Undifferentiated Fever and Fever of Unknown Origin — Written Clinical Reasoning

SAQ 1 — Integrated Diagnostic and Management Plan for Classic FUO in an Immunosuppressed Patient (20 marks, 30 minutes)

Prompt: Outline your integrated diagnostic and management plan for this patient with classic fever of unknown origin, including: (a) confirmation of the FUO definition and the leading diagnostic hypotheses; (b) the staged Tier 2 and Tier 3 investigation; (c) the role of the regional and exposure-specific serology; (d) the management of the adalimumab during the workup; (e) the threshold for empiric therapy; and (f) the high-yield exam traps in the immunosuppressed FUO patient. [1]

Model Answer

(a) Confirmation of the definition and the leading hypotheses (3 marks): [1]

This patient meets the modern (Durack and Street) definition of classic fever of unknown origin: temperature above 38.3 degrees Celsius on several occasions, duration of more than three weeks, and no diagnosis after a competent initial outpatient workup [2]. The leading diagnostic hypotheses, in order of clinical priority, are:

1. Lymphoma — the supraclavicular node, the B symptoms (drenching night sweats, weight loss), the splenomegaly, and the mild normocytic anaemia all point to a lymphoproliferative malignancy. The left supraclavicular (Virchow) node is a sentinel for upper abdominal and thoracic malignancy.
2. Tuberculosis reactivation — the prior treated TB, the adalimumab therapy (an anti-TNF biologic, the single most potent risk factor for TB reactivation in current practice), the recent travel to a TB-endemic region, and the apical scarring on the chest X-ray. The presentation may be extrapulmonary or miliary, with a normal chest X-ray.
3. Region-specific zoonotic infection — the rural New South Wales property with cattle and sheep (Q fever, brucellosis), the feral pig hunting (brucellosis, melioidosis in tropical areas, leptospirosis), and the travel to Vietnam (scrub typhus, melioidosis, enteric fever, malaria).
4. Adalimumab-related complication — drug fever is less common with biologics than with small molecules, but possible; the rare but recognised hepatosplenic T-cell lymphoma; and the broader opportunistic infection spectrum. [1]

(b) The staged Tier 2 and Tier 3 investigation (5 marks): [1]

The investigation proceeds in stages, each directed by the previous tier. The Tier 1 workup (full blood count, CRP, ESR, U&E, LFTs, blood cultures, urinalysis, CXR, HIV, hepatitis serology) is complete and non-diagnostic. The Tier 2 workup adds: [1]

• Directed imaging: CT of chest, abdomen and pelvis with contrast, to localise the supraclavicular node, the splenomegaly, any occult lymphadenopathy, and any focal infection. This is the central Tier 2 investigation and has displaced the older blind investigations from the diagnostic pathway [3].
• Autoimmune and vasculitic screen: ANA, ANCA, rheumatoid factor, anti-CCP, complement, immunoglobulins — to address the non-infectious inflammatory disease bucket, although his presentation points more to infection or malignancy.
• Tuberculosis workup: IGRA (interferon-gamma release assay) and three sputum samples for acid-fast bacilli and mycobacterial culture. The IGRA may be blunted by the adalimumab and a negative result does not exclude TB.
• Viral serology: EBV and CMV serology.
• Lymphoma markers: LDH, beta-2 microglobulin, serum protein electrophoresis, serum free light chains.
• Excisional biopsy of the supraclavicular node: preferred over core or fine-needle aspiration because the nodal architecture is often the diagnosis. The node is sent fresh for histology, immunohistochemistry, flow cytometry, and mycobacterial and fungal culture (given his TB and immunosuppression).

If the CT and the node biopsy are non-diagnostic, the Tier 3 workup adds: [1]

• FDG-PET-CT: the central Tier 3 investigation, localising metabolically active disease and directing the directed biopsy. The Dong meta-analysis reported a pooled FDG-PET-CT sensitivity of 0.982 and specificity of 0.859 in FUO [4]. The PET-CT identifies the highest-yield site for biopsy if the supraclavicular node is not diagnostic.
• Bone marrow biopsy: if haematological disease is suspected but imaging is non-diagnostic, or if miliary TB is suspected (the marrow may show granulomata).
• Liver biopsy: if the abnormal LFTs persist without another explanation, to assess for granulomatous disease, lymphoma, or miliary TB.

