Searching for sepsis

Cite this article as:
Anna Peters. Searching for sepsis, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.31160

The child with “fever” is one of the most common paediatric presentations to the emergency department. Most of these children are managed conservatively with parental reassurance and discharged home with a safety net identifying red flags. However, failing to identify those with “sepsis” has devastating consequences. How often do we get it wrong or worry about getting it wrong? We’d all love an evidence-based clear cut path for flagging and managing febrile children at risk of sepsis. Currently the approach in the UK is predicated on the NICE SEPSIS (NG 51) screening system which has anecdotally performed poorly with concerns it is poorly specific (i.e lots of false positives). Nijman and colleagues aimed to objectively assess the impact of the NICE Sepsis screening approach in children.

Nijman RG, Jorgensen R, Levin M, Herberg J and Maconochie IK. Management of Children With Fever at Risk for Paediatric Sepsis: A Prospective Study in Paediatric Emergency Care. Frontiers in Pediatric Care 2020; 8:548154. doi: 10.3389/fped.2020.548154

The lead authors looked at the various warning signs of serious infections in febrile children presenting to PED. Their aim was to then determine these children’s risk of having sepsis and to evaluate their subsequent management.

Who did they study?

Over 5000 children (5156 to be exact) aged 1 month to 16 years old presenting with fever over a period of 9 months from June 2014–March 2015 in a single PED at St Mary’s Hospital, UK were analysed.  Febrile children with no warning signs of sepsis were then excluded from the final cohort. The second largest group excluded from the final cohort was children with a complex medical history (n=119).  The decision to exclude this particular cohort is important given that ‘complex medical patients’ are more likely to have sepsis. The authors make the valid point that this group has features very different from the intended cohort, such as having different management plans in the context of fever. After these exclusions, plus a few further exclusions (lack of consent, lack of complete data or excluded because the child didn’t have any warning signs) the final cohort was of 1551 children. 

What did they do?

They first looked at the numbers of febrile children with tachycardia and tachypnea by using APLS and NICE (the National Institute of Healthcare Excellence) thresholds.  Subsequently, they looked at the numbers of febrile children fulfilling sepsis criteria by using well-known sepsis screening tools (NICE traffic light guidelines, SIRS, qSOFA, Sepsis Trust UK trigger criteria).

All the data for this study (vital signs, clinical signs and symptoms, tests, working diagnosis, need for hospital admission, timeliness of interventions) were collected electronically, having been recorded prospectively for all febrile children.

What did they look for? 

As a primary outcome the study determined:

  1. The incidence of febrile children who present with warning signs of sepsis 
  2. How often these children fulfilled paediatric sepsis criteria 
  3. How frequent invasive bacterial infections (IBIs) occurred in this population 
  4. How frequent PICU admissions occurred in this population.

Secondary outcomes included the compliance of clinicians with the paediatric sepsis 6 care bundle (PS6), what clinical interventions were and were not used from this care bundle and the timeliness of the interventions that were undertaken

What did they find? 

Almost a third of children aged 1 month to 16 years who presented to the PED had fever (28% to be exact).

41% of these febrile children had one or more warning signs (our study population).

The incidence of IBI was 0.39%. Of these children, only 0.3% required PICU admission.

This meant that using the sepsis guideline recommendations, 256 children would need to be treated to catch one IBI. Another way of saying this is the number needed to treat was 256. NNT for any serious outcome was 141.

How did the sepsis guidelines fare?

The thresholds for tachycardia and tachypnoea yielded a high false positive rate.

Adding sepsis criteria to predict the presence of a serious bacterial infection (SBI), IBI or PICU admission was also unreliable, with a lot of false positives.

Lactate levels were not significantly associated with the decision to give IV fluid bolus or presence of SBI, IBI or PICU admission. There WAS, however, a significant association between lactate levels and hospital admission.

Looking at the Paediatric Sepsis 6 Interventions, although many children triggered, two-thirds (65%) of the children with PS6 warning signs had none of PS6 interventions. And when it came to the ‘golden hour? Only a third (36%) of children with IBI or PICU admission received all PS6 interventions in the ‘golden hour with only 39 children (2%) receiving a fluid bolus

What does this all mean?

It is important to note that this study was only conducted in one single PED and in a time period that was before the NICE sepsis guidelines were formally implemented into practice.  The data was collected for this study via an electronic interface. While large amounts of data can be collected rapidly there can sometimes be gaps, either due to extraction issues or brevity on the behalf of clinicians that don’t give a comprehensive picture. Data were also only taken from initial triage and not from any clinical deterioration in the ED.  Given that acuity changes over time, especially in children with fever, this may have missed subsequent clinical change although is a pragmatic approach given the way that sepsis screening tools are applied in nearly all Emergency Departments. 

