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.

Oral or IV antibiotics?

Cite this article as:
Alison Boast. Oral or IV antibiotics?, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24974

There are many self-perpetuating myths when it comes to antibiotic use in children. A few that seem intuitive, and come up almost daily, include the idea that intravenous antibiotics are ‘better’, that children require lower doses than adults, and ‘longer is better’ when it comes to treatment duration.

A few key concepts can be helpful to understand why certain routes and doses of antibiotics are required:

  • Pharmacokinetics: the effect of the body on the drug – how the body absorbs, distributes, metabolizes and excretes the antibiotic
  • Pharmacodynamics: the effect of the drug on the body – how the antibiotic effects bacteria in the body 
  • Bioavailability: the amount of the antibiotic which is effectively absorbed when given orally and reaches the bloodstream

Here are some points to consider next time you need to chart antibiotics for a child.

 

When are intravenous antibiotics absolutely required?

  1. Speed – if there is a life (think sepsis, meningitis) or limb-threatening (eg. necrotising fasciitis) intravenous antibiotics are required as they reach peak plasma levels in seconds/minutes, rather than hours
  2. Absorption – for children with poor or unreliable oral absorption (eg. inflammatory bowel disease, short gut) intravenous antibiotics will likely be required
  3. Neonates – in general neonates are considered to have poor oral absorption, therefore antibiotics are usually given intravenously
  4. No oral options – in some cases there may be no oral option available; this is particularly relevant for highly resistant organisms such as extended-spectrum beta-lactamase producing organisms
  5. High dose – if a very high dose of an antibiotic is required the volume of liquid required for a child to consume may be excessive, in these cases intravenous antibiotics may be required
  6. Nil per os – in children who are not able to take any oral medications (eg. bowel obstruction) intravenous antibiotics may be required; remember insertion of a nasogastric tube and NG medications may be an option particularly for younger children
  7. Worsening infection on oral antibiotics – this one can be a little tricky as factors such as wrong dose (antibiotics are commonly under-dosed in the community), wrong antibiotic, and poor compliance need to be considered, but sometimes children may require admission for intravenous antibiotics

 

When can you change to oral antibiotics?

There are four general principles guiding the change from intravenous to oral antibiotics (McMullen et al.)

  • Clinical condition – note that fever alone does not need to prevent switch
  • Ability to absorb oral antibiotics
  • Availability of an appropriate oral antibiotic
  • Practical issues

The above reference gives a thorough discussion on the evidence of when to switch to oral antibiotics for a range of common paediatric infections (skin and soft tissue, urinary tract infections etc).

 

What are other factors need to be taken into account?

Bioavailability – some drugs have excellent oral absorption, therefore there it is almost criminal to give them IV if the child can swallow them! Think metronidazole, rifampicin, doxycycline, ciprofloxacin and clindamycin (which all have good tissue penetration)

“Help – my child refuses to take oral antibiotics!” – this is a tricky one and the use of an experienced paediatric pharmacist is invaluable as there are many aids that can be used to help resilient toddlers take their medications

 

Why is this important?

The implications of shortening the course of intravenous antibiotics and antibiotics overall are numerous…

  • Shorter courses of antibiotics may affect antimicrobial resistance
  • Shorter inpatient stays (required unless outpatient antimicrobial therapy available through a hospital in the home service) associated with improved quality of life in children and their families, and money-saving for the hospital system
  • Intravenous antibiotics may be associated with line complications, pain and traumatic experiences for children

 

Selected references

McMullan BJ, Andresen D, Blyth CC, Avent ML, Bowen AC, Britton PN, Clark JE, Cooper CM, Curtis N, Goeman E, Hazelton B. Antibiotic duration and timing of the switch from intravenous to oral route for bacterial infections in children: systematic review and guidelines. The Lancet Infectious Diseases. 2016 Aug 1;16(8):e139-52.

Pyrexia of Unknown Origin Module

Cite this article as:
Beatrice Zanetti. Pyrexia of Unknown Origin Module, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.27689
TopicPyrexia of Unknown Origin
AuthorBeatrice Zanetti
DurationUp to 2 hours
Equipment requiredNone
  • Basics (10 mins)
  • Main session: (2 x 15 minute) case discussions covering the key points and evidence
  • Advanced session: (2 x 20 minutes) case discussions covering grey areas, diagnostic dilemmas; advanced management and escalation
  • Quiz (10 mins)
  • Infographic sharing (5 mins): 5 take home learning points

We also recommend printing/sharing a copy of your local guideline.

To prepare for this session, learners could read the below case report article (20 minutes): 

Wood M, Abinun M. and Foster H., Pyrexia of unknown origin. Archives of Disease in Childhood, Education and Practice, 89 ep 63-69 (2004) 

And/or look at these useful resources from the web: 

https://pedemmorsels.com/fever-of-unknown-origin/ (5 minutes)

https://dontforgetthebubbles.com/recurrent-or-periodic-fevers-investigate-or-reassure/ (10 minutes)

https://dontforgetthebubbles.com/tuberculosis/ (5 minutes)

https://dontforgetthebubbles.com/claire-nourse-tuberculosis-at-dftb17/ (20 minutes)

https://gppaedstips.blogspot.com/search/label/Juvenile%20idiopathic%20arthritis  (10 minutes)

https://www.paediatricfoam.com/?s=kawasaki (10 minutes)

The term pyrexia of unknown origin (PUO) is used when a patient has more than 8 days with fever (temperature> 38°C) without a clinical diagnosis after exhaustive investigations have been carried out (in hospital or in primary care). 

Other more specific PUOs are:

  • nosocomial PUO
  • neutropenic PUO
  • HIV-associated PUO

These 3 have specific risk factors and will not be covered in this session. 

Fever is a sign of an underlying pathology. In PUO, pyrexia is usually the main symptom while other signs may be very subtle. Many times, the underlying disease is a common pathology that is presenting in an atypical or incomplete way.  

Here are 3 main clinical dilemmas for clinicians: 

In the paediatric population, 30% of PUO will not reach a final diagnosis. However, in those cases, PUO is often a self-limited and benign episode. 

When a definitive diagnosis is reached, the majority of causes are related to infectious diseases (38%), followed by connective tissue disorders/autoimmune pathology (13%) and malignancies (6%).

At present, there is not a generic PUO work-up since this wouldn’t be efficient. Remember that more than ¼ of cases are benign and self-limited! 

