What am I missing? The child with fever but no obvious cause

The fear that a significant illness wil go unreconised in a child is one that is always present for the clinician who sees acutely unwell children.  The stories that we hear of infections and other illnesses being "missed" fuels that anxiety.  The common sense side of us tells us that significant illness should manifest itself in an obvious way, but that doesn't stop us from asking the question, "What am I missing?" when we see a child with a febrile illness and no apparent cause?

Scenario

You have just seen Billy, a 1 year old child with a fever that started today.  They have no cough or runny nose.  They appear well and have a heart rate of 120.  Chest is clear, heart sounds are normal and abdomen is soft.  Tympanic membranes are not inflamed.  You may or may not have looked at their throat but if you did, there is nothing obvious to see.

What do you do?

The answer to this is to understand what the possible causes of fever are, know how to exclude them and have an idea of how likely they are.  The latter brings us onto an important question:

How likely is significant or dangerous infection in a child?

That depends on the child.

The most common risk factor that we encounter is the infant.  The likelihood of an unwell newborn having a significant infection is high.  This is further compounded by their non-specific symptoms and lack of physiological response in the first few weeks of life.  The risk of serious infection multiplied by the risk of underestimating the illness makes a baby under the age of 60 days a high risk patient.

After those first few weeks, the infant becomes less reliant on maternal antibodies and begins to produce a more vigorous response to infection, most of which are now viral.  As a result, the risk diminishes inversely.

Other risky patients are those with ongoing reasons to either have more significant infections or less obvious signs of serious illness.  These include children with neurodisability, immunodeficiency or chronic illness.

For the usually healthy child beyond early infancy, the very great probability is that an illness will be benign and that those infections that are dangerous will manifest themselves in some significant way.  This itself brings a challenge: complacency.  We become so used to good outcomes and fruitless investigations that we start to think that everything is an uncomplicated viral infection.
It usually is, but what if it isn't?  That brings us on to the next question:

What are the less common causes of fever in a child?

One way to think about the causes is within categories:

When there are so many possibilities, it is often best to consider the least common first.  Let's start with the non-infective.  These illnesses cause inflammation without active infection.  They are all very uncommon compared to other things on the list but that makes them easy to forget and therefore miss.

Kawasaki Disease - This is a vasculitis which can look like a prolonged viral illness.  The cause has not yet been identified but it is presumed to be a post-infective phenomenon.  If a child has had a fever for five or more days without a clear cause, we should check if the child fulfils the criteria for Kawasaki disease.  You can check the criteria in a book or use an online tool such as this one linked here.

Leukaemia - Haematological malignancy in children occasionally presents as an unexplained and prolonged pyrexia.  More often there are other symptoms and signs such as increasing lethargy, weight loss, pallor, bruising, bleeding and unexplained pains.

Systemic Onset Juvenile Idiopathic Arthritis (JIA) - this subtype of JIA is rare but is one possible cause of unexplained fever.  Often the fever is accompanied by a typical salmon pink rash and joint pains, even if there is no clinically obvious joint swelling yet.

These non-infective causes of fever should not be over-thought.  The presenting symptoms of childhood illness are often so non-specific that it can be all to easy to imagine zebras instead of horses.  The key to not missing these is to be aware of them as entities and to look for features of these in the child with unexplained fever, especially when that fever is prolonged.

Next, the sepsis question.  Every febrile child should be assessed for sepsis, whether a focus the fever is found or not.  That decision can be made easy for you in one of two ways.  Either the child is very well to the extent that sepsis can be ruled out, or the child is so unwell that sepsis is presumed.  Everything in between is a case of careful assessment, including risk factors and the trajectory of the illness.

So, if we have considered the very rare and the sepsis question, what we should be left with is a child who we think does not have sepsis and yet has a fever without an immediately obvious focus.  At this point we return to the list of possibilities.

The task in a child with fever and no clear focus is to rule these possibilities out, which is usually based on clinical assessment.  Start with the complications of upper respiratory tract infection (URTI) as these are the most common significant infections in children.

Mastoiditis - infection of the mastoid is usually a complication of otitis media infection there should be evidence of that.  Mastoiditis is excluded clinically if there is no erythema, swelling or significant tenderness of the mastoid process.

Peritonsillar abscess - A collection of pus in the peritonsillar tissues is manifested by swelling which displaces the tonsil.  At the time of writing this, throat examination is not routinely performed due to the COVID-19 pandemic.  However, peritonsillar abscess is highly unlikely in a child who is willing to drink or eat.  If the child is refusing all oral intake, it may be necessary to use droplet PPE, including eye protection, to visually exclude peritonsillar abscess.