Numbers needed to treat were exceptionally high. Despite the allure of a protocol-based screening and management pathway,  the benefits of catching true sepsis early must be weighed against the possible unwanted effects of overtreating or overdiagnosing mostly well children in a potentially resource-stretched PED. The study really does highlight the difficulties we face when screening for a septic child in a generally well cohort, the ‘needle in a haystack’.

Essentially, what this study shows us is that serious infections are rare and most children who are categorised as ‘at risk of sepsis’ can in fact be managed conservatively with little intervention other than observation. It is clear that our current guidelines have very poor specificity; and while they tell us to investigate and treat lots of children, a lot of the time we as clinicians choose to rely on our clinical judgement and essentially ‘do nothing’. Observation and good clear red flagging must not be underestimated.  Instead of continuing to research more and better early predictors of sepsis, such as point of care biomarkers, perhaps we should be looking at this from another angle. The focus of the lens can also be flipped; we also need more research on how it can be safe NOT to do anything too. 

We’ll end with some thoughts from the authors

The Infections in Children in the Emergency Department (ICED) study is a single centre, prospective observational study. The study describes unique and carefully curated clinical data of febrile children with warning signs of sepsis, from a period prior to the implementation of the NICE sepsis guidelines. 

Our results confirm what many paediatricians dealing with acutely unwell febrile children already suspected: that many febrile children have warning signs of sepsis, but that the large majority have non-life threatening infections. 

Our findings will hopefully contribute to ongoing discussions about the use of sepsis screening tools in paediatric emergency medicine. Our study makes it clear that current tools lead to a high number of false positive cases, and their usefulness in routine clinical care in paediatric emergency medicine should be questioned. Escalation to senior decision makers of all children with warning signs of sepsis should be aspired, but is seldomly feasible in clinical practice and with unproven impact on reducing missed cases and optimising clinical care for the total cohort of febrile children. 

Although all children with serious infections would have been detected by the various sepsis tools, it is now evident that we need better tools to more selectively identify children at the highest risk of sepsis. Future studies should explore the utility of machine learning as well as the potential of combining clinical signs and symptoms with point of care biomarkers.

Ruud Nijman

The febrile infant conundrum

Cite this article as:
Dani Hall. The febrile infant conundrum, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.28850

It’s fair to say that febrile infants can be challenging. Often presenting with insidious symptoms but looking reasonably okay, they may still have life-changing or life-limiting illnesses like sepsis or meningitis. You could argue that we should take the view of eliminating risk, performing septic screens on all febrile babies, and admitting for IV antibiotics until their cultures are returned. The vast majority will have a benign viral illness but at least you can rest assured you didn’t miss a seriously sick infant.

And that’s what we did when I started my paediatric training back when the dinosaurs roamed the earth – every baby under 6 months (yes, you heard it right, 6 months) with a fever got a full septic screen, including lumbar puncture, and was admitted to the ward for at least 48 hours pending cultures. But, from a health economics point of view, this is, let’s just say, perhaps not the best way to allocate healthcare resources.

Over the years, researchers have tried to rationalise our approach to febrile infants. 2013 saw the first NICE fever in under 5s guideline; a year later a group from Spain published the Step by Step approach to identifying young febrile infants at low risk for invasive bacterial infection; and last year, the PECARN group published a clinical prediction rule for febrile infants under 60 days, which had excellent sensitivity and negative predictive values to rule out serious bacterial infections.

Last month, the Spanish group published an article looking at the external validity of the PECARN rule in their dataset.

Velasco R, Gomez B, Benito J, et al. Accuracy of PECARN rule for predicting serious bacterial infection in infants with fever without a source. Archives of Disease in Childhood Published Online First: 19 August 2020

PICO image

Before we plunge into the paper, let’s stop and think about a couple of important definitions here:

Serious bacterial infection (SBI) is used to describe bacteraemia, meningitis and urinary tract infections, also including infections such as pneumonia, skin, bone and joint infections, bacterial gastroenteritis and sometimes ENT infections.

Invasive bacterial infection (IBI) are infections where bacteria are isolated from a normally sterile body fluid, such as blood, CSF, joint, bone etc. An IBI is a type of SBI in a sterile site.

