# Clinical Cases: Approach to Fever

## Case 1: Fever of Unknown Origin

### Patient Presentation
A 54-year-old man presents with a 4-week history of daily fevers ranging from 38.3°C to 39.2°C. He reports night sweats, fatigue, and an unintentional 10-pound weight loss. He has no localizing symptoms such as cough, dysuria, abdominal pain, or rash. He works as an accountant, has no recent travel, and has no sick contacts. Past medical history includes hypertension controlled with lisinopril.

### Vital Signs
- Blood Pressure: 128/78 mmHg
- Heart Rate: 92 bpm
- Respiratory Rate: 16/min
- Oxygen Saturation: 98% on room air
- Temperature: 38.9°C

### Physical Examination
- General: Appears fatigued but not toxic
- HEENT: No oral lesions, no lymphadenopathy
- Cardiovascular: Regular rhythm, no murmurs
- Pulmonary: Clear to auscultation
- Abdomen: Splenomegaly palpable 3 cm below costal margin
- Skin: No rashes, no petechiae

### Initial Workup
- **CBC**: WBC 11,200/μL, Hgb 10.2 g/dL, Platelets 420,000/μL
- **ESR**: 85 mm/hr (normal <20)
- **CRP**: 12.4 mg/dL (normal <0.5)
- **LDH**: 380 U/L (elevated)
- **Blood cultures**: Pending
- **Urinalysis**: Normal
- **Chest X-ray**: No infiltrates or masses
- **CT Abdomen/Pelvis**: Splenomegaly, multiple enlarged retroperitoneal lymph nodes

### Clinical Image
![Lymphadenopathy CT](image_01.png)
*Figure 1: Axial CT scan of the abdomen demonstrating multiple enlarged retroperitoneal lymph nodes (arrows) in a patient with fever of unknown origin subsequently diagnosed with lymphoma.*

**Image Source**: Educational illustration for teaching purposes.

### Questions

1. **What criteria define classic fever of unknown origin (FUO)?**
   - A) Temperature >38.3°C for >1 week without diagnosis after initial workup
   - B) Temperature >38.3°C for >3 weeks with no diagnosis after 3 days inpatient or 3 outpatient visits
   - C) Temperature >39°C for >2 weeks with negative blood cultures
   - D) Temperature >38°C for >1 week in a hospitalized patient

2. **What are the four major categories of causes for classic FUO?**
   - A) Bacterial, viral, fungal, parasitic
   - B) Infectious, neoplastic, autoimmune/inflammatory, miscellaneous
   - C) Cardiac, pulmonary, abdominal, neurologic
   - D) Acute, subacute, chronic, recurrent

3. **Given the findings of splenomegaly, lymphadenopathy, elevated LDH, and constitutional symptoms, what diagnosis is most likely?**
   - A) Systemic lupus erythematosus
   - B) Tuberculosis
   - C) Lymphoma
   - D) Endocarditis

4. **What is the most appropriate next diagnostic step?**

5. **List three infectious causes of FUO that should be considered in all patients.**

### Answers

1. **B) Temperature >38.3°C for >3 weeks with no diagnosis after 3 days inpatient or 3 outpatient visits** - Classic FUO requires fever duration >3 weeks and failure to reach diagnosis despite adequate initial investigation.

2. **B) Infectious, neoplastic, autoimmune/inflammatory, miscellaneous** - These four categories account for most cases of FUO. In developed countries, the proportion of neoplastic and autoimmune causes has increased while infections have decreased.

3. **C) Lymphoma** - The constellation of fever, night sweats, weight loss (B symptoms), splenomegaly, lymphadenopathy, elevated LDH, and anemia strongly suggests lymphoma, particularly Hodgkin lymphoma or aggressive non-Hodgkin lymphoma.

4. **Next diagnostic step**: Excisional lymph node biopsy of an accessible retroperitoneal node (CT-guided or surgical) is the most appropriate step. Fine needle aspiration is inadequate for lymphoma diagnosis as architectural assessment is required for classification.

