Pyrexia of Unknown Origin: A Practical Approach to Distinguishing Infection, Inflammation, and Malignancy

A Clinical Review for Postgraduate Trainees and Consultants

Dr Neeraj Manikath , claude.ai

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Abstract

Pyrexia of unknown origin (PUO) remains one of the most challenging diagnostic dilemmas in internal medicine. Despite advances in diagnostic technology, distinguishing between the three major categories—infection, inflammatory diseases, and malignancy—continues to test clinical acumen. This review provides a structured approach to differentiate these giants, incorporating contemporary diagnostic algorithms, clinical pearls, and evidence-based strategies gleaned from both literature and clinical experience. Understanding the subtle distinctions in presentation, temporal patterns, and diagnostic yield of investigations can significantly reduce time to diagnosis and improve patient outcomes.

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Introduction

The classical definition of PUO, established by Petersdorf and Beeson in 1961, describes fever higher than 38.3°C on several occasions, persisting for more than three weeks, with diagnosis uncertain after one week of intelligent investigation in hospital. Modern modifications account for outpatient evaluations and immunocompromised states, creating subcategories including classic PUO, nosocomial PUO, neutropenic PUO, and HIV-associated PUO.

The diagnostic landscape has evolved considerably. Historical series from the 1950s-1970s identified infections in 30-40% of cases, neoplasms in 20-30%, and inflammatory diseases in 10-20%. Contemporary studies show shifting patterns: infections now account for 20-25% of cases in developed nations, inflammatory diseases have increased to 25-30%, while malignancies represent 15-20%. Notably, the percentage of undiagnosed cases has decreased from 10-15% to approximately 5-7% with modern imaging and molecular diagnostics.

This review focuses on practical differentiation of the three major categories, providing clinicians with actionable frameworks for efficient diagnosis.

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The Clinical Framework: Pattern Recognition

Temporal Patterns: The First Clue

Pearl #1: The fever curve still matters

While continuous temperature monitoring has fallen out of favor, fever patterns retain diagnostic value:

• Sustained/continuous fever (≤0.3°C variation): Suggests gram-negative bacteremia, typhoid fever, or malignancy (particularly lymphoma)
• Remittent fever (>0.3°C variation, never touches baseline): Common in pyogenic infections, tuberculosis, and malignancies
• Intermittent fever (returns to normal daily): Classic for abscesses, malaria, lymphomas
• Pel-Ebstein fever (cyclic peaks with afebrile intervals of days to weeks): Rare but pathognomonic of Hodgkin lymphoma
• Double quotidian fever (two daily spikes): Adult-onset Still's disease, military tuberculosis, visceral leishmaniasis

Hack #1: Ask patients to maintain a fever diary with 4-hourly temperature measurements for one week. The pattern may emerge when in-hospital monitoring is brief.

Duration and Onset Characteristics

Infection clues:

• Acute-to-subacute onset (days to 2-3 weeks) suggests infection
• Relapsing pattern with brief afebrile intervals: brucellosis, relapsing fever, rat-bite fever
• Seasonal variation: leptospirosis, dengue (monsoon); Q fever (spring)

Inflammatory disease clues:

• Insidious onset over weeks to months
• Morning stiffness preceding fever: rheumatoid arthritis, polymyalgia rheumatica
• Dramatic response to NSAIDs within hours: Adult-onset Still's disease, acute rheumatic fever

Malignancy clues:

• Gradual onset over months
• B symptoms (weight loss >10%, drenching night sweats): lymphomas
• Fever develops late in solid tumors except renal cell carcinoma

Oyster #1: A patient with acute dramatic onset and rapid deterioration rarely has indolent lymphoma—think aggressive infection or vasculitis instead.

