Undifferentiated Fever and Fever of Unknown Origin — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr James Whitlam, 62 years old, retired park ranger. ^[1]

Presenting complaint: Six weeks of intermittent fever to 39.2 degrees Celsius, drenching night sweats, 6 kilograms of weight loss, and fatigue. The fever occurs most evenings, with rigors two to three times a week, and resolves with paracetamol. He has been seen by his general practitioner three times over this period, with blood tests, a chest X-ray and two sets of blood cultures, none of which has yielded a diagnosis. ^[1]

Past history:

• Pulmonary tuberculosis, treated 15 years ago with a 6-month course of rifampicin, isoniazid, pyrazinamide and ethambutol (completed). He reports no residual respiratory symptoms.
• Psoriatic arthritis, diagnosed 8 years ago, treated with methotrexate initially and with adalimumab 40 mg subcutaneously every two weeks for the past 4 years. The psoriatic arthritis is well controlled.
• Diet-controlled type 2 diabetes, last HbA1c 58 mmol/mol.
• Mild hypertension, on amlodipine 5 mg daily. ^[1]

Social and exposure history:

• Lives with his wife on a 40-hectare rural property in northern New South Wales. Keeps approximately 30 cattle and 50 sheep. A parturient ewe lambed in the paddock near the house 2 months ago.
• Hunts feral pigs in the surrounding bushland, 2 to 3 times a month.
• Travelled to Vietnam 3 months ago for a 2-week holiday, including rural areas in the Mekong Delta. Took doxycycline for malaria prophylaxis intermittently.
• No tobacco, no recreational drugs, no high-risk sexual activity. Drinks 2 to 3 standard drinks of alcohol per week.
• No known drug allergies. ^[1]

Examination findings (trainee elicits):

• Vital signs: temperature 38.9, pulse 104 regular, blood pressure 122/74, respiratory rate 18, SpO2 97 per cent on room air.
• General: thin, pale, no acute distress.
• Skin: no rash, no Janeway lesions, no Osler nodes, no splinter haemorrhages, no erythema nodosum.
• Lymph nodes: 1.5 cm firm, non-tender, mobile left supraclavicular lymph node (Virchow node). No cervical, axillary, epitrochlear or inguinal lymphadenopathy.
• Cardiovascular: heart sounds normal, no murmur, no pericardial rub.
• Respiratory: clear breath sounds bilaterally. Apical regions clear.
• Abdomen: soft, non-tender. Spleen palpable 2 cm below the left costal margin. Liver not palpable. No masses.
• Fundoscopy: normal, no Roth spots, no choroidal tubercles.
• Joints: no synovitis. Psoriatic plaques on both elbows.
• Temporal arteries: normal, no thickening or tenderness.
• Genitalia: not examined at this visit. ^[1]

Investigations (available results):

• Full blood count: haemoglobin 104 g/L (normocytic, MCV 88), white cell count 9.2 x 10^9/L (neutrophils 6.8, lymphocytes 1.6, eosinophils 0.6, monocytes 0.2), platelets 280 x 10^9/L.
• CRP 96 mg/L, ESR 78 mm/h.
• U&E: normal. Creatinine 78 micromol/L.
• LFTs: ALT 62 U/L, ALP 140 U/L, bilirubin 12, albumin 32. CK normal.
• Blood cultures: three sets drawn before antibiotics, from separate sites, negative at 5 days.
• Urinalysis: normal, no protein, no blood, no leucocytes.
• CXR: bilateral upper zone apical scarring consistent with old TB. No new infiltrate, no hilar lymphadenopathy, no pleural effusion.
• HIV serology: negative. Hepatitis B surface antigen negative, hepatitis C antibody negative.
• LDH: 420 U/L ( mildly raised).
• Beta-2 microglobulin: 3.1 mg/L (mildly raised). ^[1]

Candidate's structured presentation (model)

Opening statement (SASPOP): ^[1]

"Mr James Whitlam is a 62-year-old retired park ranger who presents 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 the past four years, diet-controlled type 2 diabetes, and mild hypertension. He lives on a rural property in northern New South Wales with cattle, sheep and feral pig exposure, and he travelled to Vietnam three months ago. ^[1]

His main problems are:

1. Classic fever of unknown origin — meeting the modern definition of 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 node, the B symptoms, the splenomegaly, the mildly raised LDH and beta-2 microglobulin.
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 parturient ewe, the cattle and the sheep; brucellosis from the cattle and the feral pigs; melioidosis, scrub typhus and enteric fever from the Vietnam travel.
5. Adalimumab-related risk — reactivation TB, atypical mycobacterial infection, opportunistic fungal infection, and the rare but recognised hepatosplenic T-cell lymphoma.

My immediate priorities are to stage the investigation systematically, to hold the adalimumab, 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 to localise the node and the splenomegaly; the excisional biopsy of the supraclavicular node with mycobacterial and fungal culture; the region-specific serology; the TB workup with IGRA and three sputum samples; and the FDG-PET-CT if the CT is non-diagnostic, to direct the biopsy of any occult lesion." ^[1]

Management plan: ^[1]