5. **Infectious causes of FUO to consider**:
   - Tuberculosis (pulmonary and extrapulmonary)
   - Endocarditis (especially culture-negative)
   - Intra-abdominal abscess
   - Osteomyelitis
   - HIV infection
   - Cytomegalovirus
   - Epstein-Barr virus

---

## Case 2: Neutropenic Fever

### Patient Presentation
A 62-year-old woman with acute myeloid leukemia presents 10 days after completing induction chemotherapy with fever and chills. She denies cough, dysuria, abdominal pain, or diarrhea. She has a tunneled central venous catheter (Hickman) in her right subclavian vein placed 3 weeks ago. The catheter site appears clean without erythema or discharge.

### Vital Signs
- Blood Pressure: 95/60 mmHg
- Heart Rate: 112 bpm
- Respiratory Rate: 22/min
- Oxygen Saturation: 96% on room air
- Temperature: 39.1°C

### Physical Examination
- General: Ill-appearing, mild rigors
- HEENT: Oral mucosa with mild mucositis, no thrush
- Cardiovascular: Tachycardic, regular rhythm, no murmurs
- Pulmonary: Clear to auscultation
- Abdomen: Soft, non-tender, no hepatosplenomegaly
- Skin: No rashes, no perirectal tenderness or fluctuance
- Central line site: No erythema, tenderness, or discharge

### Initial Workup
- **CBC**: WBC 200/μL (ANC 50/μL), Hgb 8.1 g/dL, Platelets 22,000/μL
- **BMP**: Creatinine 1.1 mg/dL, normal electrolytes
- **Lactate**: 2.8 mmol/L
- **Blood cultures**: Drawn from central line and peripherally (pending)
- **Chest X-ray**: No infiltrates
- **Urinalysis**: No pyuria or bacteriuria

### Clinical Image
![Mucositis](image_02.png)
*Figure 2: Oral mucositis following chemotherapy, representing a common portal of entry for pathogens in neutropenic patients.*

**Image Source**: Educational illustration for teaching purposes.

### Questions

1. **What defines neutropenic fever?**
   - A) ANC <1000/μL with temperature >38.0°C once
   - B) ANC <500/μL with temperature >38.3°C once or >38.0°C sustained for 1 hour
   - C) ANC <1500/μL with temperature >39.0°C
   - D) ANC <100/μL with any documented fever

2. **What is the most appropriate empiric antibiotic regimen?**
   - A) Vancomycin plus metronidazole
   - B) Ceftriaxone plus azithromycin
   - C) Cefepime or piperacillin-tazobactam monotherapy
   - D) Ciprofloxacin plus amoxicillin-clavulanate

3. **When should vancomycin be added to the initial empiric regimen?**
   - A) All cases of neutropenic fever
   - B) Hemodynamic instability, suspected catheter infection, skin/soft tissue infection, or known MRSA colonization
   - C) Only if blood cultures are positive for gram-positive organisms
   - D) After 48 hours if fever persists

4. **What is the MASCC score and how does it guide management?**

5. **When should antifungal coverage be added to the regimen?**

### Answers

1. **B) ANC <500/μL with temperature >38.3°C once or >38.0°C sustained for 1 hour** - This is the standard definition of neutropenic fever. Patients with ANC expected to decline to <500/μL should also be considered at risk.

2. **C) Cefepime or piperacillin-tazobactam monotherapy** - Monotherapy with an anti-pseudomonal beta-lactam is the standard initial treatment for neutropenic fever. Both provide broad coverage including Pseudomonas aeruginosa.

3. **B) Hemodynamic instability, suspected catheter infection, skin/soft tissue infection, or known MRSA colonization** - Vancomycin is not routinely indicated but should be added for specific indications. Empiric vancomycin does not improve outcomes in uncomplicated neutropenic fever.

4. **MASCC score (Multinational Association for Supportive Care in Cancer)**:
   - Risk stratification tool for neutropenic fever
   - Scores ≥21 indicate low risk (mortality <5%)
   - Points assigned for: burden of illness, no hypotension, no COPD, solid tumor or no fungal infection, no dehydration, outpatient status, age <60
   - Low-risk patients may be candidates for oral antibiotics or outpatient management

5. **Antifungal coverage indications**:
   - Persistent fever after 4-7 days of appropriate antibiotics
   - Clinical deterioration despite antibiotics
   - New pulmonary infiltrates during antibiotics
   - Known colonization with Candida or Aspergillus
   - Empiric coverage typically with echinocandin or voriconazole

---

## Case 3: Drug Fever

### Patient Presentation
A 38-year-old woman was admitted 8 days ago for community-acquired pneumonia and was started on ceftriaxone and azithromycin. Her pneumonia clinically improved, and she has been afebrile since day 3. On day 7, she developed a new fever to 38.6°C despite resolution of her respiratory symptoms. She feels well otherwise and denies new symptoms.