In many cases, PUO is a consequence of a late diagnosis. Clinical history taking and careful physical examination are crucial to pick up subtle signs and guide the complementary tests and imaging. New signs and symptoms, which weren’t present on initial examination, can appear later on.

In the literature, retrospective studies have shown that when imaging requests are prompted by some examination finding, they are more likely to yield a positive result. 

Here’s a table with possible differential diagnosis based on clinical findings.

Diagnosis based on common clinical findings
Rash
Maculopapular -Purpuric-Erythema Nodosum-Butterfly rashEBV, Kawasaki Disease, SOJIA, Typhoid feverCMV, Endocarditis, Leukaemias, Histiocytosis, VasculitisTB, Ulcerative colitis, Crohn’s disease, Streptococcal infectionSLE, Dermatomyositis
Adenopathies
-Infections-Connective tissue disorders-Malignancies-Other causesCMV, EBV, TB, Bartonella (Cat-scratch disease)Rheumatoid Arthritis (RA)
Lymphomas, Leukaemias, HistiocytosisSarcoidosis and Primary Immunodeficiencies
Splenomegaly
-Infections
-Connective tissue disorders-Malignancies
-Other causes
TB, Bartonella, Malaria, Visceral Leishmaniasis, Endocarditis, Brucelosis, SalmonelosisSLE, RA
Lymphomas, Leukaemias, Histiocytosis, Macrophagic Activation SyndromePrimary immunodeficiencies
Arthritis
-Infections-Connective tissue disorders-Malignancies-Other causesTB, Lyme disease, Brucella, Staphylococcal InfectionSOJIA, RA, SLE, Rheumatic fever
Leukaemias

The speed of the complementary tests will depend on the general appearance of the patient. Empirical treatment with antibiotics can blur the microbiology results resulting in a delayed diagnosis. The empirical use of steroids can mask other pathologies and again delay the diagnosis. 

For the above reasons, clinicians should reserve empirical treatment with antibiotics or steroids to the sick patient based on clinical assessment.

Causes of fever of unknown origin
Infectious: Bacterial infections: Localised: Pyelonephritis, Sinusitis, Mastoiditis, Pneumonia/pleural effusion, Osteomyelitis, Endocarditis, Intravenous catheter infectionAbscesses (intracranial, dental, intestinal, hepatic, pelvic…)
Systemic infections: Tuberculosis, Brucellosis, Bartonella (cat-scratch disease), Leptospirosis, Q fever (Coxiella), Lyme disease, Salmonellosis (Typhoid fever), Tularaemia. 
Viruses: EBV, CMV, Adenovirus, Enterovirus, HIV, Dengue
Fungal: Blastomicosis, Histoplasmosis, Coccidiomicosis
Parasites/protozoos: Malaria, Visceral Leishmaniasis, Toxoplasmosis, Visceral Larva Migrans, Tripanosomiasis
Connective Tissue DisorderKawasaki Systemic Onset of Juvenile Idiopathic Arthritis (SOJIA)Systemic Lupus ErythematousAcute Rheumatic fever
MalignanciesLeukaemia LymphomasSolid tumours (Neuroblastoma)Hemophagocytic SyndromeMyelodysplastic syndromeHistiocytosis 
Other: Drug related feversFabricated illness Inflammatory bowel diseaseCentral origin feverPeriodic feversMetabolic fevers (hyperthyroidism, dehydration)Primary immunodeficiencies

A 14-month-old girl was referred to hospital by GP due to 8 days of fever, non-tender cervical lymphadenopathies (scattered small submandibular, posterior and 1 supraclavicular lymphadenopathies) and mild cough. On examination, the patient has a good general appearance with a mildly red throat and the above described lymphadenopathies. Father is concerned as the child also had a febrile illness the previous week which was labelled as a viral infection. 

Blood tests showed raised WCC (24×109/L) with neutrophilia (18×109/L). Normal lymphocytes (6 x109/L) with a CRP of 30 mg/L. Chest x-ray showed a bilateral bronchial opacification.

The patient was admitted and started on amoxicillin and azithromycin PO. 

Despite 5 days of treatment, the patient is still spiking fevers (see chart below). Blood culture is negative. Clinically stable, cough has now disappeared. You are classifying this patient as PUO. 


What questions do you want to ask the parents? Take a detailed history. 

Why is this patient not getting better despite treatment? 

What investigations can be prompted by clinical findings?

At this point, would you escalate the antibiotic treatment?

In PUO, a detailed clinical history is the most important diagnostic tool that can guide all investigations. Instead of ordering random tests, ask more questions!

When taking the history, consider: 

  • Characteristics of the fever: when did it start, duration and intensity. Note that this child had a previous febrile illness which can be part of the same illness. 
  • Pattern of fever: there are several patterns of fever which can help with the diagnosis. If managed in an outpatient setting, ask the family to do a symptoms diary. From looking at the fever chart, the child has an intermittent fever pattern.
Type of feverCharacteristics of feverPossible causative agent
Intermittent feverSharp febrile peak which goes back to baselineBacterial infections, TB, SOJIA
Remittent feverFever peaks and elevated basal temperatureViral illness, Endocarditis, lymphomas
Sustained feverPersistent fever with minimal variationTyphoid fever, Brucellosis
Recurrent feverPeriods of fevers intercalated with afebrile periodsMalaria, Lymphomas, Borellia
Periodic feverFebrile periods are intercalated with afebrile periods with a predictable pattern of 6 monthsPeriodic fever syndromes 
  • Age of the child: PUO in young children is often caused by infections while in older children and teenagers tends to be caused by a connective tissue disorder or a malignancy.
  • Associated symptoms and signs: headaches, vomiting and diarrhoea, rash, arthralgias, myalgias, bony pain, lymphadenopathies. They can be very subtle therefore a systematic review of all systems is necessary. 
  • Systemic symptoms: fatigue, anorexia, weight loss, sweating.
  • Previous medical history: a history of many bacterial infections can be related to a primary immunodeficiency. The most common primary immunodeficiencies are: 
  1. Common variable immunodeficiency
  2. Chronic granulomatous disease

Usually the immunodeficiencies are associated with complicated infections, failure to thrive, atopic disease or autoimmune disease.