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Infection: The Protean Mimicker

High-Yield Infectious Causes

Endemic/travel-related infections:

• Tuberculosis remains the leading infectious cause globally (15-25% of PUO in endemic areas)
• Intra-abdominal abscesses: subphrenic, hepatic, splenic, appendicular
• Endocarditis: accounts for 5-10% of classic PUO
• Complicated urinary tract infections: perinephric abscess, prostatitis
• Cat-scratch disease (Bartonella henselae)
• Q fever (Coxiella burnetii)
• Brucellosis
• Malaria, typhoid in appropriate geographic context

Clinical Clues Favoring Infection

Pearl #2: The "septic" appearance

Patients with infectious PUO often exhibit:

• Rigors and shaking chills (bacteremia, abscess)
• Tachycardia disproportionate to fever (>10 bpm per °C)
• Relative bradycardia: typhoid, brucellosis, legionella, malaria
• Changing clinical signs daily
• Acute phase response: marked elevation of CRP >100 mg/L

Diagnostic approach:

1. Blood cultures remain paramount: Three sets from different sites, before antibiotics, ideally during fever spike. Yield: 10-20% in PUO

2. Imaging strategy:

   • Contrast-enhanced CT chest/abdomen/pelvis: Detection rate 30-55% for infection
   • Echocardiography: Transthoracic initially, but transesophageal has superior sensitivity (95% vs 60%) for endocarditis
   • PET-CT: Sensitivity 85-90% for infection, particularly helpful for vascular graft infections, spondylodiscitis

3. Specialized testing:

   • Serologies: Q fever, brucella, bartonella
   • PCR assays: mycobacterial, fungal
   • Interferon-gamma release assays (IGRAs): Tuberculosis screening

Hack #2: The "index of suspicion" test

When considering occult abscess, check:

• Alkaline phosphatase elevation (50% of intra-abdominal abscesses)
• Hypoalbuminemia
• Thrombocytosis (>450,000/μL) This triad warrants aggressive imaging.

Pearl #3: Endocarditis without a murmur

10-15% of endocarditis presents without cardiac findings. Risk factors in PUO:

• Recent dental/GU procedures
• Prosthetic valves
• IVDU history
• Persistently positive blood cultures (>48 hours apart)

Modified Duke criteria remain diagnostic standard. Negative blood cultures may suggest HACEK organisms, Coxiella, Bartonella, or fungi—serology and molecular diagnostics essential.

Oyster #2: A patient with suspected endocarditis but negative TEE: Consider marantic (non-bacterial thrombotic) endocarditis associated with underlying malignancy, particularly adenocarcinomas.

Tuberculosis: The Great Masquerader

Extrapulmonary TB accounts for 8-12% of PUO:

• Sites: Lymph nodes (40%), GU tract (15%), bones/joints (10%), miliary (8-10%)
• Chest X-ray normal in 50% of extrapulmonary TB
• TST/IGRA may be negative in 20-25% of active disease (anergy)

Diagnostic pearls:

• Adenosine deaminase (ADA) >40 U/L in pleural/ascitic/CSF fluid: sensitivity 80-95% for TB
• GeneXpert MTB/RIF: Rapid molecular diagnosis, detects rifampicin resistance
• Therapeutic trial justified in high-suspicion cases with negative workup (response in 2 weeks)

Hack #3: In suspected TB with repeatedly negative samples, consider:

1. Repeat sampling (minimum 3 sputum/fluid samples)
2. Bronchoscopy with BAL
3. Lymph node/tissue biopsy (gold standard)
4. Empirical anti-TB treatment with close monitoring

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Inflammatory Diseases: The Rising Giants

The incidence of inflammatory causes has increased, now representing 25-30% of PUO in developed countries.

Major Inflammatory Causes

Rheumatologic:

• Adult-onset Still's disease (AOSD): 5-7% of PUO
• Systemic lupus erythematosus
• Rheumatoid arthritis (rare as PUO presentation)
• Polymyalgia rheumatica/Giant cell arteritis: elderly patients
• Vasculitides: polyarteritis nodosa, ANCA-associated

Other inflammatory:

• Sarcoidosis
• Inflammatory bowel disease (especially Crohn's)
• Kikuchi-Fujimoto disease
• Drug fever
• Subacute thyroiditis

Adult-Onset Still's Disease: A Diagnostic Challenge

AOSD exemplifies the diagnostic difficulty of inflammatory PUO.

Yamaguchi criteria (sensitivity 96%, specificity 92%):

• Major: Fever ≥39°C for ≥1 week, arthralgia ≥2 weeks, salmon-pink rash, leukocytosis ≥10,000
• Minor: Sore throat, lymphadenopathy/splenomegaly, liver dysfunction, negative RF and ANA

Pearl #4: The "Still's triad"

• Quotidian fever spike (typically evening)
• Evanescent salmon-pink rash appearing with fever
• Marked leukocytosis (15,000-40,000) with neutrophilia

Diagnostic markers:

• Ferritin >1000 ng/mL (sensitivity 80%): but non-specific
• Glycosylated ferritin <20%: More specific (70-80%)
• Ferritin:ESR ratio: Ferritin/ESR >10 suggests AOSD

Hack #4: The "NSAID test"

Give indomethacin 50 mg TDS for 48 hours. AOSD typically shows dramatic defervescence within 24-48 hours. If no response, consider alternatives.

