an evidence free zone.
  3. Fever without a source. Influenza in particular can cause horrible febrile illnesses in children without the classic respiratory prodrome. The idea is to detect the flu to prevent unnecessary antibiotics.

A group of children you should not test for respiratory viruses is anyone with cough and coryza. They do not need a test – they can be safely diagnosed clinically, and the presence or absence of a virus on testing does not change anything.

What about in lower respiratory tract infections? We can imagine that the discovery of a virus would prevent unnecessary antibiotics. However, respiratory viruses are common (even among non-hospitalised populations) and co-infection with bacteria is also common in viral infections. The presence of a virus does not preclude a bacterial infection. As such, their use in this context is contentious, and they do not appear to reduce antibiotic use.

For a thorough look at the principles and evidence of respiratory virus testing in children, I would recommend this excellent review paper.

 

Conclusions

  • Not every child with fever and no source needs a urine dip. Do it in infants, young girls and children with fever persisting >48hrs. Otherwise, use clinical discretion.
  • You probably don’t need to urine dip febrile children with clinical bronchiolitis.
  • Only do blood cultures if you suspect bacteraemia, and take lots of blood if you do.
  • Only send a swab for MC&S from a non-sterile site if you’ve already diagnosed infection.
  • Throat swabs are usually not useful. Only do them for high risk groups.
  • Respiratory virus testing is not useful in most circumstances. Only do it if you have a definite plan for how it will change your management.
  • When in doubt – if you can’t explain how the test will change your management, don’t do the test.