Who did they study?

Velasco’s group looked back at their registry of infants with a fever without source from a busy paediatric ED (> 50,000 presentations a year) in a tertiary hospital. To match the cohort in the PECARN paper, they used the following inclusion and exclusion criteria:

Inclusion: infants younger than 60 days who presented with a recorded fever, or history of recorded fever, of >38 C over an 11 year period between 2007 (when they started measuring procalcitonin) and 2018.

Exclusion: any infants whose history and/or examination pointed towards a focus, whose results didn’t include those used in the PECARN rule (absolute neutrophil count, PCT, urine dip), who didn’t have culture results, who were critically ill on presentation or who had a past history of prematurity, unexplained jaundice, previous antibiotics or other significant past medical history.

What were they looking for?

The group were interested to see how the PECARN rule fared in their dataset by looking at how many infants were predicted to be low-risk and yet had an SBI or IBI to assess the external validity of the rule.

What did they find?

1247 infants were included in this study. Of these, 256 (20.5%) were diagnosed with an SBI, including 38 (3.1%) with an IBI.

Of the 256 infants with an SBI, 26 (10%) were considered low risk by the rule. Of the 38 with an IBI, 5 were considered low risk (13.2%) by the rule. The PECARN rule would have missed 10% of infants with an SBI.

The PECARN rule’s sensitivity dropped from 97.7% in the original study to 89.8% and specificity dropped to from 60% in the original study to 55.5%.

So, how did Velasco’s group calculate the sensitivities and specificities of the PECARN rule for different groups in their dataset? They’ve nicely shown their data in 2 x 2 contingency tables in their figures. This is the data for SBI.

Table of data from Velasco study

So, we can see that sensitivity (those patients testing positive for the SBI as a proportion of all patients who definitely have SBI) = 230 / 256 = 89.8%. This means that 10.2% are falsely negative.

Specificity (those patients who test negative for SBI as a proportion of all of those who don’t have SBI) = 550 / 991 = 55.5%. This means that 44.5% are falsely positive.

What about infants with a really short duration of fever?

When the group looked at infants with a history of less than 6 hours of fever (n=684, a little over half of the cohort), the sensitivity dropped further to 88.6%.

Why did the PECARN rule perform less well in this study?

The authors offer up a number of suggestions, some of which are outlined below.

The populations may be slightly different. Although the authors attempted to exclude ‘critically ill’ infants from this study (as the PECARN study excluded ‘critically ill infants’), a precise definition wasn’t coded in the original Spanish registry. Instead, they excluded infants from this study if they were ‘not well looking’ or admitted to ICU. Because of the way the data was coded, some critically ill infants may have been included in this study’s dataset, skewing the results.

The Spanish database was of febrile infants without a source, excluding babies with respiratory symptoms, which may explain why the rates of SBI and IBI were much higher in this study than the PECARN database of febrile infants. So, although the PECARN rule was highly sensitive in their group of febrile infants, as in this study it may not perform so well in febrile infants without a source.

This study showed that the PECARN rule performed less well in infants with a short duration of fever. Overall, infants in the PECARN study had a longer history of fever at presentation – over a third of the PECARN infants had fever >12 hours compared to 11% in this study. Over half of the infants in this study presented within the first 6 hours. Blood tests are less sensitive in the first few hours of a febrile illness and this may well partially explain why the rule performed less well outside the PECARN dataset.

It’s important not to ignore this study’s limitations. The PECARN dataset recruited infants from multiple centres, while the registry for this study came from only one ED. As this study was a secondary analysis of a dataset, a power calculation wasn’t performed. Generally, a minimum of 100 cases is recommended for validating a model, but only 38 infants in this study had an IBI.

Study bottom line

This study showed that in the Spanish dataset of infants under 60 days with a fever without source, the PECARN rule performed less well than in the original study. This was especially true for infants with a short history of less than 6 hours of fever.

Clinical bottom line by Damian Roland

In Kuppermann et al’s original 2019 study febrile infants 60 days and younger were demonstrated to be at low risk of SBIs using 3 laboratory test results: Urinalysis, Absolute Neutrophil Count (ANC), and serum procalcitonin (PCT) levels. The study was well designed and therefore compelling in providing a framework in which to manage these challenging presentations. However, with respect to knowledge translation, external validity is critical. The availability of PCT is a significant limiting factor to being able to show the PECARN approach could be reproduced internationally. While PCT is used in Europe and Australia, it’s certainly not widespread in the UK where I practice, and then it is only used routinely in a very small number of hospitals. This makes Velasco and colleagues’ work really important as they were able to replicate the requirements of the original study and helps answer an important question: should centres start introducing PCT into their diagnostic pathology panels? The results of this study will be interpreted differently by different observers as ultimately the question is of risk tolerance. Personally, a 10% false-negative rate (if this is indeed the case) for an outcome that could result in long term disability feels uncomfortable. Counselling a parent that they could return home without treatment knowing this would probably be quite challenging. I am not sure many departments would be rushing to buy point of care PCT.

