Ep14: Fever of Unknown Origin

Ep14: Fever of Unknown Origin
28 August 2016

Pyrexia, or fever of unknown origin (PUO) is a syndrome that challenges the diagnostic skills of every physician. It is defined by frequent fevers over 38.3 degrees Celsius, persisting for 3 weeks, which have eluded diagnosis by standard baseline tests.

Dr Rohan Beresford, Advanced Trainee in infectious diseases and microbiology and Professor Iain Gosbell of the University of Western Sydney, review the condition in September's issue of the RACP's Internal Medicine Journal. In a recent case series, they write, 22% of PUO cases were auto-inflammatory, 16% were attributed to infection, 7% were neoplastic, and 4% were due to drugs or other miscellaneous causes. But over 51% of patients with PUO were left with no diagnosis at all.

On this this episode, Dr Beresford explains how to rationally investigate patients with persistent fevers and manage their anxiety through the process. He is joined by paediatrician and infectious diseases specialist Dr Philip Britton FRACP (Children's Hospital Westmead), describing some of the conditions that more likely explain PUO in children, and Dr David Spriggs FRACP (Auckland City Hospital), who provides examples of the complexity of PUO in geriatric patients.

Links to resources discussed to the podcast are provided below. Fellows of the RACP can claim CPD points for listening and further reading on this topic via MyCPD.


This episode was produced by Mic Cavazzini with recording assistance from Justin Gregory. Music from Chris Zabriskie ('I Am Running with Temporary Success from a Monstrous Vacuum in Pursuit'), Jahzaar ('Gramaphone', 'Aisles') and Scott Holmes ('Close to the Distance'); photo courtesy Armle. Pomegranate's executive producer is Anne Fredrickson.
Editorial feedback was provided by RACP Fellows Dr Bruce Foggo, Prof David Gordon, Dr Michael Herd, Dr Marion Leighton and Dr Christian Lueck.


Web Resources
Pyrexia of Unknown Origin: Causes, Investigation and Management [IMJ]
Fever of Unknown Origin: A Clinical Approach [American Journal of Medicine]
Distinguishing Among Prolonged, Recurrent, and Periodic Fever Syndromes: Approach of a Pediatric Infectious Diseases Subspecialist [Pediatric Clinics of North America]
Fever of Unknown Origin in Children: A Systematic Review [World Journal of Pediatrics]


ROHAN BERESFORD:  They called it Sutton’s Law from a newspaper story which was a classic story from the 20’s of a bank robber, supposedly called Sutton, who was caught robbing a bank. And when he was asked in court as to why he was robbing the bank he gave the response of because, “That’s where the money is.” And that’s the same process we like to take through to fever of unknown origin. You go where the money is rather than a battery ordering of tests which may not contribute to the diagnosis and just muddy the waters, so to speak.

CAMILLE MERCEP: You’re listening to Pomegranate, a CPD podcast from the Royal Australasian College of Physicians. In this episode, Rohan Beresford talks us through Pyrexia of Unknown Origin- how to work up a diagnosis and best manage patients with unexplained fevers.

Dr Beresford is an advanced trainee in infectious diseases and microbiology at Liverpool Hospital, and his review on PUO can be found in the Internal Medicine Journal. We’ll also hear some intriguing case studies of PUO, or fever of unknown origin, from paediatrician Philip Britton, and geriatrician David Spriggs.

Fever of unknown origin is defined by frequent temperatures over 38.3 degrees Celsius that persist for three weeks or more. Critically, the cause of fever has eluded diagnosis by standard baseline tests.

In the past, an equal proportion of cases were eventually attributed to infections, cancers, and non-infectious inflammatory conditions. But this distribution has changed as diagnostic techniques have improved, and an increasing fraction of PUO cases end up with no explanation at all.

ROHAN BERESFORD:  Fever of unknown origin’s a syndrome that’s actually changed a lot as we increase our understanding of how to diagnose these conditions. And also the modes of investigation. And now we’re looking at maybe 15-20% are infections, similar proportions of cancer. But what we’re seeing is sometimes up to 50% of patients have no diagnosis at the end. So I think this is a really important time to have a discussion about what makes up fever of unknown origin and what people can do as clinicians to work it up.