For more information: https://dontforgetthebubbles.com/ent-infections-immunodeficiency/

  • Vaccination history: patient is fully vaccinated as per UK protocol. This includes BCG due to risk factors (Parents are from a country where incidence of TB is > 40/100,000 or more). 
  • Regular medications or any exposure to new medication (think about drug- related fevers).
  • Family History: Ethnic background, consanguinity. Family is from India and there is no consanguinity. 
  • Environmental risk factors: TB contacts, area where family lives, exposure to animals, vectors (mosquitos, ticks…), food intake (unpasteurised dairy products, uncooked meat and fish), international travels (place, malaria prophylaxis and compliance of prophylaxis). 

Patient travelled to India to visit grandparents when she was 9 months old. She was exposed to some mosquito bites.  She lived in an urban area for 3 months. Parents were not aware of any TB contacts.

For international travellers, the following website provides relevant information on potential risks and outbreaks occurring on each country: https://travelhealthpro.org.uk/

When a patient has received a provisional diagnosis plus empirical treatment for at least 48 hours and there is no improvement, clinicians should use a systematic approach to understand the reasons behind the poor response to treatment. 

Here are the four main questions to be answered: 

  1. Is there a problem with the medication? 

The diagnosis is right but the problem is within the treatment. Issues with the treatment could be related to: 

-Drug resistances (MRSA, ESBL bacteria).

This website will provide a map with all antibiotic resistances over the world:  https://resistancemap.cddep.org/AntibioticResistance.php, treatments should, when possible, be guided by microbiological culture results.

-Underdosages of the antibiotics which don’t reach the effective concentration.

-Very virulent bacteria creating a toxin that requires more antibiotics (eg. Staph. aureus PVL) 

-Adherence to treatment (low compliance) 

-Malabsorption of medication (for example vomiting, diarrhoea when taking oral medications)

-The selected antibiotics are not reaching the right place of infection (bone, abscess…)

2. Are we targeting the wrong bug?

Antibiotics are mainly covering for bacteria but the actual infection can be caused by other microbes like viruses, atypical bacteria, TB, parasites and fungal infections. 

3. Is there a problem with the host? 

Consider whether the episode could be only a prolonged febrile syndrome for a common disease due to host problem.  The problem can reside in the immunity (immunodeficiencies), structural problems that can predispose to localized infections (for example a patient with previous abdominal surgery who now has an abscess) or whether the patient has a foreign body or a central catheter that can be the source of the infection.

4. The problem is not infectious: fever can be a sign of a tissue connective disorder, malignancies and other illnesses like a central origin related fever, drug related fever or a factitious illness.

This child has now had at least 12 days of fevers. It could be even longer if we consider that he had a febrile illness labelled as “viral” before this episode. 

On examination, the main clinical sign are the small cervical lymphadenopathies bilaterally with 1 small supraclavicular lymphadenopathy. This clinical finding could prompt the clinician to investigate for others cause: URTI, EBV, CMV, pneumonia, pleural effusion, TB, Bartonella, connective tissue disorders, malignancies, histiocytosis.

After 18 days of intermittent fever, cervical lymphadenopathies and some fatigue, the patient underwent a fine-needle aspiration of the supraclavicular lymphadenopathy. The histology showed a caseating granuloma and the microbiology sample showed acid fast bacilli. TB GeneXpert of the sample and culture were positive for non-resistant Mycobacterium Tuberculosis. Patient was diagnosed with tuberculous cervical lymphadenitis (extrapulmonary TB).

Probably not. Use of antibiotics can delay microbiological diagnosis since the blood cultures’ yield is decreased. If the patient has a good general appearance and fevers are well managed with PRN antipyretics, then clinician can consider withholding the antibiotics until a definitive diagnosis is reached. 

Reaching the definitive diagnosis: 
After 5 days of treatment with amoxicillin and azithromycin and no clinical improvement, basic investigations were repeated and further were added.

Bloods tests
WCC 22 x109/L with neutrophils of 18 x109/L,
Lymphocytes 4 x109/L, CRP 36 mg/L
ESR >60 mm/h
Normal renal and liver function
Blood film normal: No reactive lymphocytes, no lymphoblasts seen
Blood cultures Negative.
CMV Serology: IgM negative, IgG Negative
EBV serology: IgM negative, IgG Negative

Microbiology
Mantoux /TST (Tuberculin skin test): 10 mm induration
(Patient received BCG vaccination)
IGRA (Interferon gamma release assay): Positive
Gastric aspirate for AFB smear: negative 
Gastric aspirate for TB GeneXpert: negative

Imaging
Repeated chest XR: similar features compared to previous one, peri-bronchial shadowing.
Ultrasound of lymph-nodes: several lymph-nodes with nodal matting and surrounding soft tissue oedema. Prominent vascularity in the hilum.

After 18 days of intermittent fever, cervical lymphadenopathies and some fatigue, the patient underwent a fine-needle aspiration of the supraclavicular lymphadenopathy. The histology showed a caseating granuloma and the microbiology sample showed acid fast bacilli. TB GeneXpert of the sample and culture were positive for non-resistant Mycobacterium Tuberculosis. Patient was diagnosed with tuberculous cervical lymphadenitis (extrapulmonary TB).

  • Systemic symptoms 
  • Supraclavicular lymph-node
  • Firm and/or fixed lymph-nodes
  • CXR changes, abnormal Full blood count or increased ESR
  • Adenopathies > 1 cm in a neonate 
  • Suspicion of TB 
  • Persistent lymphadenopathies for more than 4 weeks despite antimicrobial treatment
  • Sometimes in acute lymphadenitis if a patient is not responding after 48 hours of treatment

To note, the patient had received the BCG vaccine. However, it has about 50% efficacy which implies that patients with BCG vaccination can still have tuberculosis. BCG is more effective in preventing children from developing disseminated (Miliary) TB or TB meningitis. She was probably exposed to TB and became infected while in India, subsequently developing the disease over the next few months. 

Contact tracing of family members is mandatory to identify the source case. Usually, children are not very infectious since the majority of cases tend to be paucibacillary (low bacterial load) unless they have lung cavities or extensive lung involvement. 

TB in children often presents in a non-specific way. The typical symptoms are weight loss or failure to gain weight, fever, night sweats and fatigue. When children present with pulmonary TB, this is usually confined within the intrathoracic nodes. Patients may have persistent cough and asymmetrical and persistent wheeze caused by airway compression due to enlarged tuberculous peri-hilar nodes. 