### Vital Signs
- Blood Pressure: 118/72 mmHg
- Heart Rate: 78 bpm
- Respiratory Rate: 14/min
- Oxygen Saturation: 98% on room air
- Temperature: 38.7°C

### Physical Examination
- General: Comfortable, appears well
- HEENT: Clear oropharynx
- Cardiovascular: Regular rhythm, no murmurs
- Pulmonary: Clear to auscultation, improved from admission
- Abdomen: Soft, non-tender
- Skin: Faint maculopapular rash on trunk
- Extremities: No edema, IV site without erythema

### Initial Workup
- **CBC**: WBC 9,800/μL with 8% eosinophils (elevated)
- **BMP**: Normal
- **Repeat chest X-ray**: Improved infiltrate
- **Blood cultures**: No growth (drawn day 7)
- **Urinalysis**: Normal

### Clinical Image
![Drug Rash](image_03.png)
*Figure 3: Maculopapular drug eruption, commonly associated with beta-lactam antibiotics and often accompanying drug fever.*

**Image Source**: Educational illustration for teaching purposes.

### Questions

1. **What clinical features suggest drug fever?**
   - A) High fever, rigors, elevated WBC
   - B) Relative bradycardia, eosinophilia, rash, patient appears well
   - C) Fever immediately after drug administration
   - D) Fever with hypotension and altered mental status

2. **Which medication class is most commonly associated with drug fever?**
   - A) Fluoroquinolones
   - B) Beta-lactam antibiotics
   - C) Macrolides
   - D) Aminoglycosides

3. **What is the typical time course for development of drug fever?**
   - A) Within hours of first dose
   - B) 7-10 days after starting medication (or earlier with re-exposure)
   - C) After completing the full course
   - D) Only with intravenous medications

4. **What is the most appropriate management?**

5. **How quickly should fever resolve after discontinuing the offending agent?**

### Answers

1. **B) Relative bradycardia, eosinophilia, rash, patient appears well** - Drug fever classically presents with a patient who "looks too good for their fever." Relative bradycardia, peripheral eosinophilia, and concurrent rash are supportive findings.

2. **B) Beta-lactam antibiotics** - Beta-lactams (penicillins, cephalosporins) are the most common cause of drug fever. Other common culprits include sulfonamides, anticonvulsants, and allopurinol.

3. **B) 7-10 days after starting medication (or earlier with re-exposure)** - Drug fever typically develops 7-10 days after initiation of a new medication. With prior sensitization, fever can develop within hours of re-exposure.

4. **Management**:
   - Discontinue the suspected offending agent (ceftriaxone)
   - If antibiotics are still needed, switch to a different class
   - Supportive care; antipyretics are not typically necessary
   - Monitor for resolution of fever
   - Drug fever is a diagnosis of exclusion; ensure no other source

5. **Resolution timeline**:
   - Fever typically resolves within 48-72 hours of discontinuing the offending drug
   - May take longer (up to 5-7 days) for drugs with long half-lives
   - Rapid resolution supports the diagnosis
   - Persistent fever beyond 72 hours should prompt evaluation for alternative causes

---

## Learning Points

1. **Classic FUO** requires temperature >38.3°C for >3 weeks without diagnosis after adequate workup; major categories include infectious, neoplastic, autoimmune, and miscellaneous causes.

2. **Neutropenic fever** is a medical emergency requiring prompt empiric broad-spectrum antibiotics; anti-pseudomonal beta-lactam monotherapy is first-line.

3. **Drug fever** should be suspected when fever develops 7-10 days after starting a new medication, especially with relative bradycardia, eosinophilia, and rash.

4. **Systematic approach** to fever includes thorough history (travel, exposures, medications), physical examination, and targeted workup based on clinical suspicion.

5. **Specific fever patterns** (e.g., Pel-Ebstein in Hodgkin lymphoma, tertian in malaria) may provide diagnostic clues but are rarely pathognomonic.