Oyster #3: Very high ferritin (>10,000 ng/mL) narrows differentials to: AOSD, hemophagocytic lymphohistiocytosis (HLH), and occasionally catastrophic antiphospholipid syndrome. Check for cytopenias (HLH) and check anticardiolipin antibodies.

Vasculitis in PUO

Giant cell arteritis (GCA):

• Age >50 years
• New headache, jaw claudication, visual symptoms
• ESR typically >50 mm/hr (but can be normal in 10%)
• Temporal artery ultrasound: Halo sign (sensitivity 75%, specificity 85%)
• Temporal artery biopsy: Gold standard (skip lesions possible—3-5 cm specimen needed)

Pearl #5: PUO in the elderly

In patients >65 years with PUO and very high ESR/CRP:

1. Rule out GCA first
2. Consider polymyalgia rheumatica
3. Don't forget occult malignancy (multiple myeloma, lymphoma)
4. Nosocomial infections if recent hospitalization

Other vasculitides:

• Polyarteritis nodosa: Systemic features, livedo reticularis, mononeuritis multiplex, renal/GI involvement, HBV association (30%)
• ANCA-associated: Pulmonary-renal syndromes, sinusitis, check PR3-ANCA and MPO-ANCA
• Takayasu arteritis: Young females, pulse deficits, vascular bruits, elevated inflammatory markers

Drug Fever: The Forgotten Diagnosis

Accounts for 3-5% of PUO, often overlooked.

Temporal pattern:

• Typically develops 7-10 days after drug initiation
• Can occur months after starting drug
• Fever persists despite antipyretics
• Resolves within 48-72 hours of drug cessation

Common culprits:

• Antibiotics: beta-lactams, sulfonamides, nitrofurantoin
• Antiepileptics: phenytoin, carbamazepine
• Allopurinol
• Heparin
• Minocycline

Clinical clues:

• Relative bradycardia
• Eosinophilia (25%)
• Rash (20%)
• Patient appears well despite high fever

Hack #5: The "medication withdrawal trial"

In diagnostic uncertainty with recent medication exposure:

1. Stop all non-essential medications simultaneously
2. Monitor temperature 4-hourly for 72 hours
3. Sequentially reintroduce essential medications one at a time
4. Monitor for fever recurrence

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Malignancy: The Stealthy Adversary

Malignancy accounts for 15-20% of PUO, with lymphomas (especially Hodgkin and non-Hodgkin) representing 50-60% of malignant causes.

Major Malignant Causes

Hematologic:

• Lymphomas: Hodgkin and non-Hodgkin (most common)
• Leukemias: Acute myeloid, acute lymphoblastic
• Multiple myeloma
• Myelodysplastic syndromes

Solid tumors:

• Renal cell carcinoma (10-20% present with PUO)
• Hepatocellular carcinoma
• Atrial myxoma
• Colon cancer (with occult abscess)

Clinical Clues Favoring Malignancy

Pearl #6: The "B symptoms complex"

• Weight loss >10% over 6 months
• Drenching night sweats (requiring clothing change)
• Profound fatigue/malaise Triad strongly suggests lymphoma (especially Hodgkin)

Laboratory patterns:

• Moderate anemia without obvious blood loss
• Lactate dehydrogenase elevation: Lymphomas, leukemias
• Elevated uric acid: High cell turnover
• Thrombocytosis: Renal cell carcinoma, other solid tumors
• Hypoalbuminemia: Advanced disease
• Polyclonal hypergammaglobulinemia: Chronic stimulation

Hack #6: The "LDH-ferritin-CRP trio"

When all three are markedly elevated (LDH >500 U/L, ferritin >1000 ng/mL, CRP >100 mg/L):

• Consider: lymphoma, hemophagocytic syndromes, severe infections
• If cytopenic: bone marrow examination mandatory
• If lymphadenopathy: excisional biopsy (not FNA)