Chest XR can be helpful in the diagnosis of early primary infection by detecting intrathoracic lymph-node enlargement. However, these changes may be subtle as a strong index of suspicion is required. More information on radiological features of paediatric TB can be found on the following link: doi: 10.1101/cshperspect.a017855

Sputum and gastric aspirate mycobacterial cultures have a low diagnostic yield since most children have paucibacillary TB. Recently, diagnostic sensibility for these samples has increased due to the rollout of new molecular techniques (GeneXpert TB PCR).

TST (Mantoux test) and new immunological assays such as IGRAs detect exposure. TST is performed by injecting 0.1ml of tuberculin purified protein derivative (PPD) intradermally into the inner surface of the forearm. The skin reaction produced by the PPD should be read between 48 and 72 hours. The reaction is measured in millimetres of induration, not redness. There are different measures to define a positive result depending on patient background history (for example BCG vaccination) and there are also many causes of false positive and false negative results.For more information (https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm).

On the other hand, IGRA is a blood test which measures the body’s immune response (interferon-gamma production) to TB antigens. Our patient had a positive Mantoux test (10 mm) but the result might have been affected by previous BCG vaccination.  However, this result, combined with a positive IGRA, demonstrated that the child had been previously exposed to TB. Unfortunately, neither of these tests can distinguish between latent infection and active disease. 

The patient was treated with Isoniazid (with Pyridoxine), Rifampicin, Ethambutol, and Pyrazinamide for 2 months and Rifampicin and isoniazid for another 4 months. Corticosteroids were not deemed necessary in this case since the lymphadenopathies were not compressing other structures. Empirical treatment of tuberculosis is usually limited to clinical cases where milliary or CNS TB are suspected, as a treatment delay in these cases will often lead to worse outcomes.

3-year-old boy with a 5-day history of fever and loss of appetite presented to the emergency department with his mother as he had been crying all night and refused to put his T-shirt on. No history of trauma reported. On examination, he looked skinny and he was crying when the right arm was moved. Bloods test showed
Hb 9 g/L
WCC 4 x109/L
Neutrophils 1.5 x109/L
Lymphocytes 2.5 x109/L
Platelets 120 x109/L.
CRP 40 mg/L.

Right arm x-ray was normal. The patient was admitted for observation. On the ward, it was noted that he was spiking fevers every night. 

After 3 days of admission, MRI of the right upper limb was performed. MRI showed possible osteomyelitis of the right distal clavicle.  He was diagnosed with acute pyogenic osteomyelitis and was started on ceftriaxone 50mg/kg IV OD. Blood cultures (taken before administration of antibiotics) were negative. Fever settled after 5 days of antibiotics. Patient was discharged home on oral antibiotics for 3 weeks.  

10 days later, the patient was reviewed in the clinic. Mother was worried since the patient had had fevers again over the last 2 days, felt fatigued and was reluctant to walk.

At this stage, what is the differential diagnosis? 

What investigations would you perform? 

What treatment would you give? If you were to suspect an autoinflammatory disease, would you give steroids? 

What is the role of PET-CT in PUO?

Infectious diseases: 

Osteomyelitis: 

Every time a patient presents with reduced range of movement due to a bony pain, osteomyelitis should be considered. In non-verbal children, it can present with irritability and inability to bear weight. It usually affects the metaphysis of the long bones (femur, tibia…). Therefore, the original diagnosis of clavicle osteomyelitis was quite rare. Now that the patient presented again with fever and a new similar problem after receiving adequate antibiotic therapy, another diagnosis should be considered. 

Septic Arthritis: 

It has a similar presentation to osteomyelitis but usually the joint is swollen, red and hot. Ultrasound of the joint can detect joint effusion which can be a sign of septic arthritis. Urgent orthopaedic referral for aspiration +- surgical washout is necessary. 

Connective tissue disorder: 

Transient synovitis: Fever and inability to bear weight can be a common presentation for transient synovitis. In this particular case, the initial diagnosis might have been wrong and the first inflammatory/infectious process could have triggered the production of antibodies causing inflammation over the joint. 

SOJIA (Systemic Onset of Juvenile Idiopathic Arthritis): Usually the joints affected by the arthritis are hot, tender and erythematous. We can suspect this pathology when there are different joints affected at different times. It is usually associated with systemic symptoms (fever and salmon pink rash, splenomegaly, serositis).

Diagnosis is made by elevated ESR, elevated ferritin, absence of antibodies, rheumatoid factor negative and exclusion of malignancy or infectious process.

CRMO (Chronic Recurrent Multifocal Osteomyelitis): this is an idiopathic inflammatory bone disorder with chronic multifocal bone pain. Sometimes systemic symptoms like fever can appear. Clavicle involvement is characteristic of this pathology.

Diagnosis is made by lesion’s biopsy: this will show an inflammatory reaction with no microbiological growth. 

Malignancies: 

Leukaemia: can present with bony pain and fatigue, lethargy and weight loss. Pancytopenia and blast can be seen in the blood film. LDH and uric acid are raised. Definitive diagnosis is reached with the bone marrow aspirate and flow cytometry.

Neuroblastoma: This is a malignancy that usually presents with abdominal mass. Sometimes mass can be found in the thoracic cavity. It appears in children below 5 years. The neuroblasts infiltrate the bone marrow. Therefore, patients can present with bony pain and pancytopenia. 

Diagnosis is reached by abdominal ultrasound and further imaging to evaluate the stage of the disease. Bone marrow aspirate is necessary along urine Vanillylmandelic Acid (VMA). 

Bone tumours (osteosarcoma /Ewing’s Sarcoma): 

Even though bone tumours are much less common than leukaemia and neuroblastoma, the presence of bony pain and prolonged fevers would prompt the diagnosis. LDH is usually elevated with raised calcium. 

X-Ray show bony abnormalities and further imaging with MRI or CT can provide more information. Sometimes biopsy of the lesion is necessary to confirm the diagnosis. 

Bone marrow is recommended in Ewing’s sarcoma. Metastasis and benign bone tumour should also be considered in the differential diagnosis.

Other: Histiocytosis:  this is a systemic illness which can affect bones. Associated symptoms are erythematous skin lesions, oral ulcers, lymphadenopathies, cough, shortness of breath, hepatosplenomegaly, malabsorption. Diagnosis is reached by seeing Langerhans cells in the biopsy of the lesion.