Like a lot of medicine, making a diagnosis 90% is in the history. The important things that we really want to know about the fever is, when did this fever start - was there anything that happened around the time that could have triggered this off. Has there been recent surgery, recent travel. And one of the big things also is a very thorough medication history and particularly things like antidepressants, antibiotics, antiepileptics -  which can all be associated with fever.

We’re also looking for a couple of red flags, so some of the big ones are unintentional weight loss which can be a red flag for malignancy. The other thing is patients who typically almost have to get up in the night and change their sheets because they’ve sweated so much. That can be a red flag for either things like tuberculosis or haematological malignancy.

In Western Sydney we have a large population who move in and out of the country on a regular basis, and commonly see now Brucella melitensis in people who have gone to a small village where there’s unpasteurised dairy products and then come back to Australia with a chronic fever and chronic symptoms.

So there are important things to note both from international travel point of view and domestic travel as well. Some of the big things in Australia are things like Q Fever or Coxiella Burnetii which is associated with animal workers. And we do have conditions like Barmah Forest Virus and Ross River Fever which is also present in Australia.

PHILIP BRITTON: Doctor Phillip Britton is my name – I'm a paediatrician and infectious disease physician at the Children’s Hospital at Westmead.

I was involved with a child around the age of 10 I think, female, had seen multiple physicians with progressive sort of weight loss, fevers - what we call B or constitutional symptoms. Travel overseas to the subcontinent- my memory is it’s India - she had the particular high-risk exposure in travel medicine which is the visiting friends and relatives subgroup who tend not to seek pre-travel advice or prophylaxis, and tend to be exposed to the general population in the locations they go to in a way that tourists aren't.

ROHAN BERESFORD: The blood tests we'd expect people to have before they've been labelled as a fever of unknown origin because they’d be part of the basic investigations would be things like full blood count, creatinine, liver function tests, inflammatory markers, and some of the basic autoimmune things.

And what we hope with those is to look at well what are the risks they've actually got. People with a low C-reactive protein or ESR are very unlikely to have a significant infective cause. People with rheumatoid factor you might start thinking more about the inflammatory conditions – and they might also have positive extractable nuclear antibodies.

Do they have an elevated white cell count maybe indicative of infection? Or is it dramatically elevated in one cell line which could indicate a haematological malignancy? Same looking at things like anemia which can be present in chronic disease, malignancies, and same with thrombocytopenia.

PHILIP BRITTON: Now it so happens with this child actually that they’d come into hospital and had really quite a bit of advanced testing before our infectious disease was consulted.  So, she had weight loss and the constitutional symptoms, chronic disease, non-specific signs of chronic disease on her blood testing. And she had an anemia that’s not consistent with iron deficiency- microcytosis. In the context of raised inflammatory markers those two things together really suggest a subacute or chronic inflammatory process in the body.

ROHAN BERESFORD: It’s really about the initial investigations helping to decide what your secondary investigations are – what is the diagnostic test that is most likely to get you a response for the patient?

If they've got deranged liver function tests my next step may be to get a liver ultrasound or do a CT abdomen. So we’ll typically do advanced imaging unless we can pin down a cause quite quickly, and would usually include it of chest, abdomen and pelvis to make sure we’re not missing anything, ideally with intravenous contrast to really show inflammatory type structures.

The things we’re looking for from an infection point of view, we’re looking for small abscesses, for obvious malignancies, and also looking for lymphadenopathy in multiple sites of the body.

There has been some work around the world recently looking at CT with PET in order to show increased uptake of glucose in lesions.

PHILIP BRITTON: And in this kid, I mean almost very nodal site in the body in this child lit up- intraabdominal, intrathoracic. The other place in this child that lit up was the gastrointestinal system and that widespread nodal involvement is either cancer or it’s TB. And in this child with that particular history, it’s TB.

And that’s a really characteristic point- in adult PUO a really considerable fraction of true PUO is going to be cancer.  Whereas in children cancer is a very small fraction of PUO diagnoses.

And one of the other things that in childhood is different to in adulthood is the indirect tests for TB infection in children- the Mantoux Test or the Interferon Gamma Release Assays- in children particularly in a low prevalence environment, they perform well in actually diagnosing active disease that’s very different in adults.