However, there are two very important caveats.  Firstly, is the validation cohort different from my own local cohort? The prevalence of disease has a huge bearing on the accuracy of any test. Knowing the local incidence of SBI and IBI in your own institution is important (but actually getting the numbers is harder than you may think!). It is likely that the PECARN approach may perform more effectively in other centres. Importantly the original paper highlights that implementation may be more effective in the second month of life due to the impact of HSV and other peri-natal infections present at 0-30 days. Secondly, what is the threshold for undertaking the blood tests in the first place? Fever in an infant less than 3 months is an interesting area as it’s one of the very few presentations in which a solitary symptom or sign is independently predictive of risk. Regardless of how the child appears to a health care professional, there is a risk of SBI and IBI (of anywhere between 2-10%) just by having a fever. This does mean that sometimes there is variation in approaches when there is a history of fever rather than a documented fever (for fear of not wanting to do a battery on tests on a neonate who in front of you appears completely well and has normal observations). But more importantly, this has led to an approach where although blood tests are taken, the results are often disregarded as an LP will be done and antibiotics will be given regardless. There are many cultural practices that have evolved around the management of the febrile neonate both within individuals and institutions. While in a study situation these are controlled for, their influence in the real world can not be underestimated and this is why it’s so important we have some pragmatic studies in this area.

This study makes me more determined to define our incidence of SBI locally and work out what impact new approaches to management may have. I think all centres should probably be doing this. However knowing the potential uncertainty in the sensitivity of the PECARN approach means it’s unlikely to be adopted in the immediate future without further validation.  

**post blog addendum 1st September 2020**

While this blog was in post production phase Kuppermann and colleagues have released further data on implementing their original predictive rule. This work has been summarised by Dr. Kuppermann below (click on to go to the original thread) and provides useful context to the discussion about external validity and implementation – DR.

Does Every Child With Fever Have Sepsis? Damian Roland at DFTB19

Cite this article as:
Team DFTB. Does Every Child With Fever Have Sepsis? Damian Roland at DFTB19, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.20382

Damian Roland is a Paediatric Emergency Medicine and Honorary Associate Professor, who is also the chair PERUKI (Paediatric Emergency Research United Kingdom and Ireland). Damian delivered this thought-provoking talk on guidelines, gestalt and real-world practice on behalf of Rachel Rowlands, who was unable to attend. You can follow him in Twitter at @Damian_Roland 

#doodlemed on this talk by @char_durand below

This talk was recorded live at DFTB19 in London, England. With the theme of  “The Journey” we wanted to consider the journeys our patients and their families go on, both metaphorical and literal. DFTB21 will be held in Brisbane, Australia.

If you want our podcasts delivered straight to your listening device then subscribe to our iTunes feed or check out the RSS feed. If you are more a fan of the visual medium then subscribe to our YouTube channel. Please embrace the spirit of FOAMed and spread the word.

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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Surviving Sepsis Campaign International Guidelines

Cite this article as:
Damian Roland. Surviving Sepsis Campaign International Guidelines, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.23460

The lens with which you view sepsis is dependent on the environment and emotion in which you associate the term. For a parent, this may be the spectrum from having never heard the term before “Your child is well enough to go home, we’ve ruled out sepsis and other serious conditions” to the anguish of being told, “I’m afraid your child died of sepsis“. This spectrum remains equally wide for health care professionals. A family doctor or general practitioner may never see a case of confirmed sepsis, and an emergency clinician can potentially go years between seeing a truly shocked child. An intensivist, however, may deal with the consequences on a weekly basis. Even in the last month, we have seen two papers from the same publishing group; one highlighting the global burden of sepsis and the other challenging the current hype surrounding its recognition and management.

Regardless of your viewpoint, the publication of the Surviving Sepsis campaign’s international guidance will have been of interest.

 

Weiss, S.L., Peters, M.J., Alhazzani, W. et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 46, 10–67 (2020). https://doi.org/10.1007/s00134-019-05878-6

 

It is important to recognize two features of this publication which should carry an important health warning in its interpretation.