At this point, the patient has had a fever on and off for more than 3 weeks. A provisional diagnosis of osteomyelitis was made based on imaging findings. However, treatment is failing and the patient is now presenting with new symptoms (unable to bear weight). 

Repeated basic investigations:

Full blood count Hb 8.5 g/LWCC 1.0 x109/LLymphocytes 9.0 x109/LPlatelets 100 x109/LBlood cultureNegative
Peripheral blood film NormalUrine cultureNegative
CRP15 mg/LMantoux testNegative
ESR>40 mm/hHIV serologyNegative
Renal functionNormal rangeSickle cell testNegative
Liver function Normal range Chest XR Normal.
LDH900 U/L (240-480)
Uric Acid 12 μmol/L (High)

If after the above investigations, the clinician does not reach a diagnosis, then: 

  • Re-take a good clinical history 
  • Re-assessment of the patient
  • Withhold current medications
  • Do specific imaging (XR/Ultrasound/MRI of the new affected area)
  • Perform immunological studies: rheumatoid factor, ANA and anti-DNA antibodies, Immunoglobulins
  • Perform a bone marrow aspirate and trephine for histology, cytology and microbiology.

In this case, the diagnosis of osteomyelitis was discarded. SOJIA vs Leukaemia were the 2 main differential diagnoses.  Discussion regarding therapeutic steroid treatment for SOJIA was raised. 

Usually in PUO, steroid treatment should be avoided until malignancy is ruled out.  Steroids are used therapeutically in many oncology protocols. The use of steroids in an unconfirmed case of leukaemia can improve symptoms but it can blur the histological picture required for the diagnosis and confuse the staging process. This would lead to a delayed and potentially incorrect treatment. 

It is crucial to perform a bone marrow aspirate before steroid treatment is given, especially if there are symptoms and signs compatible with malignancies. 

In the above case, the full blood count showed mild pancytopenia which can be related to a bone marrow infiltration. The peripheral blood film was normal. Finally, the patient underwent a bone marrow biopsy and this confirmed the diagnosis of T-cell ALL. 

PET-CT is an imaging technique that localises anatomical parts with high metabolic activity, detecting hidden infections, malignancies or any inflammatory foci. 

PET-CT has proven to be useful in patients with PUO who are generally unwell, sick-looking, since early diagnosis is urgent in those patients. Otherwise, PET-CT can be used in those patients who have had extensive investigations done, have not had clinical improvement and still no diagnosis has been reached.

4-year-old boy presented with 5 days of fever, diarrhoea and vomiting and abdominal pain. No relevant past medical history. Fully vaccinated, BCG not included.

Initial blood test showed WCC 24.5 x109/L with neutrophils of 18 x109/L. CRP 139 mg/L. Hb 110 g/L and Platelets of 395 x109/L. He was admitted and started on amoxicillin, gentamicin and metronidazole. Blood cultures were negative and urine culture showed a sterile pyuria (WCC 2250 with no growth). Stool sample was negative. Abdominal ultrasound showed free fluid in the right iliac fossa. On examination, his abdomen was soft with some tenderness in lower quadrants.  He had a second ultrasound which showed findings suggestive of an appendicular mass. A repeated urine sample had 64 WBC and no growth. 

Meanwhile, fevers persisted: on day 7, he was changed to piperacillin-tazobactam and gentamicin. He underwent a laparoscopic appendicectomy on day 8. After operation, he was afebrile for more than 48 hours and antibiotics were stopped. Histological results of the appendix were normal. On day 12 of admission, the patient started again with fever and no focus on examination.

Now that the fever has restarted, and considering the previous history, what investigations would you ask? 

Would you re-start antibiotics? 

Looking at the pattern of fever below, what can you observe? 

Would an echocardiogram help in reaching the final diagnosis?

You should probably start by repeating basic investigations. Results: raised WCC with neutrophilia and thrombocytosis. Hb 101 g/L, WCC 32 x109/L with neutrophils of 24 x109/L, Platelets of 961 x109/L. He had normal renal and liver function.

Infectious diseases investigations: 

Microbiology cultures: Blood cultures were negative, even the prolonged culture for atypical bacteria. Stool sample was negative for viruses, bacteria and parasites. Urine sample became negative (previous sterile pyuria)

Toxoplasma serology:  IgG and IgM negative

CMV serology: IgM positive and IgG positive.  Second sample sent for CMV IgM negative. CMV PCR was negative. The initial positive IgM CMV was considered to be a false positive. IgM positivity in virology/microbiology assays may be non-specific, in patients with autoimmune diseases, cross-reactions.

EBV serology: IgM and IgG negative. 

Blood PCR for EBV, CMV and adenovirus negative.

Respiratory sample PCR: negative.

Lumbar puncture: LP was performed on day 14 of admission: WBC < 3/mm3. RBC <3/mm3. Viral PCR for enterovirus, parechovirus, mumps, VHS1&2 and VVZ negative. Negative culture.

Interferon Gamma Release Assay for TB negative. 

Inflammatory conditions investigations: 
Faecal calprotectin: negative. Since the patient had gastrointestinal symptoms and fever, Inflammatory Bowel Disease (IBD) should be considered as a potential differential diagnosis.

ESR: 50 mm/h.

Ferritin 222 ng/mL: important marker for inflammation. Especially high in Hemophagocytic lymphohistiocytosis /Macrophage Activation Syndrome.

Malignancies: 
Blood film: no atypical cells. Polychromasia and raised platelet count. Neutrophilia.

LDH 446 U/L (high)

Imaging
Day 12 Chest XR: normal
Day 13 Abdominal Ultrasound: normal kidneys and bladder. Normal liver, spleen, gallbladder and bile ducts. No abnormal masses or bowel wall thickening. Trace of fluid in right iliac fossa postoperatively. No fluid collection. 

The patient was clinically stable, so it was decided to wait and hold antibiotic treatment. The patient continued to have daily fevers up to 39°C. On day 14, he had one bilious vomit and became more lethargic therefore antibiotics were restarted (Piperacillin-Tazobactam and gentamicin). The following day, he underwent a Bone marrow aspirate and MRI under general anaesthesia with results as below: 

BMA: Trilineage haematopoiesis. No evidence of abnormal infiltration. No increased haemophagocytic activity. Appearances in keeping with a reactive marrow. Negative for AAFB, both microscopy and culture. 