So she had what we would call pretty bog standard TB therapy – highly efficacious. She was much much better, rapidly put on weight, the fevers settled, those B-symptoms the night sweats and malaise all improved fairly rapidly. And I think sometimes for non-ID clinicians this is not appreciated about TB. We should demystify particularly in children the adverse effects of treatment that’s a little more common in adults.

And so it’s incredibly rewarding you get people who’ve had a lead-in of 3 months of progressive worsening symptoms, nobody knows what’s causing it, you start the treatment within a week they say they’re feeling fabulous.

ROHAN BERESFORD: By definition most causes of true fever of unknown origin have been going for several weeks so the patient’s usually aren't deteriorating rapidly. We know that over, say, six months of follow-up with patients with fever unknown origin the mortality is less than 10%. But almost all those deaths in 6 months will be in the patients who have a malignancy so commencing antibiotics or antipyretics or steroids were never going to have a benefit for these patients.

And a lot of people won’t have symptoms other than the fever and if they’re on regular antipyretics they sort of maybe disappear off the radar and go home thinking they’re well and not re-presenting. You don’t get a sense of how high the fevers are or when they’re occurring. So the only infections we recommend treating empirically is tuberculosis which is disseminated because these patients can deteriorate rapidly.

The other one is if you have a very strong suspicion the patient might have endocarditis. We often look for very closely for surgical history and any sort of metal or plastic can easily become coated in infections, and these might be bacteria you wouldn't normally expect, which were all typically in the past much harder for us to find from blood cultures. We’re finding with improved blood culture systems, culture-negative endocarditis is sort of a shrinking diagnosis in medicine.

Other important second line investigations is consideration of echocardiography, particularly transoesophageal echocardiography would be the gold standard behind that. But obviously it can be an invasive test so you are looking for patients who are at risk, so patients who are immunosuppressed are more likely to have endocarditis, patients who are intravenous drug users are very high risk for this.

DAVID SPRIGGS: Because of the multiple causes of fever some of our older patients present with more than one at a time, and the complex patients that we see have had many interventions- each one individually predisposes them to infective complications which makes it clinically and diagnostically challenging.

My name is David Spriggs I'm a general physician and geriatrician working for Auckland District Health Board in New Zealand.

This chap was 76, I think. He’d come from a neurosurgical ward where he’d presented with a brain abscess almost certainly related to an infection on his heart- he’d undergone open heart surgery about 4 weeks prior to that.

He’d had the abscess drained and an unusual organism called Nocardia had been identified. Now they had placed him on dual antibiotics and for the first three or four days under my care his fever settled, his white cell count improved and his CRP improved. However after about four days he started to develop further fevers. He didn't shake and shiver with it, he didn't have sweats, but it was persistently elevated without any obvious diurnal pattern.

The first thing to do is to determine whether or not the infection that we know about is being adequately covered. Blood cultures were persistently negative and further a ultrasound of his heart and a scan of his brain revealed that there was no obvious ongoing or new infection. The inflammatory markers were high but improving. He himself was rehabilitating actually superbly but the ongoing fevers persisted over the course of the next week while we were working him up. So our attention turned to his drugs.

Now co-trimoxazole which is a sulphonamide antibiotic combined with trimethoprim is recognised as a not-infrequent cause of fevers. So rather reluctantly we decided to withdraw the co-trimoxazole and continue the patients on meropenem, and because Nocardia is an unusual bug we then added in some amikacin. Within 24 hours the fever had melted away and I've no doubt that the fever in that context was due to the antibiotics. 

ROHAN BERESFORD: What was originally described as collagen disorders, but we really now think of as the inflammatory disorders that are non-infective, can cause chronic fever in their own right. And particularly with the autoimmune ones sometimes they’re missed.

They often occur in a younger population so we often don’t think of these people as particularly unwell. But we can often miss, especially in teenagers, that they have things like Still’s disease, juvenile idiopathic arthritis which can cause fever and joint pain. And the same in you know people in their 20s or 30s we might miss early development of lupus erythematosus.