(c) The role of the regional and exposure-specific serology (3 marks): [1]

The exposure history is decisive and the serology panel is built around it: [1]

• Q fever (Coxiella burnetii) — phase I and phase II IgG and IgM, given the sheep and cattle exposure.
• Brucellosis (Brucella abortus and melitensis) — serology and blood culture on Castaneda medium, given the cattle and feral pig exposure.
• Melioidosis (Burkholderia pseudomallei) — serology and blood culture on Ashdown's medium, particularly given the tropical exposure potential (northern New South Wales and Vietnam).
• Scrub typhus (Orientia tsutsugamushi) — serology, given the travel to Vietnam and the eschar that may be overlooked.
• Leptospirosis — serology, given the rodent and fresh water exposure.
• Enteric fever (Salmonella typhi and paratyphi) — blood cultures and serology (Widal, though the latter has limited sensitivity), given the travel.
• Malaria — thick and thin blood films, given the travel to Vietnam (a malaria-endemic region, particularly for Plasmodium vivax). [1]

(d) Management of the adalimumab during the workup (2 marks): [1]

The adalimumab is held for the duration of the workup. The reasoning is threefold: (1) it may be contributing to the fever (drug fever is uncommon but possible); (2) it is the central risk factor for TB reactivation and opportunistic infection, and removing it may allow the immune system to express the infection more clearly; (3) 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 involved early, and an alternative strategy for the psoriatic arthritis (such as NSAIDs or low-dose prednisolone) is considered only after the diagnosis is established, because empiric steroids would mask lymphoma and TB. [1]

(e) The threshold for empiric therapy (4 marks): [1]

Empiric therapy is discouraged as a diagnostic manoeuvre in the stable FUO patient, because it obscures the diagnosis — empiric antibiotics suppress the blood culture yield, empiric steroids mask lymphoma and reactivate TB. The exception is clinical deterioration, which justifies empiric therapy even before the definitive diagnosis is reached [5]. The thresholds are:

• New hypotension or rising lactate — empiric broad-spectrum antibiotics covering the most likely pathogens, after repeating the blood cultures. Given his exposures and his anti-TNF therapy, the cover includes TB (empirical quadruple therapy if TB is the leading hypothesis), melioidosis (meropenem or ceftazidime), and a broad-spectrum agent for healthcare-associated and nosocomial pathogens.
• A high-probability single diagnosis — if the clinical picture makes a single diagnosis highly probable (for example, miliary TB with characteristic imaging), targeted therapy may begin pending the definitive workup.
• Visual symptoms in suspected giant cell arteritis — high-dose glucocorticoids immediately, with temporal artery biopsy within 1 to 2 weeks. (Not directly relevant to this patient but a general principle.) [1]

The diagnostic workup (the node biopsy, the PET-CT, the serology) proceeds in parallel with the empiric therapy, because the deterioration does not abandon the diagnostic strategy. [1]

(f) High-yield exam traps in the immunosuppressed FUO patient (3 marks): [1]

The traps in the immunosuppressed FUO patient are: [1]

1. A negative IGRA does not exclude TB in the patient on anti-TNF therapy. The diagnosis requires sputum for AFB, biopsy of accessible tissue with mycobacterial culture, and a low threshold for empirical therapy in the deteriorating patient.
2. The blind bone marrow is lower-yield than the directed biopsy of a PET-avid lesion. In the patient with possible lymphoma and a non-diagnostic CT, the PET-CT identifies the highest-yield site for biopsy, and the blind bone marrow is reserved for when PET is not available or when miliary TB is suspected.
3. Empiric steroids are doubly dangerous in this patient because they mask lymphoma (which is high on the differential) and they reactivate TB (which is also high on the differential). The steroid trial as a diagnostic manoeuvre is reserved for the patient in whom vasculitis is the leading hypothesis and infection and malignancy have been excluded — not this patient.
4. The adalimumab must not be resumed until the diagnosis is clear. Resuming anti-TNF therapy in the face of active TB or untreated lymphoma would be dangerous, and the rheumatology team must be engaged in the decision.
5. The region-specific serology is non-negotiable in the patient with the exposure history. The standard "infection screen" will not detect Q fever, brucellosis, melioidosis, scrub typhus or leptospirosis, and these are common in the Australian rural population. [1]

SAQ 2 — Culture-Negative Endocarditis in a Prosthetic Valve Patient (10 marks)

Prompt: A 66-year-old woman with a prosthetic aortic valve placed 4 years ago presents with five weeks of fever, fatigue and weight loss. Three sets of blood cultures drawn before antibiotics are negative at 7 days. Her transthoracic echocardiogram shows no vegetation. She has a new aortic systolic murmur and an erythrocyte sedimentation rate of 95 mm per hour. Outline: (a) the diagnosis you are considering and the reasons for the negative cultures and the negative transthoracic echo; (b) the further investigations you would arrange; (c) the criteria you would apply to make the diagnosis; and (d) the initial management once the diagnosis is confirmed or highly probable. [1]