Abdominal MRI:  There is moderate distention of the proximal small bowel with an apparent jejunal transition point due to ileus, adhesions or oedema from handling.  Some free fluid but no abdominal collections.  No retroperitoneal collection.  No bone marrow abnormality.

On day 16, he did not spike any temperatures.  After 48 hours (on day 18 of admission), he had an evening temperature of 38.5°C.

The patient had 2 episodes when he was apyrexial:

  • the first one between day 9- 11 after antibiotics were escalated (Piperacillin-Tazobactam and Gentamicin (D7)) and after surgery under general anaesthesia (D8).
  • The second afebrile period was on day 16-18 after being re-started on Piperacillin-Tazobactam and Gentamicin (D15) and after he underwent a procedure under general anaesthesia. 

In the first episode, the lack of fever was linked to a good response to antibiotics whereas in the second episode given the fact that a non-infectious condition was highly suspected as a differential diagnosis, the afebrile episode could be linked to the anaesthesia.

A very important investigation to perform in PUO is an echocardiogram to rule out infective endocarditis. In this case, there were no positive cultures or risk factors to point towards an infective endocarditis but it would be useful to rule out this disease. Echocardiography can also help to diagnose Kawasaki disease. In this particular scenario, it would be an incomplete case of KD. 

Reaching the diagnosis: 
On day 19, the patient had an echocardiogram which revealed dilated circumflex artery and an aneurysm of the left anterior descending artery. This finding confirmed the diagnosis of Incomplete Kawasaki. The ophthalmology review showed no pathological findings.  

DIAGNOSTIC CRITERIA FOR KAWASAKI DISEASE
Full case of KawasakiIncomplete case of Kawasaki
Fever (>38°C) every day for 5 days        +At least 4 of the following 5 featuresNon purulent bilateral conjunctivitisCervical lymphadenopathyPolymorphous rashLips/oral mucosa involvementFingers/toes: acute erythema and oedema of palms and soles and then peeling.
Or positive echocardiogram at any time with less than 4 features.
Fevers (>38°C) every day for 3 days+ less than 4 features but diagnosis supported by: Lack of alternative diagnosis (lack to respond to antibiotics, no other pathogen found)High inflammatory markers (high CRP, ESR, NeutrophiliaPresent of other clinical features: Irritability without CNS infectionBCG scar inflammationOther system involvement: CSF pleiocytosis, uveitis, arthritis, gastroenteritis, myocarditis, dysuria, sterile pyuria.

In our particular case: the patient had prolonged fevers with high inflammatory markers (CRP, ESR, Neutrophilia), irritability without CSF infection, sterile pyuria, low albumin, anaemia, thrombocytosis and lack of alternative diagnosis. Furthermore, he had a characteristic echocardiographic finding of Kawasaki Disease.

Patient was started on IVIG and aspirin. Steroids were included in the treatment since the patient already had evolving coronary and or peripheral aneurysm.

For more information on criteria for steroid use in Kawasaki disease, you can read: Eleftheriou D, et al.Managment of Kawasaki disease. Arch Dis Child,99,1 2013 

With regards to the antibiotics, gentamicin was stopped while Piperacillin-tazobactam was continued while evaluating response to IVIG. Piperacillin-tazobactam was stopped after 48 hours. 

Kawasaki disease is rare but early diagnosis is important to avoid cardiological sequelae. Incomplete Kawasaki can present a clinical challenge to diagnose.

You are in an Ethiopian rural hospital. A 7-year-old boy presents to clinic severely malnourished (marasmic type). Mother is complaining of daily fevers for an unknown period of time. 

Patient has cerebral palsy due to an obstructed labour resulting in hypoxic-ischaemic injury. He was in hospital for some time after delivery. He is not vaccinated. He is on phenobarbitone 100mg OD PO for seizures. 

You admit the child to the malnutrition ward and start the appropriate treatment with F-75 Milk. Part of the SAM protocol (Severe Acute Malnutrition) includes a course of at least 7 days with Amoxicillin.  On examination, the patient has a papular rash over hands and groin compatible with scabies but no other clinical findings. On the ward, he spikes a high temperature (39°C) and he is shivering. 

Available investigations at your hospital are performed:

Blood tests: 
Hb 9.1 g/LRenal function and CRP not available in this setting.
WCC 12 x109/L with neutrophils 8 x109/L and lymphocytes 4 x109/LUrine dipstick: leucocytes and nitrates positiveUrine microscopy: many white cells. No culture available.
Platelets 300 x109/LStool: negative for parasites
Blood film: No parasites seen
GGT 61 IU/LHIV antibodies negative
GOT 72 IU/LHepatitis B and C antibodies negative
Bili < 0.5  μmol/L

Based on the above clinical picture and results, what is your differential diagnosis and management? 

Patient was empirically treated but fevers persisted. Given his background of CP and the geographical area, what other infections would you consider?

What other non-infectious causes should be considered? How can you reach the diagnoses in this low-resource-setting?

This is a very challenging patient. Due to their reduced ability to communicate and cognitive impairment, these children are difficult to assess. Furthermore, this patient is malnourished which increases the risk of infections. 

The above results showed a possible UTI which is in keeping with the clinical picture (high fevers, shivering in a patient with high risk of UTI due to his cerebral palsy and poor bladder control). Antibiotics were changed from amoxicillin to amoxicillin-clavulanic to give broader cover for gram negative bacteria (E. Coli, Klebsiella…).

To note, the patient has scabies which is a very common parasitic skin infection that affects mainly the palms and soles and the groin area. If the patient has been scratching over the genital area, it could have triggered a UTI. Furthermore, there are poor hygiene conditions in the area with limited access to water.

The slightly raised GGT and GOT was correlated to the use of phenobarbitone. The hepatitis B and C were negative but the hospital did not have the test for hepatitis A. Nevertheless, the clinical symptoms were not fitting with hepatitis A. 

The patient was treated with co-amoxiclav for 7 days. He initially improved and fevers were spacing in time. However, on day 9 he started again with very high fevers and shivering. He was looking unwell during the fever episodes so he was started on ceftriaxone IV. His baseline temperature was always raised, he had abnormal movements and was irritable. Temperature persisted despite treatment

Another urine sample was requested to rule out a UTI due to a resistant bacterium, since microbiological cultures were not available in the rural hospital. The urine microscopy was negative for WCC and urine dipstick did not show any abnormalities.