Some of the things you can look for in a history is fever chronicity, joint pain which is typically poly articular and tends to be worse in the morning indicating an inflammatory nature. Sometimes patients might come with rheumatoid factor or an antinuclear antibody, but often a panel of specific antibodies associated with more common autoimmune diseases are very useful.

PHILIP BRITTON: There’s a couple of other elements in children that we think if very carefully in PUO. The first is primary immunodeficiency. And then the other is what we call the periodic fever syndromes. And occasionally they’ll be presented to you as PUO. But that area of the autoinflammatory diseases is really a big little section of PUO in children.

So this child came from New Caledonia with prolonged fever, loss of weight, deconditioning. This child had non-specific features of inflammation but lots and lots of tests that were normal.

This was early in the days of PET scanning and what that showed in that child was really, innumerable small foci in her bones, and she was ultimately diagnosed with non-bacterial osteitis which is non-infective, we think, inflammation of the bones.

There's no specific test for this condition, it was really the context, the history, the pattern on the PET scan. And it really allowed us to make treatment, you know, educated treatment decisions. And we’ve got scans 3 months apart of really these innumerable foci in her bones 3 months later, none present and a well child.

So it was the right imaging, I’m sure, in that child. But the educational element here is to be aware of the role of imaging- the niche role of imaging in PUO- but where it has been published on it has an enhanced sensitivity and specificity relative to the other modalities that are used in this area. And we would have a high threshold to do advanced imaging in kids with PUO, but if you reach that threshold where you've done lots of the usual tests you want sensitivity.

Because if there's nothing there on a PET scan, there's unlikely to be something serious that you’re missing – we would take an observational approach with that child and not pursue a diagnosis anymore. Whereas if you've got a positive PET scan we use that as a directing modality that says ok well let’s go for that – that’s where the money is. The other reason we like to go for it is you can get a high yield from the radiation exposure.

ROHAN BERESFORD: One of the really big ones that we focus on in the paper is giant cell arteritis or what used to be called temporal arteritis – so this is a vasculitis of blood vessels typically in the scalp and head. And it’s important because you can develop blindness.

And so it particularly presents in people over the age of 70 who have unilateral headaches, scalp tenderness, maybe tightness of the jaw. And if you’re suspecting this condition we’d advise people to start treatment early with steroid therapy in order to preserve people’s vision.

Patients usually come with a reasonable level of investigation and it’s usually from the blood tone review maybe finding one or two extra tests that we think might be useful. Thyroid function testing is one thing that’s often overlooked – patients can often have a physiological fever from an overactive thyroid gland. LDH is a good marker of very high cell lysis and turnover so we can see it very high in haematological malignancies, but also some solid organ tumours as well.

We have a lot of tumour markers and I guess it’s partly about using them in the right circumstance rather than ordering a whole bunch of tumour markers which might be non-specific. And again, does that lead us down the wrong path? Does it increase the patient anxiety unnecessarily?

Things that are more invasive like bone marrow biopsies we typically try and avoid because it’s useful usually only for people who might have a myeloproliferative disorder or a haematological malignancy. And you can usually pick those patients quite well and you’re looking for things like drenching night sweats, very severe weight loss, particularly an anemia or a thrombocytopenia is going to indicate to you that something abnormal has happened potentially with their bone marrow. Those are the patients that it might be necessary to do that, we’d avoid that test in the majority of patients.

DAVID SPRIGGS: One that sticks in my mind was a patient now from a couple of years ago who was a 68 year old Chinese chap who had a cancer in the back of his nose. And he came to us relatively soon after his radiotherapy with a pneumonia, almost certainly due to food and fluid going down into the lungs because of his difficulty swallowing.

Now we put him on the standard treatment for an aspiration pneumonia - the signs of infection started to settle, his blood tests started to improve but he continued every evening to have a raging fever going up to over 40, rigors, shaking and sweating. And every time he had a good shiver doctors were called and they took cultures from various bits including one of his IV lines which is a source of infection that often gets missed.

And nothing was grown from these cultures. First thought was that it was his aspiration pneumonia that wasn't settling, and we made some changes to his antibiotics. The second thought that he had sepsis somewhere else in his nasopharynx – but scans of that area did not show anything to suggest infection.

