Undifferentiated Fever and Fever of Unknown Origin — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mr James Whitlam is a 62-year-old retired park ranger presenting with six weeks of intermittent fever to 39.2 degrees, drenching night sweats, and 6 kilograms of weight loss. He has treated pulmonary tuberculosis 15 years ago, psoriatic arthritis on adalimumab for four years, and diet-controlled type 2 diabetes. He lives on a rural property in northern New South Wales, keeps cattle and sheep, hunts feral pigs, and travelled recently to Vietnam. [1]

His main problems are:

1. Classic fever of unknown origin — meeting the modern Durack and Street definition: temperature above 38.3 degrees for over three weeks, undiagnosed after a competent Tier 1 workup [2].
2. Lymphoma as the leading malignancy hypothesis — the left supraclavicular (Virchow) node, the B symptoms, and the splenomegaly.
3. Tuberculosis reactivation as the leading infection hypothesis — the prior treated TB, the anti-TNF therapy, and the travel to a TB-endemic region.
4. Region-specific zoonotic infection as a serious consideration — Q fever from the sheep and cattle, brucellosis from the cattle and feral pigs, melioidosis and scrub typhus from the tropical and Vietnam exposures.
5. Adalimumat-related risk — reactivation TB, atypical mycobacterial infection, and the rare but recognised hepatosplenic T-cell lymphoma.

My immediate priorities are to stage the investigation systematically, to withhold empiric therapy unless he deteriorates, and to engage the infectious diseases, rheumatology and haematology teams early. The central next steps are the CT of chest, abdomen and pelvis with contrast to localise the node and the splenomegaly and to identify any other sites; the excisional biopsy of the supraclavicular node with mycobacterial and fungal culture in addition to the standard histology; the region-specific serology for Q fever, brucellosis, melioidosis, scrub typhus and leptospirosis; the TB workup with IGRA and three sputum samples for AFB; and the FDG-PET-CT if the CT is non-diagnostic, to localise any occult malignancy or focal infection and to direct the biopsy. I would hold the adalimumab for the duration of the workup, and I would communicate the staged plan to the patient and his wife honestly and clearly." [1]

Examiner probing questions and model answers

Q1: "Walk me through your decision to hold the adalimumab." [1]

"The adalimumab is held for three reasons. First, it may be contributing to the fever — drug fever is uncommon with biologics but possible, and a clean defervescence after cessation would support a drug contribution. Second, it is the central risk factor for TB reactivation and for opportunistic infection, and removing it may allow the immune system to express the infection more clearly on the imaging and the cultures. Third, and most importantly, it must not be resumed until the diagnosis is clear, because resuming an anti-TNF in the face of active TB or untreated lymphoma would be dangerous. The rheumatology team is engaged early, the psoriatic arthritis is managed with simple analgesia during the workup, and the decision to resume the adalimumab — or to switch to an alternative such as a non-anti-TNF biologic or a JAK inhibitor — is made after the diagnosis is established. I would not start empiric steroids or methotrexate as a bridge, because empiric steroids would mask lymphoma and TB." [1]

Q2: "The CT shows the supraclavicular node and the splenomegaly, but no other abnormality. The node is being biopsied. What is your next investigation, and why?" [1]

"My next investigation is the FDG-PET-CT. The principle is that the PET-CT localises metabolically active disease that the anatomical CT misses, and it directs the directed biopsy of any avid lesion. The Dong meta-analysis reported a pooled FDG-PET-CT sensitivity of 0.982 and specificity of 0.859 in FUO, and modern reviews place the diagnostic contribution at around half to two-thirds of cases [4] [5]. The PET-CT tells me whether the palpable node is the only site or one of several — if there is a PET-avid lesion in the marrow, the liver, or the spleen, that lesion becomes the directed biopsy target alongside the node. The PET-CT also screens for large-vessel vasculitis, sarcoidosis, and focal infection. If the PET-CT is negative, that itself is informative — it carries a high negative predictive value for focal malignancy and vasculitis, and it supports an observational strategy if the node biopsy is also negative and the patient is stable. The sequence the examiner wants is: non-diagnostic CT, then FDG-PET-CT to direct the biopsy, then the directed biopsy itself."