The first is that the authors are clear that they are focusing on severe sepsis or septic shock. While in adult practice definitions have changed, these have not been formalized or ratified for children:

 

“For the purposes of these guidelines, we define septic shock in children as severe infection leading to cardiovascular dysfunction (including hypotension, need for treatment with a vasoactive medication, or impaired perfusion) and “sepsis-associated organ dysfunction” in children as severe infection leading to cardiovascular and/or non-cardiovascular organ dysfunction.”

 

The authors clearly recognize that the absence of a clear definition of paediatric sepsis is challenging health care providers and organizations. The group has steered away from suggesting management options in the ‘pre-sepsis’ group i.e. those children with potential infections that may result in sepsis and have physiological instability but without organ dysfunction. They suggest that management practices for this group aren’t radically different, however:

 

Even though these guidelines are not intended to address the management of infection with or without SIRS when there is not associated acute organ dysfunction, we recognize that sepsis exists as a spectrum and some children without known acute organ dysfunction may still benefit from similar therapies as those with known organ dysfunction

 

The second is that this is a consensus document. It is neither a systematic review nor a clinical practice guideline (in a local hospital sense). It comprises the opinions of an expert group of clinicians (49 in fact) from a variety of international settings using the best available evidence. The publication is essentially a list of recommendations. This approach is valid in situations where evidence may be heterogeneous and that randomized controlled trials can not be performed for all possible permutations of clinical practice. As with all things in science, however robust the data is, it still needs interpreting and that interpretation is subject to all manner of explicit and implicit bias.

 

The panel supports that these guidelines should constitute a general scheme of “best practice,” but that translation to treatment algorithms or bundles and standards of care will need to account for variation in the availability of local healthcare resources.

 

Without becoming meta it’s important that this blog itself needs a health warning. It’s an interpretation of an interpretation of evidence.

So the big-ticket items

1. A child was defined as beyond 37 weeks gestation and up to 18 years old.

2. They apply to children with severe sepsis or septic shock as defined by the 2005 International Pediatric Sepsis Consensus Conference or inclusive of severe infection leading to life-threatening organ dysfunction.

2005 definition:

  • greater than or equal to two age-based systemic inflammatory response syndrome (SIRS) criteria
  • confirmed or suspected invasive infection, and cardiovascular dysfunction
  • acute respiratory distress syndrome (ARDS), or greater than or equal to two non-cardiovascular organ system dysfunctions

Septic shock was defined as the subset with cardiovascular dysfunction, which included hypotension, treatment with a vasoactive medication, or impaired perfusion.

3. Panel members were selected through recommendations from chairs and vice-chairs of the 12 worldwide member organizations. Each panel member was required to be a practicing healthcare professional with a focus on the acute and/or emergent care of critically ill children with septic shock or other sepsis-associated acute organ dysfunction. There was lay representation and the final membership was felt to be demographically diverse with regard to sex, race, and geography.

4. The panel was assisted by various methodological experts and split into six groups

  • recognition and management of infection
  • hemodynamics and resuscitation
  • ventilation
  • endocrine and metabolic therapies
  • adjunctive therapies
  • review research priorities in pediatric sepsis

5. A list of critical questions was developed in the PICO format (Population, Intervention, Control, and Outcome) which was then rigorously searched for by a specialist medical librarian and the resulting literature assessed according to GRADE criteria a well-recognized methodology for systemically presenting summaries of evidence.

6. Following discussion and debate recommendations would be made:

 

We classified recommendations as strong or weak using the language “We recommend…” or “We suggest…” respectively. We judged a strong recommendation in favor of an intervention to have desirable effects of adherence that will clearly outweigh the undesirable effects. We judged a weak recommendation in favor of an intervention to have desirable consequences of adherence that will probably outweigh the undesirable consequences, but confidence is diminished either because the quality of evidence was low or the benefits and risks were closely balanced.

 

The paper goes into considerable detail (which is why it is 55 pages long) into the rationale behind the recommendations. They are all summarised in the appendix (commencing page e102). It is beyond the scope of this blog to explore all the recommendations in detail, and it is important that health care providers read the paper itself. The following highlights some of the areas which may prompt debate or query.