Another important differential diagnosis was meningitis. Patient was irritable, had abnormal movements and a fever. The abnormal movements consisted of small twitching of the arms while crying inconsolably. There were considered either shivering or behavioural but there was a lot of discussion if those movements could represent a seizure event. Furthermore, mother was unable to describe the usual seizures that he had at home. The team subsequently realised that there was an error with the regular medications: he was prescribed 100mg of phenobarbitone but mother clarified that at home he was taking 200mg, therefore his daily phenobarbital dose was increased to 200mg OD. To note, the patient did not have any devices (VP shunt) which could increase the risk of infections. In this rural setting, clinicians were not able to perform a lumbar puncture due to lack of laboratory equipment, so the patient was started on ceftriaxone high dose empirically. 

Pneumonia can be a common cause of infection in patients with cerebral palsy since they can have drooling, unsafe swallow prompting for aspiration. Usually, pneumonia in these children can be very silent. In addition, poor nutritional status can increase the risk of severe pneumonia. Patient was not desaturating or with respiratory symptoms but a chest XR was done (in a private clinic) and no lung abnormalities were detected. Furthermore, based on local antimicrobial resistances, the antibiotics he received earlier should have been covered for the most common bacteria causing pneumonia. Gastric aspirate for GeneXpert MTB/Rif was negative. 

Dental infections with abscesses can also present with fever and no other major symptoms. The patient had poor oral hygiene plus the lack of proper tongue movement, drooling and lack of routine dental care made him more prone to these types of infections. These infections are mainly due to anaerobes which should be covered by amoxicillin-clavulanic or ceftriaxone. On examination, no suspicious dental masses were found. 

Viruses can also cause non-specific symptoms. However, they shouldn’t last for very long. He did not have any gastrointestinal symptoms or respiratory symptoms. No palpable lymph-nodes. Unfortunately, in the hospital there were no laboratory diagnoses for viruses.  Full blood count differential was never lymphocytic. 

The most common parasites in this rural area are intestinal parasites (Giardia, Entoaemabeas) and blood parasites (Malaria). Entoaemebas can present with a dysentery which can cause fever. However, our patient did not have any diarrhoea. 

This area has a moderate risk of malaria, especially during the rainy season. Patients with malaria present with very unspecific symptoms: from fever with general malaise or headache and vomiting to seizures, coma and shock. Therefore, any patient with a fever in a tropical setting should prompt investigations for malaria. The most important element in the clinical diagnosis of malaria is a high index of suspicion. 

To reach the laboratory diagnosis, parasites should be seen or detected in blood. Blood film microscopy (thin and thick blood films) is the gold standard for malaria diagnosis, identifies the Plasmodium species and also quantifies the parasitaemia. However, in low resource settings, where microscopy is not always available or reliable, rapid diagnostic tests (RDT) are used to diagnose malaria. The RDTs detect Plasmodium antigens confirming the presence of parasites in the blood but don’t provide any information regarding the species or the parasitaemia. 

Patients with malaria can be classified into severe or non-severe malaria based on clinical and laboratory findings as per the WHO 2015 Malaria Guidelines. This classification is crucial as it will guide treatment. The most important complications of malaria infection in children are cerebral malaria, severe anaemia, respiratory distress due to acidosis and hypoglycaemia. 

Severe Malaria
Clinical findingsLaboratory
-Impaired consciousness/unrousable coma (Glasgow score <11, Blantyre score <3)- More than 2 convulsions in 24 hours- Prostration- Deep breathings/respiratory distress- Shock- Bleeding – Jaundice with parasitaemia > 2% – Severe anaemia with parasitaemia- Acidosis- Hypoglycaemia- Hyperparasitaemia- Haemoglobinuria- Renal impairment

Patients with severe malaria should receive parental antimalarial treatment with Artesunate and supportive management followed by a full course of oral artemisin combination therapy (ACT). Patients with non-severe malaria can be managed with oral antimalarial medication. 

On admission, the initial blood film was negative for haemo-parasites. Repeat blood films and a Malaria RDT (rapid diagnostic test which detects Plasmodium falciparum antigens in blood after 20 minutes) were requested. Repeat Blood film revealed presence of Plasmodium falciparum trophozoites with a parasitaemia of 2%. 

So the patient was diagnosed with Severe Malaria given the suspicion of CNS involvement and started on IV Artesunate. The patient had a good clinical response with resolution of fever and completed a course of oral Artemisin combination treatment (Artemeter Lumefantrine). However, after one week, the fever reappeared. This time, it was a low-grade fever with maximum peaks at 38.5. Repeat blood tests were normal. 

Malignancies: In this case, blood film did not reveal any blasts, chest XR was normal and abdominal ultrasound did not reveal any masses. BMA was not available locally and since the patient was otherwise well, this was not considered necessary. 


Connective tissue disorders: 

SOJIA, AR are very uncommon but still a differential diagnosis of persistent fever. In this setting, no resources were available for auto-antibodies testing, therefore clinical findings are the main way of diagnosing it. Since the patient did not have any rash, arthritis… this diagnosis was not considered. 

Acute Rheumatic Fever (ARF): this condition is quite common in low resource countries due to increased risk of streptococcal tonsillitis due to poor hygiene, overcrowding, poor accessibility to health facilities, fake drugs…  Acute rheumatic fever is an illness caused by an inflammatory reaction to streptococcal infection. It causes an acute, generalised inflammatory response. This illness targets specific parts of the body including the heart, joints, brain and skin. ARF typically leaves no lasting damage to the brain, joints or skin, but can cause persisting heart damage.  Our patient did not meet the Jones’ Criteria of ARF. 

Miscellanea (other possible causes of fever): 

Central origin fever: children affected with cerebral palsy or other neurological disorders relatively often present with chronic intermittent febrile episodes persisting for months. These episodes are not related to any infections but are actually arising from an abnormal thermal regulation resulting from the brain injury.

Hyperthermia from severe dystonia: children with cerebral palsy with dystonia can present with fevers and elevated basal temperature associated with elevated creatinine phosphokinase levels. 

Drug related fever: medications can trigger fevers. Common medications used in cerebral palsy are anticholinergic drugs (e.g. hyoscine) which can provoke unwanted fevers as a side effect. In addition, withdrawal of medications can present with fever (baclofen withdrawal syndrome). 

Lastly, factitious fever is a very challenging diagnosis. Sometimes admissions to hospital and close measurement of fevers plus observation of patient and carer interaction is as important as complementary tests. 