Model Answer

(a) Diagnosis and reasons for the negative workup (3 marks): [1]

The leading diagnosis is culture-negative infective endocarditis of the prosthetic aortic valve. The reasons for the negative blood cultures are: (1) infection with fastidious or intracellular organisms that do not grow on routine blood culture media — Coxiella burnetii (Q fever), Bartonella henselae and Bartonella quintana, and the HACEK group (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella); (2) prior antibiotic exposure before the cultures (less likely here, as the cultures were drawn before antibiotics); and (3) non-bacterial thrombotic endocarditis (marantic, in the setting of malignancy or antiphospholipid syndrome). The reasons for the negative transthoracic echocardiogram are: (1) the lower sensitivity of transthoracic echo relative to transoesophageal echo for vegetations (around 60 per cent versus above 90 per cent), particularly in the prosthetic valve where acoustic shadowing obscures the valve; (2) small vegetations below the resolution of transthoracic imaging; and (3) paravalvular abscess or dehiscence that the transthoracic does not detect. [1]

(b) Further investigations (3 marks): [1]

• Transoesophageal echocardiography — the imaging modality of choice for suspected prosthetic valve endocarditis, with sensitivity above 90 per cent for vegetations and paravalvular complications.
• Serological testing for the culture-negative organisms — Coxiella burnetii (phase I and phase II), Bartonella henselae and Bartonella quintana, and the HACEK group.
• Repeat blood cultures held for prolonged incubation (up to 21 days) and on special media if the fastidious organisms are suspected; molecular techniques (16S ribosomal RNA PCR on the valve or on blood) in selected cases.
• FDG-PET-CT — abnormal prosthetic valve uptake is now included as a major criterion in the 2023 Duke-ISCVID criteria, and it identifies distant embolic and metastatic foci.
• ECG to look for conduction delay (prolonged PR interval suggesting aortic root abscess).
• Renal function, urinalysis and urinary sediment — immunological phenomena (glomerulonephritis) are supporting evidence. [1]

(c) The diagnostic criteria (2 marks): [1]

The diagnosis is made by the modified Duke criteria (or the 2023 Duke-ISCVID update), which combine major and minor criteria. The major criteria are: (1) positive blood cultures for a typical organism or persistently positive cultures; (2) evidence of endocardial involvement on imaging (vegetation, abscess, new partial dehiscence of a prosthetic valve) — transoesophageal echo and FDG-PET-CT uptake both qualify as major criteria in the 2023 update. The minor criteria are: (1) predisposition (a prosthetic valve, prior endocarditis, injecting drug use); (2) fever above 38.0 degrees; (3) vascular phenomena (arterial embolus, septic pulmonary infarct, mycotic aneurysm, intracranial haemorrhage, conjunctival haemorrhage, Janeway lesion); (4) immunological phenomena (glomerulonephritis, Osler node, Roth spot, rheumatoid factor); (5) microbiological evidence not meeting the major criterion. Definite endocarditis is two major, or one major and three minor, or five minor criteria. This patient has a prosthetic valve (minor), a fever (minor), and a raised ESR; the transoesophageal echo and the serology are awaited to establish the major criteria. [1]

(d) Initial management once confirmed (2 marks): [1]

Once the diagnosis is confirmed or highly probable, the management is prolonged intravenous antibiotic therapy with an organism-specific regimen, in collaboration with the infectious diseases team and the cardiothoracic surgical team. The duration is typically 4 to 6 weeks for native valve endocarditis and 6 weeks or more for prosthetic valve endocarditis. The organism drives the choice — Coxiella endocarditis requires prolonged doxycycline and hydroxychloroquine (to achieve an acidic intracellular environment that allows the doxycycline to act), Bartonella requires a combination of a beta-lactam or aminoglycoside with doxycycline, and the HACEK organisms require a third-generation cephalosporin. Surgery is indicated for heart failure from valvular dysfunction, uncontrolled infection (persistent bacteraemia, fungal or highly resistant organism), prosthetic valve dehiscence or obstruction, perivalvular abscess or extension, and embolic events with residual large vegetations. The patient is anticoagulated according to the prosthetic valve protocol, with the recognition that anticoagulation in endocarditis carries a risk of intracranial haemorrhage from mycotic aneurysm. Communication with the general practitioner and the anticoagulation clinic is part of the discharge plan. [1]