Lymphoma Diagnosis

Imaging strategy:

1. CT chest/abdomen/pelvis with contrast: Initial screening
2. PET-CT: Sensitivity 90-95% for FDG-avid lymphomas
   • Identifies occult disease
   • Guides biopsy site
   • Assesses treatment response

Pearl #7: Not all lymph nodes need biopsy

Biopsy should target:

• Nodes >2 cm
• Nodes in uncommon locations (epitrochlear, supraclavicular)
• Persistent nodes >4-6 weeks
• Hard, fixed, non-tender nodes
• Excisional biopsy preferred over FNA (architecture assessment crucial)

Oyster #4: PET-positive nodes in suspected lymphoma but negative initial biopsy: Consider repeat biopsy of different site. FDG uptake can represent reactive changes, granulomas, or sampling error.

Renal Cell Carcinoma: The Occult Fever

Classic triad (only 10% of cases):

• Flank mass
• Hematuria
• Flank pain

Paraneoplastic manifestations (30-40%):

• Fever (20%)
• Hypertension (40%)
• Hypercalcemia (10-20%)
• Polycythemia (5%)
• Stauffer syndrome (hepatic dysfunction without metastases)

Diagnostic approach:

• Renal ultrasound: Initial screening
• CT abdomen with IV contrast (triple phase): Definitive imaging
• Urinalysis: Hematuria in 60%

Hack #7: In cryptogenic PUO with hematuria, always image kidneys thoroughly—even microscopic hematuria warrants attention.

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The Integrated Diagnostic Algorithm

First-Line Evaluation (Week 1-2)

Comprehensive history:

• Travel (last 12 months)
• Animal exposure
• Occupation
• Sexual history
• Family history (periodic fever syndromes, autoimmune diseases)
• Medications (complete list including over-the-counter)
• Dental procedures
• Immunization status

Physical examination pearls:

• Daily examination: New findings may appear
• Examine during fever spike: Rashes, lymph nodes more apparent
• Special attention: Temporal arteries, cardiac auscultation, hepatosplenomegaly, lymph nodes (including epitrochlear), fundoscopy, genital/rectal examination

Initial investigations:

• Complete blood count with differential
• ESR, CRP
• Comprehensive metabolic panel, LDH
• Urinalysis with microscopy
• Blood cultures × 3 (from different sites)
• Chest X-ray
• Tuberculin skin test or IGRA
• HIV testing
• ANA, RF, ANCA
• Serum protein electrophoresis
• Ferritin

Second-Line Evaluation (Week 2-4)

If initial workup negative:

Imaging:

• CT chest/abdomen/pelvis with contrast: Detection rate 40-55%
• Echocardiography: TTE initially, consider TEE if high suspicion
• Consider temporal artery ultrasound if age >50 years

Specialized serology:

• Q fever, brucella, bartonella
• CMV, EBV
• Toxoplasma
• Geographic-specific: dengue, leptospirosis, scrub typhus

Immunologic workup:

• Complement levels (C3, C4, CH50)
• Antiphospholipid antibodies
• Cryoglobulins
• Bone marrow if cytopenic

Third-Line Evaluation (Week 4-6)

Advanced imaging:

• PET-CT: Sensitivity 85-90%, particularly useful for:
  • Vasculitis (large vessel)
  • Lymphoma
  • Occult infections (vascular grafts, prosthetics)
  • Inflammatory diseases

Invasive procedures:

• Lymph node biopsy (excisional)
• Bone marrow examination
• Temporal artery biopsy
• Liver biopsy (if infiltrative disease suspected)
• Colonoscopy (if GI symptoms/occult blood)

Pearl #8: The diagnostic yield hierarchy

1. PET-CT: 50-60% diagnostic contribution
2. CT imaging: 40-50%
3. Bone marrow: 15-20% (higher if cytopenic)
4. Liver biopsy: 10-15% (often granulomatous disease)
5. Laparoscopy/laparotomy: <5% (reserved for refractory cases)

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Distinguishing the Giants: A Comparative Framework

Speed of Onset and Progression

Feature	Infection	Inflammation	Malignancy
Onset	Acute to subacute (days-weeks)	Subacute to chronic (weeks-months)	Chronic (months)
Progression	Rapid deterioration possible	Fluctuating course	Gradual decline
Response to antibiotics	May improve	No response	No respon