After 2 months of intermittent fever, it finally stopped. Basal temperature was always slightly elevated. Patient was diagnosed with central origin fever.

 The majority of PUOs are caused by: 

A: Malignancy

B: Connective Tissue Disorder 

C: Infections

D: Other diagnosis

E: Unknown diagnosis

The correct answer is C.

Infectious diseases are the main cause of PUO (about 38%), especially in younger children. No diagnosis is reached in 30% of cases but these tend to be benign and self-limited. This is followed by connective tissues disorders (13%) and Other diagnosis (13%). Lastly, malignancies are very uncommon but very important to consider given the severity of the disease.

A patient admitted to your hospital has been spiking fevers every day for 12 days. No other clinical findings are present. What is your next step? 

A: Repeat basic investigations, re-take clinical history, re-examine the patient, perform a Bone marrow aspirate.

B: Repeat basic investigations, re-take clinical history, re-examine the patient and do adequate imaging depending on clinical findings.

C: Perform a PET-CT to localise the pathology.

D: Perform autoimmune studies.

E: Perform a bone marrow aspirate.

The correct answer is B.

In many PUO cases, clinical findings are very subtle and can appear days after the fever. Therefore, re-taking the clinical history and re-examining the patient carefully is key to guide the complementary tests.

A Turkish 5-year-old girl presented with high fevers, profuse night sweating for 21 days.  Clinical detailed history revealed that parents are not consanguineous. She doesn’t have any relevant past medical history. She is fully vaccinated. The whole family was in Turkey for 2 months over the summer holidays. They were living in a farm in rural Turkey where they had goats, cows and chickens. They were drinking fresh milk from the cow. Based on the history, what diagnosis would you consider? 

A: Tuberculosis 

B: Bartonella (Cat-scratch)

C: Brucellosis

D: Toxoplasmosis

E: Lyme disease

The correct answer is B.

Brucellosis is a zoonotic infection caused by ingestion of unpasteurized milk from infected animals. It is also known as the Mediterranean fever. It is caused by a bacterium called Brucella melitensis. The main symptoms are fever, profuse sweating and joint and muscle pain. 

An unaccompanied asylum seeker from Uganda has just arrived in the UK. He refers to being a 12-year-old. He has had fevers for a prolonged time. On examination, he has splenomegaly. Blood tests revealed pancytopenia. Blood film is negative for malaria. HIV and hepatitis B, C negative. He said that in his country many people have these symptoms and they call it Kala-azar. What kind of tropical infection is he referring to? 

A: Visceral Leishmaniasis 

B: Schistosomiasis. 

C: Non falciparum malaria 

D: Visceral Larva Migrans

E: Echinoccocus granulosus

The correct answer is A.

Kala-azar is the local term for Leishmaniasis. This is a parasitic disease spread by the sand-fly. Main symptoms are fever, enlargement of spleen and liver and pancytopenia. Leishmaniasis is the second-largest parasitic killer in the world after malaria. Diagnosis is made by histological finding of amastigotes on spleen aspiration/bone marrow aspiration and RK39 Antigen detection.

A roadmap for fever of unknown origin in children- Rigante, D; Esposito S., International Journal of Immunopathology and Pharmacology. Vol.26 no 2, 315-326 (2013)

Fever in Children and Fever of Unknown Origin- Rajeshwar Dayal, Dipti Agarwal, Indian Journal of Paediatrics, 83 (1): 38-43 (2016)

Pyrexia of unknown origin-Mark Wood, Mario Abinun and Helen Foster. Archives of Disease in Childhood, Education and Practice, 89 ep 63-69 (2004) 

Barbi E, Marzuillo P, Neri E, Naviglio S, Krauss BS. Fever in Children: Pearls and Pitfalls. Children (Basel). 2017;4(9):81. Published 2017 Sep 1. doi:10.3390/children4090081

Antoon J,Peritz D, Parsons M., Skinner A.,Lohr J. Etiology and resource use of fever of unknown origin in Hospitalized children. Hospital Pediatrics, 8 (3).: 135-140(2018)

For malaria: 

https://apps.who.int/iris/bitstream/handle/10665/79317/9789241548526_eng.pdf;jsessionid=AD1DDC86455A8D51D25CFEEADF7E1C75?sequence=1

Website resources: 

https://pedemmorsels.com/fever-of-unknown-origin/

https://dontforgetthebubbles.com/ent-infections-immunodeficiency/

https://dontforgetthebubbles.com/recurrent-or-periodic-fevers-investigate-or-reassure/

https://dontforgetthebubbles.com/tuberculosis/

https://dontforgetthebubbles.com/claire-nourse-tuberculosis-at-dftb17/

https://radiopaedia.org/articles/tuberculous-cervical-lymphadenitis

https://gppaedstips.blogspot.com/search/label/Juvenile%20idiopathic%20arthritis

https://www.paediatricfoam.com/?s=kawasaki

https://gppaedstips.blogspot.com/search?q=kawasaki

https://dontforgetthebubbles.com/josh-francis-rheumatic-heart-disease-at-dftb17/



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The DFTB Podcast – Antibiotic Myth Busting

Antibiotics. I’m sure we’ve all been guilty of giving a child in our department a course of antibiotics “just in case”. After all, what harm can it do? In this week’s podcast we talk to Dr Alasdair Munro, a Clinical Research Fellow in Paediatric Infectious Diseases about this and much more as we go antibiotic myth busting!!

Don't Forget the Bubbles
Don't Forget the Bubbles
The DFTB Podcast - Antibiotic Myth Busting







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Antibiotic stewardship: Amanda Gwee at DFTB18

Cite this article as:
Team DFTB. Antibiotic stewardship: Amanda Gwee at DFTB18, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.20592

Dr Amanda Gwee is a clinician-scientist fellow in the MCRI Infectious Diseases and Microbiology group. Her area of research interest revolves around the appropriate dosing of antibiotics.

Respiratory Tract Infections in children

Cite this article as:
Patel,S and Munro, A. Respiratory Tract Infections in children, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.18906

Emily is a 2 year old girl brought to the emergency department with her mum, following two days of fever and poor intake. She has a temperature of 39°C and looks a little unhappy, but has no red flags for sepsis. On examination of her throat you see she has enlarged, red tonsils bilaterally with exudate. Her examination is otherwise normal. Should you prescribe her antibiotics?