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Case Summary

1. Pyrexia Under Evaluation (PUE)
2. Severe Iron Deficiency Anemia (IDA)

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PART 1: SEVERE IRON DEFICIENCY ANEMIA

What Is Iron Deficiency Anemia?

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Iron Metabolism - The Foundation

• Daily loss: only 1-2 mg/day (shed mucosal and skin cells) - there is no regulated excretion pathway
• Normal Western diet: 10-20 mg/day; only 20% of heme iron and 1-2% of nonheme iron is absorbed
• Absorption occurs in the proximal duodenum
• Iron transport in plasma: bound to transferrin (normally ~33% saturated)
• Normal serum iron: ~120 ug/dL (men), ~100 ug/dL (women)
• Normal TIBC: 300-350 ug/dL

• Hepcidin (liver peptide) degrades ferroportin on enterocytes and macrophages → blocks iron absorption and release
• When iron stores are LOW → hepcidin falls → ferroportin survives → more iron absorbed
• When inflammation is HIGH → hepcidin rises → iron is trapped → "anemia of chronic inflammation"
• This is clinically important here because if Sultana has an active infection causing her fever, the inflammatory state may worsen functional iron availability

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Causes of Iron Deficiency

1. Dietary lack - insufficient iron in diet (especially low-resource settings, vegans, elderly, infants)
2. Impaired absorption - gastrectomy, celiac sprue, malabsorption syndromes
3. Increased requirement - pregnancy, growing children, premenopausal women
4. Chronic blood loss - most common cause in adults - menstrual blood loss in premenopausal women, GI bleeding (peptic ulcer, colorectal cancer, hookworm), urinary tract

For Sultana at 47 years old, she is perimenopausal/premenopausal. Likely causes to investigate: menorrhagia (very common), GI blood loss, poor dietary intake. At her age, GI blood loss must be ruled out (colorectal cancer, peptic ulcer).

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Stages of Iron Depletion

1. Pre-latent - iron stores depleted (↓ ferritin, ↓ bone marrow iron), Hb still normal
2. Latent - ↓ serum iron, ↑ TIBC, transferrin saturation falls (<15%), Hb still normal
3. Iron deficiency anemia - Hb drops, microcytic hypochromic anemia develops

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Morphology on Peripheral Blood Smear

• Microcytic (MCV <80 fL)
• Hypochromic (central pallor >1/3 of cell diameter, MCH <27 pg)
• Pencil cells (elongated poikilocytes)
• Bone marrow: absent stainable iron on Prussian blue stain

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Laboratory Diagnosis

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Clinical Features

• Fatigue, weakness, exertional dyspnea
• Palpitations, tachycardia
• Pallor (conjunctival, palmar, mucosal)
• Headache, dizziness, poor concentration

• Koilonychia - spoon-shaped nails
• Alopecia
• Angular stomatitis, glossitis (atrophic tongue)
• Pica - craving for non-food items (clay, ice/pagophagia, dirt)
• Plummer-Vinson syndrome - triad of microcytic hypochromic anemia + esophageal web + atrophic glossitis
• Impaired cognitive function (iron depletion in CNS)
• In children: developmental delay, poor school performance

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Treatment of Severe IDA

1. Blood Transfusion (PRBC) - Already Done

• Hb <7 g/dL (generally)
• Hb <8 g/dL with symptoms (angina, hemodynamic instability)
• Symptomatic severe anemia regardless of precise Hb level

• Febrile non-hemolytic transfusion reaction (most common)
• Transfusion-related acute lung injury (TRALI)
• Hemolytic reaction (ABO mismatch)
• Fluid overload (transfuse slowly, especially with severe anemia)
• Infection transmission
• Iron overload with repeated transfusions

2. Oral Iron Supplementation (Mainstay of Long-term Treatment)

• Take on an empty stomach for best absorption
• Vitamin C (ascorbic acid) enhances absorption - give concurrently
• Avoid with tea, antacids, calcium - they inhibit absorption
• Side effects: nausea, constipation, dark stools, abdominal cramping

• Ferrous gluconate 300 mg BD (better tolerated, less elemental iron)
• Ferrous fumarate 200 mg BD

• Reticulocytosis in 5-7 days (first sign of response)
• Hb rises ~1-2 g/dL per 2 weeks
• Continue treatment for 3-6 months after Hb normalizes to replenish iron stores
• Check ferritin to confirm stores are repleted

3. Parenteral Iron (IV iron) - when oral fails or is not tolerated

• Iron sucrose, ferric carboxymaltose, iron dextran
• Indicated in malabsorption, intolerance to oral iron, chronic kidney disease, inflammatory bowel disease, or when rapid correction is needed
• Risk: anaphylaxis with iron dextran (less common with newer formulations)

4. Treat the Underlying Cause

• Investigate menstrual history (menorrhagia?)
• