FRCEM SBA practice questions is a core part of UK Emergency Medicine practice. Pyrexia of unknown origin (PUO) sits at the intersection of clinical medicine’s most challenging diagnostic territory and one of the highest-yield themes in the FRCEM SBA exam. For the emergency registrar, the problem is not merely academic: a patient with weeks of unexplained fever arrives through your department, physiologically compensated but diagnostically opaque, and the pressure to act safely before a diagnosis is secured is real. Understanding the structured approach to PUO, grounded in current UK evidence and guidelines, is therefore both a clinical and an examination imperative.
Key Points: PUO in the ED for FRCEM SBA Candidates
- The classic Petersdorf and Beeson definition (fever above 38.3 degrees C on multiple occasions, persisting more than three weeks, undiagnosed after one week of inpatient investigation) rarely applies in the acute ED encounter, but the underlying diagnostic framework does.
- Infectious causes now account for only 20 to 25% of PUO in resource-rich settings; non-infectious inflammatory disease and neoplasia each account for a comparable proportion.
- Malaria must be excluded with urgent thick and thin blood films in every febrile traveller returning from an endemic region, regardless of prophylaxis history.
- The Sepsis-6 bundle, as recommended by the UK Sepsis Trust and underpinned by NICE NG51, must be initiated within one hour when sepsis is suspected, before a definitive diagnosis is established.
- Adult-onset Still disease, lymphoma, and infective endocarditis are the three diagnoses most frequently embedded in FRCEM SBA clinical scenarios involving prolonged unexplained fever.
- A substantial minority (15 to 25%) of PUO cases are never diagnosed; this group generally carries a favourable prognosis when fever spontaneously resolves.
FRCEM SBA practice questions: Definition and Clinical Context
The Petersdorf and Beeson definition, published in 1961, established PUO as fever exceeding 38.3 degrees C recorded on at least two occasions, persisting for more than three weeks, and remaining undiagnosed after one week of structured inpatient investigation. This definition was designed for the inpatient setting and has been refined over subsequent decades to account for immunocompromised patients, nosocomial fever, and HIV-associated presentations, each constituting recognised sub-categories with distinct differentials. In the ED, the working definition is necessarily pragmatic: any patient with documented persistent fever without an immediately apparent source warrants a structured approach modelled on the PUO framework, even if the formal three-week criterion has not yet been satisfied.
The epidemiology of PUO has shifted significantly in high-income settings over the past four decades. Infectious causes, once responsible for nearly 40% of cases, now account for approximately 20 to 25%, reflecting improved diagnostics and earlier treatment of common bacterial infections. Non-infectious inflammatory disease (NIID), which encompasses autoimmune and autoinflammatory conditions, and neoplastic disease each contribute a further 20 to 25%. Miscellaneous causes including drug fever, pulmonary embolism, haematoma resorption, hyperthyroidism, and rare entities such as Familial Mediterranean Fever account for 10 to 15%. In a clinically important minority, no diagnosis is established despite thorough investigation; these patients generally do well if fever eventually resolves spontaneously. This epidemiological landscape matters for FRCEM SBA practice questions because examiners construct distractors around the assumption that candidates default to infectious causes and miss inflammatory or neoplastic diagnoses.
Pathophysiology: Fever Generation and Its Diagnostic Relevance
Fever is generated through the action of endogenous pyrogens, principally interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha), acting on the hypothalamic thermoregulatory centre via prostaglandin E2 synthesis. This shared final common pathway explains why fever is diagnostically non-specific: infection, malignancy, immune complex deposition, and drug hypersensitivity reactions all converge on the same cytokine-mediated mechanism. In lymphoma, for example, constitutional B symptoms including drenching night sweats, weight loss exceeding 10% body weight over six months, and fever above 38 degrees C arise from cytokine secretion by malignant lymphocytes and activated macrophages within lymph node architecture. In adult-onset Still disease (AOSD), the characteristic quotidian fever, spiking once or twice daily to above 39 degrees C and returning to normal, reflects dysregulated IL-18 and IL-1 beta secretion. Recognising these fever patterns is clinically and exam-relevant: a quotidian spike pattern with evanescent salmon-pink rash, arthralgia, and markedly elevated ferritin (often above 10,000 micrograms per litre) should prompt consideration of AOSD before a diagnosis of sepsis of unknown source is accepted.
Drug fever, an underappreciated and frequently missed diagnosis, arises through several mechanisms: type I to IV hypersensitivity reactions, idiosyncratic pharmacological effects, and direct pyrogen release. Common culprits include beta-lactam antibiotics, sulfonamides, phenytoin, allopurinol, and procainamide. The temporal relationship between drug initiation and fever onset may be days to weeks, and resolution typically follows within 48 to 72 hours of drug withdrawal. The patient with drug fever is often paradoxically well-appearing given the degree of pyrexia, a clinical clue that should feature in your FRCEM SBA revision strategy.