Q3: "The node biopsy returns a diagnosis of Hodgkin lymphoma. How does this change your management?" [1]

"The diagnosis changes the problem from a diagnostic one to a therapeutic one, and the haematology team takes the lead. The immediate steps are: staging with the PET-CT that has already been arranged (which now serves the dual purpose of FUO workup and lymphoma staging); a bone marrow biopsy if the PET-CT shows marrow involvement or if the staging requires it; a full pre-treatment workup including hepatitis B and C and HIV serology (already done, negative), a baseline echocardiogram (for anthracycline cardiotoxicity), fertility counselling if relevant, and a discussion of the treatment regimen. The adalimumab remains held — there is no indication to resume it, and the anti-TNF therapy is associated with a small but real increase in lymphoma risk that is now moot given the established diagnosis. The tuberculosis workup proceeds to completion, because the patient will be receiving immunosuppressive chemotherapy and any latent TB must be treated before that begins. The prognosis of Hodgkin lymphoma is excellent with modern ABVD or similar regimens, and the communication with the patient and his wife moves from the diagnostic frame to the therapeutic frame — the fever has a name, the name is treatable, and the next steps are clearly defined." [1]

Q4: "He deteriorates overnight with a new rigour, a temperature of 39.8, and a blood pressure of 92 over 58. What do you do?" [1]

"He has crossed from a diagnostic problem to a therapeutic emergency, and empiric therapy is now justified even before the definitive diagnosis is reached. I repeat the blood cultures, then start empiric broad-spectrum therapy covering the most likely pathogens given his exposures and his immunosuppression. The cover must address TB (empirical quadruple therapy with rifampicin, isoniazid, pyrazinamide and ethambutol, given his prior TB and his anti-TNF therapy), melioidosis (meropenem or ceftazidime, given his tropical and Vietnam exposure), brucellosis (doxycycline and gentamicin), and the broader hospital-acquired and Gram-negative spectrum (piperacillin-tazobactam). I involve the infectious diseases team immediately and I admit him to a monitored bed. The node biopsy and the PET-CT proceed in parallel — the deterioration does not abandon the diagnostic workup, because the diagnosis still determines the definitive therapy. The empiric therapy is narrowed as soon as the cultures and the biopsy return, and the duration is determined by the confirmed diagnosis." [1]

Q5: "How do you communicate the uncertainty of an evolving FUO workup to a patient who is anxious about the six weeks of undiagnosed fever?" [1]

"I use three frames. First, the honesty frame — I acknowledge that the fever has not yet been explained, that several diagnoses are being considered in parallel, and that the next step (the CT, the biopsy, the PET-CT) is the one most likely to make the diagnosis. I do not minimise the uncertainty, because false reassurance damages the trust that will be needed later. Second, the structure frame — I explain that there is a staged, evidence-based approach to FUO, that each step is directed by the findings of the last, and that the workup is more likely to find the cause than not (modern series confirm a diagnosis in around half of cases after a thorough workup, with the remainder generally self-limiting). Third, the safety frame — I explain that the fever itself is being monitored, that the team is watching for any sign of deterioration, and that the threshold for empiric therapy is the clinical course, not the calendar. I give the patient and his wife a clear point of contact, a clear timeframe for the next test and the next review, and a clear instruction on what to report urgently (new rigours, breathlessness, confusion, bleeding). The communication is not a single conversation but a continuing series, and the registrar who maintains the relationship through the uncertainty is the one who delivers the diagnosis well when it comes." [1]

Q6: "What is the single most important lesson from this case for a registrar managing an FUO patient?" [1]

"The single most important lesson is that the diagnosis in FUO is made by a careful, repeated history and examination, directed imaging, and a targeted biopsy — not by a scattergun battery of tests, not by empiric therapy, and not by impatient escalation. Mr Whitlam's diagnosis was made by the palpation of the supraclavicular node at the bedside, the CT that localised the node and the spleen, and the excisional biopsy that returned the Hodgkin lymphoma. The PET-CT directed the staging. The adalimumab was held. The empiric therapy was reserved for the deterioration. Each step earned its place by changing the diagnosis, the imaging, or the management. The registrar who follows the staged protocol, who waits for the cultures and the biopsy, and who examines the patient every day, will find the cause — and the registrar who shortcut the protocol with empiric therapy or a scattergun battery will not." [1]

Short Case Discussion

The focused examination of the FUO patient

Examiner instruction: "You are asked to examine a 58-year-old woman who has been an inpatient for three weeks with an undiagnosed fever. Describe your systematic examination, the three findings you most hope to elicit, and your approach to the patient who has no abnormal findings despite the fever." [1]

Candidate's model answer: [1]

"My examination follows a systematic, complete and repeatable routine, and I commit to repeating it daily throughout the admission, because the finding that emerges on day 5 is often the one that makes the diagnosis. [1]

I begin at the end of the bed — the general appearance. Is she cachectic (chronic illness, malignancy, TB)? Is there a rash visible from the door (Still disease, vasculitis)? Is she in pain (the abscess, the osteomyelitis, the mesenteric ischaemia)? The experienced clinician's gestalt of 'sick or not sick' in the first five seconds is rarely wrong. [1]