I then talked to his wife with an interpreter. She told me that actually he’d had these sweats before and he’d started on ibuprofen for the sweats. Now this is a drug that I spend a lot of time stopping - it has all sorts of side effects and when he came to me it was not clear why he was taking this. We recommenced the ibuprofen and he never had another rigor or sweat.

Now what’s happening here? What is almost certainly happening here is that the fever was due to the cancer, so this is what we call a paraneoplastic fever. What had happened is he was treating rather serendipitously his PUO with the ibuprofen, and clearly my attempt to de-prescribe unmasked the PUO.

I'm afraid I don’t remember what happened to him down the track but it’s certainly the case that in lymphomas and other haematological malignancies patients may sense recurrence of the tumour by the first symptom being the recurrence of their fever.

ROHAN BERESFORD: For some people this might be a normal physiological change for them. So we know that some people just sit outside a normal temperature range. They may have had an infection, they have a post-infective type syndrome and their condition is slowly settling. Some people seem to manifest a fever and it drops away over several months and that’s what I see in a lot of patients in clinic. But some people might manifest low-grade fevers throughout their life and if they’re not particularly concerned by them, they’re not associated with other symptoms then that’s not a concern we might not need to do anything about them. Patients who it’s distressing for it might be useful looking at antipyretics.

PHILIP BRITTON: That’s pretty standard fare in PUO management in children as well that we have kids, and we watch them for a period of time, and then they just seem to get better, no cause made. That’s a fairly common and dissatisfying experience as a clinician in as much that it’s hard to learn from those kind of non-experiences or non-diagnoses.

A small proportion of them will have another similar episode down the track, and I'm putting aside the periodic fever group there, I'm talking about the kid who seems to have a funny illness nobody really makes sense of and then a few years later comes back with another funny illness. You never want to sort of write it off as a non-event and you certainly want to be able to say to families look we don’t know what happened we think your child is well, but should this happen again give people a list of red flags that you would worry about.

ROHAN BERESFORD: A lot of people who come with fever of unknown origin are unwell, they may have seen multiple different doctors, they’re frustrated that they haven't had an answer provided to them and they’re worried about their health. So you know most people may have been told that 30% of people with fever of unknown origin have cancer - or they may have read that on the internet. So if you can tell them that’s not what’s going on they’re going to be quite reassured.

So we've always found it’s a really good idea just to sit down and explain the process- so exactly what tests we’re going to plan to do and also that there may not be a diagnosis made. So they don’t get to the end of three months of investigation and only be told “We don’t know,” and they weren't expecting that might have been the result.

PHILIP BRITTON: And in paediatrics it’s a cliché but we manage families not children - that’s absolutely true. And a huge part of managing those sorts of kids is minimising the anxiety surrounding observational management.

And people have very different expectations of what modern healthcare can and can’t do for them and people have very different risk tolerance. There's no doubt I've had patients who’ve upped and left - fortunately I think that’s the minority and most people you can talk through the experience, or at least help them understand that you do take their symptoms seriously and that you do have an approach. Most people come to understand it and you’ll maintain the relationship and trust.  

ROHAN BERESFORD: Probably the take home message is to think about fever of unknown origin as non-acute fevers that have resisted identification despite reasonable testing. And some of the key points behind it is, avoidance of over-ordering tests and only choosing tests that are aimed at the condition the patient may have.

DAVID SPRIGGS: PUO is full of false leads- I should also stress the importance of time. There is a tendency to rush into the treatment of PUO’s and particularly in the elderly, if they’re not desperately sick watching and waiting carefully is often a very good diagnostic tool.  

CAMILLE MERCEP: That was David Spriggs, closing this episode of Pomegranate. Many thanks also to Rohan Beresford and Phillip Britton for their participation. The views expressed are their own, and may not represent those of the Royal Australasian College of Physicians

For Dr Beresford’s review and other resources on fever of unknown origin, visit the Pomegranate website at racp.edu.au/pomcast. And please explore the Internal Medicine Journal, academic publication of the Royal Australasian College of Physicians. To join in the conversation use the hasthtag #RACPpod, or email us at pomcast@racp.edu.au.

Pomegranate was produced by Mic Cavazzini, with recording assistance from Justin Gregory. I’m Camille Mercep, and we hope you can join again us next month.


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