ED Assessment and Management
History
A systematic history is the single most powerful discriminator in PUO. Key domains include: fever pattern and duration; travel history (including travel within the preceding twelve months and specific regions visited); occupational and animal exposure (brucellosis, Q fever, leptospirosis); sexual history and intravenous drug use (HIV, infective endocarditis); medication history including over-the-counter and herbal preparations; family history of periodic fever syndromes; and a thorough systems review with particular attention to weight loss, night sweats, lymphadenopathy, joint symptoms, rash, and urinary or respiratory symptoms. Epidemiological clues embedded in the vignette are precisely where FRCEM SBA emergency medicine questions reward careful reading.
Examination
Examination should be systematic and unhurried. Lymphadenopathy, hepatosplenomegaly, skin rashes (including the evanescent Still rash, the target lesions of erythema multiforme, and petechiae suggesting endocarditis or meningococcal disease), murmurs suggesting valvular vegetations, and signs of weight loss or cachexia each carry significant diagnostic weight. Fundoscopy for Roth spots and inspection of the nail beds for splinter haemorrhages must not be omitted when infective endocarditis is under consideration.
Investigations
First-line ED investigations should include: full blood count with differential (eosinophilia suggests parasitic infection or drug reaction; lymphocytosis with atypical lymphocytes raises EBV or CMV); erythrocyte sedimentation rate and CRP; urea, electrolytes, and liver function tests (LFTs) including lactate dehydrogenase (LDH, which is elevated in lymphoma and haemolysis); blood cultures drawn from at least two separate sites before antibiotics are given; urine microscopy and culture; a blood film with malaria antigen testing in any traveller from an endemic region; monospot and EBV/CMV serology; and a chest radiograph. HIV testing should be offered universally in the UK ED in line with NICE guidance on HIV testing. Serum ferritin, antinuclear antibody (ANA), and ANCA should be requested when NIID is under consideration, though these may be deferred to the inpatient team depending on clinical urgency.
Management: Sepsis First
When PUO is associated with physiological instability, the clinical priority is treatment of probable sepsis ahead of diagnostic certainty. The NICE guideline NG51 on sepsis mandates risk stratification using the NEWS2 score, and the UK Sepsis Trust Sepsis-6 bundle (high-flow oxygen, blood cultures, IV antibiotics, IV fluid resuscitation, lactate measurement, and urinary catheterisation for fluid balance monitoring) must be initiated within one hour of recognition in high-risk patients. This clinical imperative is frequently tested in FRCEM SBA critical care revision scenarios where the candidate must choose between deferring antibiotics for diagnostic purposes and treating empirically: the correct answer is to treat empirically when sepsis is suspected, as delay in antibiotic administration beyond one hour of sepsis recognition is associated with increased mortality.
Empirical antibiotic choice must be guided by the suspected source, local resistance patterns, and trust antimicrobial guidelines as referenced by the British National Formulary. Clinicians should not withhold treatment on the basis that a definitive diagnosis has not been established.
Disposition
Safe disposition is a core FRCEM SBA competency. Criteria for admission include physiological instability, concern for a life-threatening underlying diagnosis (endocarditis, lymphoma, disseminated TB, haematological malignancy), immunocompromise, failure to thrive, or social circumstances precluding safe outpatient management. Patients who are stable, have had basic investigations initiated, and in whom the most dangerous diagnoses have been reasonably excluded may be discharged with robust safety-netting advice and expedited outpatient follow-up. Clear written instructions detailing red-flag symptoms (rigors, haemodynamic symptoms, new rash, confusion, severe localising pain) and a defined return pathway are mandatory before any discharge.
How the FRCEM SBA Exam Tests PUO
The FRCEM SBA exam tests PUO across several curriculum domains: infectious disease, haematological emergencies, rheumatological presentations, and clinical reasoning under uncertainty. Candidates preparing with FRCEM SBA practice questions should anticipate stems that present a returning traveller with fever and are designed to distinguish malaria (the correct answer) from typhoid, dengue, or a flare of inflammatory bowel disease. A second common pattern presents a patient with weeks of fever, weight loss, and mediastinal lymphadenopathy on the chest radiograph, requiring the candidate to identify lymphoma as the unifying diagnosis and select the most appropriate next investigation (CT of the chest, abdomen, and pelvis with contrast, or lymph node biopsy referral rather than empirical antibiotics).