The vital signs are next — temperature, pulse, blood pressure, respiratory rate, oxygen saturation. I note the relationship between the temperature and the pulse: a relative bradycardia (the pulse is slower than expected for the fever) raises drug fever, typhoid, leptospirosis, and factitious fever. A normal diurnal pattern with a proportional tachycardia is consistent with a true organic fever. [1]

I then examine the skin, including the palms and soles, the nailfold and the conjunctiva — looking for Janeway lesions and Osler nodes of endocarditis, splinter haemorrhages, the evanescent salmon-pink rash of Still disease, erythema nodosum (sarcoid, TB, IBD), livedo reticularis (polyarteritis nodosa, antiphospholipid syndrome), and petechiae (vasculitis, meningococcaemia). [1]

Fundoscopy is next and is the one examination most often omitted and most often rewarding — Roth spots suggest endocarditis, choroidal tubercles suggest miliary TB, and cytoid bodies suggest SLE. [1]

The lymph node survey is complete: occipital, pre- and post-auricular, cervical, supraclavicular (Virchow node — a sentinel for upper abdominal malignancy), axillary, epitrochlear, and inguinal. A new or changing node is biopsied, and the preferred method is excisional biopsy because the nodal architecture is often the diagnosis. [1]

The cardiovascular examination listens carefully for a new murmur, with attention to the timing, the site, the radiation, and the change with posture. The absence of a murmur does not exclude endocarditis. [1]

The respiratory examination includes the apical regions in particular for tuberculosis. The abdominal examination looks for hepatomegaly, splenomegaly, and localised tenderness (abscess, IBD, mesenteric ischaemia), and includes a rectal examination for a perianal mass or prostate tenderness. The joint examination screens for synovitis (Still disease, rheumatoid, SLE, reactive, the spondyloarthropathies). [1]

In any patient over 50 with an unexplained fever and a raised ESR, I palpate the temporal arteries for thickening, tenderness, or an absent pulse — this single examination may prevent blindness from giant cell arteritis. The genital examination looks for epididymal tenderness (brucellosis, TB) and for penile or vulval ulceration (Behcet disease). [1]

The three findings I most hope to elicit are: one, a new or changing heart murmur, because it raises infective endocarditis, which is treatable, lethal if missed, and confirmable with a transoesophageal echocardiogram; two, a palpable lymph node, particularly supraclavicular, because the excisional biopsy is often the diagnosis — lymphoma, Kikuchi, TB, Castleman, metastatic malignancy; and three, a cutaneous clue — a Roth spot, a Janeway lesion, the salmon-pink rash of Still disease, the erythema nodosum of sarcoid — because each points to a specific diagnosis and its confirmatory test. [1]

In the patient who has no abnormal findings despite the fever, I do not abandon the clinical assessment for a scattergun battery. I repeat the examination daily, I stage the investigation in tiers (Tier 1, then Tier 2 with CT, then Tier 3 with FDG-PET-CT and directed biopsy), and I reserve empiric therapy for clinical deterioration. The diagnosis in FUO is made at the bedside more often than in the laboratory, and the registrar who examines the patient every day is the registrar who finds the diagnosis." [1]

Examiner: "What is the role of the fever pattern in the diagnostic workup?" [1]

"The fever pattern is less discriminant than historically taught, but two patterns carry weight. The double-quotidian fever — two spikes in 24 hours — is associated with adult-onset Still disease, miliary TB, and visceral leishmaniasis. The tertian or quartan periodicity raises malaria. Beyond these, the fever pattern is rarely diagnostic on its own, and I weight the associated symptoms more heavily: drenching night sweats and weight loss raise lymphoma and TB; arthralgia and rash raise Still disease, vasculitis, and SLE; back pain raises osteomyelitis, endocarditis (embolic), and psoas abscess; abdominal pain raises abscess, IBD, and mesenteric vasculitis; a new headache in the elderly raises giant cell arteritis. The fever pattern is a clue to be noted, but it is the history and the examination — not the pattern — that directs the workup." [1]

Examiner: "When do you stop investigating the undiagnosed FUO?" [1]

"I stop investigating when a thorough staged protocol is negative and the patient is stable or improving. The undiagnosed FUO after a competent workup — including a non-diagnostic CT and a negative FDG-PET-CT, with no localising signs on a careful repeated examination — is generally a self-limiting inflammatory illness with a favourable prognosis. I arrange outpatient review, document the workup and the findings, and reassure the patient. I do not escalate to invasive testing — blind bone marrow, blind liver biopsy, laparoscopy — unless a new localising sign emerges or the fever recurs with new features. The principle is that the undiagnosed FUO that is getting better is best observed; the undiagnosed FUO that is getting worse is re-investigated from the beginning." [1]