 

‘Screening’ remains in

For those in emergency and acute care, this recommendation may have come as a surprise given a large amount of anecdotal feedback and experience suggesting that current screening mechanisms for the un-differentiated child are neither specific nor sensitive. It is worth nothing again the panel was looking at severe sepsis or shock and the evidence for ‘bundles’ of care i.e. targeted or mandated treatments once recognized is relatively robust. There is a further section on protocols/guidelines for treatment but it may have been useful to separate the afferent limb (recognition) from the efferent limb (response) in relation to collated evidence. This is important as the evidence for ‘bundles’ is cited under screening, with minimal evidence of screening approaches alone put forward (or to be fair to the panel perhaps of insufficient quality to make a judgment on).

Although subtle I think the panel recognized how important local buy-in is in relation to quality improvement. Of note, there is nothing on national guidance for recognizing sepsis. They also highlight how blindly integrating screening with any other scoring system may not be as beneficial as believed.

Ultimately no one particular screening system is recommended.

 

There is no target lactate

There appears to be a palpable sense of regret that the evidence didn’t support any particular threshold for lactate. Despite evidence of rising mortality with increasing lactate, the panel was not able to determine a specific level.

However, no RCTs have tested whether initial or serial measurement of blood lactate directly informs evaluation and/or management in children. Lactate levels should, therefore, be interpreted as a part of a more comprehensive assessment of clinical status and perfusion.

 

Take blood cultures but don’t delay treatment to obtain them

Appreciating this isn’t a particularly scientific response, but well, duh.

 

One hour time to treatment for those in shock but up to three hours without it. 

This is the potential game-changer from this body of work. While the evidence shows a temporal relationship between the administration of antibiotics and outcome in severe sepsis some pooled data demonstrated that it was unlikely the hour alone made the difference. Given the numerous papers showing a linear relationship between time to administration and outcome the ‘golden hour” was maintained. In the absence of shock, the panel felt, based on data showing a three-hour threshold effect, this would be a reasonable time point. This will be a welcome relief for those working in areas where there are associated penalties for not reaching the hour window and hopefully will remove some of the gaming associated with this target.

 

Broad spectrums antibiotics, but narrow when pathogens available

Little controversy here. The panel highlight that 48 hours should be the maximum time that is allowed to pass before re-evaluation in the absence of culture growth rather than a standard time to elapse.

If no pathogen is identified, we recommend narrowing or stopping empiric antimicrobial therapy according to clinical presentation, site of infection, host risk factors, and adequacy of clinical improvement in discussion with infectious disease and/or microbiological expert advice.

There are a number of recommendations on immunocompromised children and source control which appear pragmatic.

 

Bolus if intensive care available, if not then don’t unless documented hypotension

In units with access to intensive care, 40-60ml/kg bolus fluid (10-20ml/kg per bolus) over the first hour is recommended. With no intensive care, and in the absence of hypotension, then avoiding bolus and just commencing maintenance is recommended. It is not clear how long access to intensive care has to be to switch from fluid liberal to restrictive.

**Post-publication note (13/02/20): A more correct description of no intensive care would be “in health systems with no access to intensive care”. The guidance states, “For children with septic shock without signs of fluid overload in low-resource settings where advanced supportive and intensive care is not available, the panel recommends against bolus fluid administration,”. This question is raised in the comments section below as for units in without intensive care on site but it will resourced health systems then ‘access’ to intensive care should be assumed**

For purposes of this weak recommendation, hypotension can be defined as:

 

The panel suggests crystalloids, rather than albumin, and balanced/buffered crystalloids rather than 0.9% saline. They recommend against using starches or gelatin.

 

Use advanced haemodynamic variables, not bedside clinical signs in isolation

The evidence didn’t support a target mean arterial blood pressure but suggested avoiding using clinical signs to differentiate into cold and warm shock. No one monitoring approach was advised but included cardiac output, cardiac index, systemic vascular resistance, and central venous oxygen saturation.

 

Intensive care vasoactive and ventilation management is given but acknowledged as weak recommendations 

There is a list of suggestions regarding vasoactive infusion and ventilatory strategies that are very specific to intensive care management. While a number of recommendations are given (epinephrine rather than dopamine for septic shock for example) these are generally based on the panels summation of weak evidence.

There are further suggestions on corticosteroid management, nutrition, and blood products which will be of interest to those in intensive care and anaesthetic settings.