AOSD is a classic FRCEM SBA clinical scenario: the typical stem describes a young adult with daily fever spikes, salmon-pink rash appearing with fever, arthralgia, and a serum ferritin in the tens of thousands. The correct answer is usually to arrange urgent rheumatology review rather than to administer broad-spectrum antibiotics. Infective endocarditis scenarios typically embed subacute fever, a new or changed cardiac murmur, and a history of intravenous drug use or recent dental work, requiring the candidate to select blood cultures and echocardiography as the priority investigations rather than proceeding directly to empirical therapy without culture.
The RCEM curriculum maps PUO to the domains of undifferentiated illness, infectious disease management, and clinical decision-making. Candidates using FRCEM SBA online revision resources should ensure they cover all four aetiological categories systematically and resist the temptation to default to infectious diagnoses exclusively. The Royal College of Emergency Medicine publishes the curriculum framework against which all FRCEM SBA exam questions are mapped, and familiarity with that framework should inform your revision strategy.
Revision Pearls: High-Yield Facts for FRCEM SBA Candidates
- Malaria must be excluded in every febrile traveller returning from an endemic region with urgent thick and thin blood films; a single negative film does not exclude the diagnosis and should be repeated at 12 and 24 hours if clinical suspicion remains.
- Serum ferritin above 10,000 micrograms per litre in a young adult with quotidian fever, arthralgia, and a transient salmon-coloured rash is virtually pathognomonic of adult-onset Still disease and should prompt urgent rheumatology referral.
- Infective endocarditis may present subacutely over weeks and must be considered in any febrile patient with a murmur, vascular phenomena (splinter haemorrhages, Osler nodes, Janeway lesions), or a history of IVDU or recent instrumentation.
- Drug fever should be actively sought in any febrile patient without an obvious infective source; a temporal association with medication introduction and paradoxical clinical wellness are the key clues.
- In PUO, LDH elevation is an important red flag for haematological malignancy and haemolysis; it should be measured routinely alongside LFTs in the initial workup.
- The Sepsis-6 bundle must be initiated within one hour when sepsis is suspected regardless of whether a source has been identified; deferring treatment for diagnostic clarity is the most common dangerous pitfall in clinical practice and the most frequently tested wrong answer in FRCEM SBA exam questions on this topic.
- A substantial proportion of PUO cases resolve without a diagnosis; this is not a management failure and generally carries a favourable prognosis, but requires structured outpatient follow-up and clear safety-netting.
Common Pitfalls: Where Candidates Lose Marks
- Defaulting to an infectious diagnosis in every PUO scenario without considering neoplastic and inflammatory differentials with equal rigour.
- Failing to take a travel history and omitting malaria films in a febrile traveller, even when prophylaxis has been taken.
- Selecting empirical antibiotics before drawing blood cultures, thereby compromising the diagnostic yield of the most important investigation in suspected endocarditis.
- Missing AOSD by misinterpreting markedly elevated ferritin as an acute-phase reactant rather than a diagnostic pointer.
- Discharging a patient with unexplained fever without written safety-netting advice and a defined follow-up plan.
- Overlooking drug fever as a diagnosis in patients on multiple medications, particularly when the patient appears clinically well for the degree of pyrexia recorded.
How EM Learning Centre Supports Your FRCEM Single Best Answer Revision
Mastering PUO and the breadth of the FRCEM SBA syllabus requires structured, expert-written content that mirrors the depth and clinical reasoning expected on exam day. The FRCEM Single Best Answer revision course at EM Learning Centre provides a comprehensive question bank with detailed explanations, curriculum-mapped to the RCEM framework, and written at the clinical level expected of a senior emergency medicine trainee. Each question is accompanied by a full explanation of why the correct answer is correct and, crucially, why the distractors are wrong, the most effective way to develop discriminatory clinical reasoning for the FRCEM SBA exam.
Pyrexia of unknown origin is one of many high-yield clinical scenarios covered across the platform. Whether you are working through FRCEM SBA practice questions in infectious disease, haematology, rheumatology, or undifferentiated illness, the platform provides the depth of explanation that revision notes alone cannot replicate. Visit the EM Learning Centre homepage to explore the full range of courses available for MRCEM SBA and FRCEM SBA exam preparation and to begin a structured, evidence-based revision programme that prepares you for the clinical reasoning demands of both the examination and your consultant career.
References
- National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. NICE guideline NG51. 2016 (updated 2017). NICE NG51.
- Royal College of Emergency Medicine. RCEM Curriculum and Assessment Framework. Royal College of Emergency Medicine.
- National Institute for Health and Care Excellence. HIV testing: increasing uptake among people who may have undiagnosed HIV. NICE guideline PH33. NICE.
- British National Formulary. Antibacterials: principles of therapy. British National Formulary.
- Resuscitation Council UK. Advanced Life Support guidelines. Resuscitation Council UK.
- The BMJ. Pyrexia of unknown origin. BMJ Best Practice and associated clinical reviews. The BMJ.