Lymph node abscess - Inflamed or enlarged lymph nodes are a common finding in children with URTI. Occasionally, the lymph node becomes bacterially infected.  When this happens, the lymph node is more enlarged and painful.  The overlying skin is often erythematous.  Another common feature is that the child becomes reluctant to turn their neck due to the pain from inflammation of the surrounding tissues.  These infected lymph nodes may respond to high dose oral antibiotics, however they may require incision and drainage.  Discussion with or referral to ENT is therefore advisable.

Osteomyelitis and septic arthritis - This is a good example of something that is rare but also often missed when it is a cause of unexplained fever.  Infection in a bone or joint can be visible or hidden.  If a parent has noticed a swollen, red or hot area or that the child has localising signs in a limb, that can lead to early diagnosis.  It is also the case that in a significant number of cases, the infection is not identified early on.  It is no surprise when a febrile child is miserable and moves less.  It is not common practice for clinicians to examine every bone and joint in a febrile child.  However, this is something that needs to be done if a child has an unexplained fever.  If limbs have not been examined for swelling, hot spots or erythema at first presentation, I would suggest that this should be done at the second assessment should fever persist and remains unexplained.

Urinary tract infection (UTI) - UTI is probably the most common cause of fever without a clinically obvious focus in children.  The younger the child, the less likely they are to present with specific symptoms.  Fever without obvious cause is an indication to screen the child for UTI.  Blind treatment with antibiotics is not recommended.  Urine should ideally be sent for culture so that treatment is based on the most robust result - a significant bacterial growth.

Meningitis and encephalitis - Central nervous system (CNS) infection is the most feared of the causes of fever without focus.  In the younger child, symptoms are less specific.  Infants may be irritable, jittery and not feeding well.  Vomiting and excessive sleeping are also common features but again, non-specific.  In an infant with an open fontanelle, this should be examined.  A bulging fontanelle (when not crying) is a red flag sign.  Older children may exhibit classical signs of neck stiffness, headache and photophobia.  Younger children are more likely to stand out because they just won't settle or have an abnormal tone or conscious level.  CNS infection is usually ruled out by the child demonstrating normal interaction or behaviour, often after adequate analgesia has been provided.

Appendicitis - In an older child, recognising appendicitis is done in a similar way to adult practice.  Appendicitis is rare in younger children but when it does occur, it can easily be missed.  Guarding tends to be a later sign in the pre-school child because their abdominal wall muscles are not very strong.  Children often cry or otherwise appear distress when their abdomen is examined, leaving the clinician uncertain.  Analgesia and reassessment is a good way of clinically ruling out appendicitis if the initial assessment is ambiguous.

Pneumonia and empyema - Lower respiratory tract infection (LRTI) is common in children.  Cough and fever are non-specific symptoms and are not grounds for diagnosing LRTI on their own.  Hearing crepitations on auscultation is also a common finding that should not be given too much weight.  Many LRTIs in children are viral and self-limiting.  Important discriminators are how unwell the child is, their work of breathing and more specific focal signs such as localised reduced air entry or a dull percussion note.

Tropical diseases - If a child has an unexplained fever and has recently returned from an area with e.g. malaria, they need to be referred to secondary care for investigation.

And finally...

So if Billy looks well and behaves in a way that effectively rules out sepsis and meningitis, his fever without clear focus means that we should look just a bit harder.  A urine sample should be taken to exclude UTI; blind treatment with antibiotics is not recommended without good evidence of UTI.

If there are reasons to suspect one of the less common (than uncomplicated viral infection) causes of fever, referral to secondary is likely to be the way forward.  If there is no evidence of a significant cause and what you are left with is a reasonably well child with an unexplained fever, the final question is, "should I refer this child or send them home with safety-netting advice?"

Both options are valid and the choice should be made in the best interest of the child.  In secondary care, the assessment of the child should be clinical in the majority of cases.  As such, referral may simply add a further clinical history and examination.  If a second opinion or physical period of observation is felt to in the child's interest, that is fine.  If not, it may be best to keep the child away from hospital and the risks associated with a secondary healthcare setting/

Before a final decision is made, risk should be considered.  For the majority of healthy children presenting to Primary Care (including the Emergency Department) with no specific risk factors, the likelihood of any febrile illness being a serious bacterial illness is very low.  That makes it perfectly reasonable for a child who has had a careful clinical assessment to be managed conservatively and with good safety-netting advice.

There are children who have a significantly higher risk.  As mentioned above, the most commonly encountered risk factor is the baby.  If your patient is a baby, especially if not yet started on their primary vaccinations, fever without focus warrants a referral to paediatrics.

Fever in a child who does not have an immediately obvious focus is a clinical conundrum for all of us.  Many children can be managed with a thorough history and examination.  If there are significant risk factors or specific findings then appropriate referral is likely to be the next step.

Edward Snelson
99% Type 1 decision maker
@sailordoctor

Disclaimer: If it's the clinician who has no focus, there's nothing I can do for you.