1. Confirm the syndrome and stage the investigation. The Tier 1 workup is complete and non-diagnostic. Proceed to Tier 2: CT of chest, abdomen and pelvis with contrast; autoimmune screen (ANA, ANCA, rheumatoid factor, anti-CCP, complement, immunoglobulins); IGRA and three sputum samples for AFB and mycobacterial culture; EBV and CMV serology; region-specific serology for Q fever, brucellosis, melioidosis, leptospirosis, scrub typhus and Bartonella; excisional biopsy of the supraclavicular node.
2. Proceed to Tier 3 if Tier 2 is non-diagnostic. FDG-PET-CT to localise occult malignancy, large-vessel vasculitis, or focal infection, and to direct the directed biopsy of any avid lesion. Bone marrow biopsy if the imaging is non-diagnostic and haematological disease remains the leading hypothesis. Liver biopsy if the abnormal LFTs persist without explanation.
3. Hold the adalimumab. The anti-TNF therapy is held for the duration of the workup, because it may be contributing to the fever, it is the central risk factor for TB reactivation and opportunistic infection, and it must not be resumed until the diagnosis is clear. The rheumatology team is engaged early. No empiric steroids or methotrexate as a bridge, because they would mask lymphoma and TB.
4. Withhold empiric therapy unless he deteriorates. The workup depends on the blood cultures and the biopsy. Empiric antibiotics would suppress the culture yield; empiric steroids would mask lymphoma and reactivate TB. The exception is clinical deterioration (new hypotension, rising lactate, new organ dysfunction), which would justify empiric broad-spectrum therapy covering TB, melioidosis, brucellosis and the hospital-acquired spectrum, after repeating the blood cultures. The diagnostic workup proceeds in parallel with the empiric therapy.
5. Communicate the uncertainty honestly. Explain to Mr Whitlam and his wife that the fever has not yet been explained, that several diagnoses are being considered in parallel, and that the next step (the CT, the node biopsy, the serology, the PET-CT) is the one most likely to make the diagnosis. Frame the conversation with honesty, structure, and safety — acknowledge the uncertainty, explain the staged approach, and give a clear point of contact, a clear timeframe for the next test, and a clear instruction on what to report urgently. ^[1]

Examiner discussion questions

Q1: "He was treated for TB 15 years ago. How does that history, combined with the adalimumab, change your TB risk assessment and your investigation approach?" ^[1]

"The combination of prior treated TB and four years of anti-TNF therapy places him at substantially elevated risk of TB reactivation. Anti-TNF therapy is the single most potent pharmacological risk factor for TB reactivation in current practice, because TNF is central to the granuloma that contains latent TB. The risk applies even with a fully treated prior episode, because treated TB leaves residual dormant organisms in the old granulomas that can reactivate under immunosuppression. My investigation approach reflects this: the IGRA may be blunted by the adalimumab and a negative result does not exclude TB, so I send three sputum samples for AFB and mycobacterial culture regardless of the IGRA result. The TB may be extrapulmonary or miliary, with a normal chest X-ray (the apical scarring is consistent with his old TB but does not exclude new disease). The lymph node biopsy is cultured for mycobacteria and fungi in addition to the standard histology. And I have a low threshold for empirical quadruple anti-TB therapy if he deteriorates, because the workup for TB takes weeks (the culture alone takes 2 to 6 weeks) and the deteriorating patient cannot wait." ^[1]

Q2: "His adalimumab is being held. How do you manage the psoriatic arthritis in the interim?" ^[1]

"With simple analgesia — paracetamol and a short-acting NSAID if there is no contraindication (his renal function is normal and he has no gastrointestinal contraindication). I do not bridge with corticosteroids or methotrexate, because empiric steroids would mask lymphoma and reactivate TB (both high on the differential), and methotrexate adds further immunosuppression. The psoriatic plaques can be managed with topical therapy. The rheumatology team is engaged from the outset, and the decision to resume the adalimumab — or to switch to an alternative agent — is made after the diagnosis is established. If the diagnosis turns out to be unrelated to the adalimumab (for example, a region-specific infection that has been treated), the adalimumab can be resumed; if the diagnosis is TB or lymphoma, the adalimumab is held for the duration of the treatment and an alternative strategy is considered." ^[1]

Q3: "The CT shows the supraclavicular node, the splenomegaly, and a 1.5 cm para-aortic lymph node. The node biopsy is arranged. When would you do a bone marrow biopsy?" ^[1]

"The bone marrow biopsy is not the first invasive test — the directed biopsy of the supraclavicular node and the PET-CT-directed biopsy of the para-aortic node are higher-yield. The bone marrow is reserved for two scenarios: one, if the node biopsy and the PET-CT are non-diagnostic and haematological disease remains the leading hypothesis (the marrow may show lymphoma, leukaemia, or a plasma cell dyscrasia); two, if miliary TB is suspected and the sputum is negative (the marrow may show granulomata, and the mycobacterial culture of the marrow is positive in a substantial proportion of disseminated TB). The principle that governs invasive investigation in FUO is 'never biopsy blindly' — the bone marrow is lower-yield than the directed biopsy of a PET-avid lesion, but it is still performed when the directed biopsy is not possible or non-diagnostic and the suspicion of marrow-based disease is high." ^[1]

Q4: "He deteriorates overnight. Walk me through your empiric therapy." ^[1]

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

Q5: "The node biopsy returns Hodgkin lymphoma. How does this change the 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 a baseline echocardiogram (for anthracycline cardiotoxicity), fertility counselling if relevant, and a discussion of the treatment regimen (ABVD or a similar combination for classical Hodgkin lymphoma). The adalimumab remains held — there is no indication to resume it, and the anti-TNF therapy is associated with a small increase in lymphoma risk that is now moot. The tuberculosis workup proceeds to completion, because the patient will be receiving immunosuppressive chemotherapy and any latent TB must be treated before that begins (typically with a 1-month course of isoniazid or rifampicin, in consultation with infectious diseases). The prognosis of Hodgkin lymphoma is excellent with modern 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]

Q6: "How do you decide when to stop investigating the undiagnosed FUO, if the workup had been unrevealing?" ^[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. The Bleeker-Rovers 2007 prospective multicenter study reported that 51 per cent of classic FUO cases remain undiagnosed after a structured protocol, and the majority of those resolve without recurrence ^[3]. 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."