 

Summary

This is a very rich piece of work that is well structured and easy to read (even if you are not an expert on a particular field of practice). For most paediatricians there is unlikely to be an immediate change in practice but the softening of antibiotic time to delivery in the non-shocked child and emphasis of local review of sepsis incidence and performance will be welcome. How these filter into national guidance will be determined country by country but it is unlikely that radically different views can be drawn from the available evidence. What is still sorely needed is a working definition for the non-hypotensive child with sepsis (or an acknowledgment that perhaps this isn’t really a clinical entity…)

 

Hot Garbage: Mythbusting fever in children

Cite this article as:
Alasdair Munro. Hot Garbage: Mythbusting fever in children, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.22916

Juniper is a 3yr old girl brought in with her mother, with a 48hr history of fever. Her mum is particularly concerned because her fever was up to 39.8°C, didn’t come down with paracetamol and she describes an episode which sounds like a rigor. On examination, she has a temperature of 39.3°C, a runny nose and bright red tonsils, and looks otherwise well. You go to discharge her, but your colleague asks if you should wait to see if her temperature comes down with ibuprofen before sending her home?

 

Introduction

Febrile illnesses are the most common cause of presentation to acute paediatric medical services. This means that fever is the most common presenting symptom seen by paediatricians, and it is clearly a huge cause of concern for parents. Despite this fact, it is clear that in day-to-day practice that there is a widespread misunderstanding about fever, its purpose, and its clinical interpretation.

Well, no longer! Once you have finished reading, you will be a master of all things related to fevers in children. We will start with some basic understanding of the processes surrounding fever, and finish off with some mega myth-busting!

What is fever?

Fever is an elevated core body temperature, as part of a physiological response to infection regulated by the hypothalamus. This is crucial to understand – your body is in control of your temperature. This is not something an infection is doing to your body; it is something your body is doing to the infection. This is different from pathological hyperthermia, where your temperature is elevated by either hypothalamic dysfunction or external heat. These are extremely rare.

Note: there are other, non-infectious causes of fever, such as cancer, Kawasakis, and autoinflammatory conditions, but these are rare in comparison to infectious fever and are covered elsewhere.

 

What temperature counts as a fever?

At what threshold do we say a child has an elevated body temperature? This is more controversial than one might think, as actually the data from which we derive “normal” body temperature is extremely poor. The most common cut off for defining a fever is 38°C – but it is important to remember that there is nothing magic about 38°C compared to 37.9°C, and temperature is better taken in context or a trend, if possible.

How do we get fevers?

The process of developing fever is extremely complex, and our understanding is still developing. At present, our best explanation is that the process is triggered by the presence of chemicals referred to as pyrogens. Pyrogens can either be exogenous (such as parts of the microbe itself, like the lipopolysaccharide on the outside of bacteria), or endogenous, such as cytokines like IL1, TNF, Prostaglandin E2 and importantly IL6, which are released by immune cells when they detect an invader. These pyrogens act to increase body temperature peripherally, but importantly also trigger receptors in the preoptic nucleus in the brain. This releases PGE2 into the hypothalamus, which then sets a new target temperature. This target is met by many facets designed to increase heat, including:

  • Release of noradrenaline by the sympathetic nervous system, increasing thermogenesis in brown adipose tissue and causing peripheral vasoconstriction and piloerection (reducing heat loss)
  • Acetylcholine release stimulating muscle myocytes to induce shivering
  • Feeling cold”, inducing heat-seeking behaviours (warm clothes and blankets)

It is important to remember that the body is trying to get hotter. If you intervene with non-medicinal efforts to cool it down, it will work even harder to try to heat up.

Why do we get fevers?

The process of having a fever has been conserved across species from lizards to mammals, and even plants! This is because it is a beneficial response to an infection. The mechanisms by which a fever helps protect you from infection include:

  1. Higher temperatures inhibiting growth/replication of pathogens
  2. Higher temperatures promoting the immune response to infection

It is also worth noting that bacteria are killed more easily by antibiotics at higher temperatures, so there is also a potential third mechanism.

 

Summary

Fever is beneficial. When a pathogen causes infection, pyrogens stimulate the hypothalamus to increase the body temperature through several mechanisms, and this increased temperature helps inhibit the growth of the pathogen AND stimulates the immune system to fight it.

That was a lot of science. Don’t worry – it’s time to get clinical! All this science stuff is lovely, but what does this mean for our patients?

Clinical significance of fever

As we have ascertained, fever is beneficial. For this reason, when a child presents with fever, the fever itself is actually of no concern. What we are interested in is the reason for the fever. Is this fever the result of a benign, self-limiting, childhood infection – or is it associated with a serious bacterial infection? Trying to determine this is enough for its own blog article (the most important thing is the end of the bed assessment – see Andy Tagg’s excellent breakdown of the paediatric assessment triangle).

Ignore the fever itself – what’s important is ascertaining its cause.

Now, let’s get on and bust some myths that persist surrounding fever in children!

 

Myth 1 – Higher temperature indicates a serious infection

This is one of the most common concerns amongst parents. The particular height of temperature may be what prompts them to come to hospital, or even what prompts the health care provider to initiate more aggressive management or investigations.

The truth is that the relationship between the height of temperature and risk of serious illness is at best complicated, and at worst a dangerous distraction. There is a very poor correlation, with such woeful sensitivity and specificity that it will both grossly over and under-call serious infections (either if the high temperature is used to rule in, or lower temperature to rule out). The caveat to this is in younger infants (particularly under 60 or 90 days), who have a higher baseline risk of serious infections (and more to the point – once they spike a temperature will be managed aggressively regardless of how high it was). Some studies have shown an extremely weak association in older children, but not enough for it to have any meaningful influence on our management. A fever is a fever – higher temperatures should not be managed any differently than lower ones.

 

Myth 2 – Temperature not relieved by antipyretics indicates a serious infection

Another common misconception also linked to the myth above. Some fevers respond well to antipyretics, and some do not. We do not understand why this is the case, however, studies have not demonstrated that failure to respond to antipyretics is a useful indicator of a more serious infection. It is not very pleasant for the child to remain hot, but it does not mean they are at any higher risk. A child whose temperature does not respond to antipyretics should not be treated any differently to one that does.

Myth 3 – Rigors indicated a serious infection

This has been covered in-depth in a separate blog post – but to summarise; there is extremely weak evidence that rigors are associated with an increased risk of bacterial infection in children, which is irrelevant when factors that are more important are taken into account. There is also evidence of no increased risk. The presence or absence of rigors should not be a deciding factor in the management of febrile children.

Myth 4 – You must wait for a fever to come down before discharge

This may seem common practice for many of you working in acute paediatrics. If a child is febrile on arrival, people often want to wait to see the temperature come down before allowing them to be discharged (this should be differentiated from seeing observations normalize in the absence of fever – which is a more understandable if still slightly questionable practice). As we have seen, a fever merely indicates the presence of an infection. If you have ascertained the cause of the fever, or at least ruled out any red flags for serious causes, the ongoing presence or absence of a fever means nothing for the child. If it comes down before discharge, it will probably just go up again once they are home! There is no need to make them wait around for hours for no reason.

Myth 5 – Fever should be treated with antipyretics

We have established that fever is beneficial. Therefore, there is essentially no reason to treat a fever in and of itself. It will not cause harm, and it is probably helping. Some children tolerate having higher temperatures extremely well, so if they are playing happily or do not seem terribly bothered about their temperature of 39°C then you leave them well alone.

Treat the child, not the fever.

Myth 6 – Fever should not be treated with antipyretics

There is an opposing school of thought, which says that since fevers are beneficial, we should not treat them at all. Given how absolutely dreadful it can feel to have a fever (which many of us adults should be able to vouch for), many of us give medicines to try to bring the temperature down and make the child more comfortable. This is the right thing to do. Despite the potential benefits having a fever confers, there is no evidence of any clinically meaningful harms to treating temperatures in unwell children, or even in adults in ICU. If the child is distressed by the temperature, they should have antipyretics to make them feel more comfortable.

Summary

  • Fever helps your body to fight infection and is not dangerous (no matter how high)
  • The fever itself is not important. The cause of the fever is what matters
  • There is little to no evidence that higher temperatures, temperatures that don’t respond to antipyretics, or rigors indicate an increased risk of serious infection
  • Persisting fever on its own is not a reason to postpone discharge
  • Only treat fevers if they are causing distress. Treat the child, not the fever

 

Postscript: Febrile convulsions

When I posted my initial thread on twitter about fevers, there were many comments asking why I didn’t address febrile convulsions. This was mainly because these are worth a post to themselves (which they have here). In brief, febrile convulsions are extremely distressing for parents to observe, but they are common and they are very benign. We do not advise treating fevers to prevent febrile convulsions, and until recently, this was because there was no evidence that they had any effect in preventing them. A recent study from Japan did demonstrate a decrease in recurrence of febrile convulsions in children who had already had one if given regular PR paracetamol, however, there are major caveats to this study discussed in depth here.

 

For the more visual oriented, the talented Emma Buxton has created an infographic of the key reminders from this blog post: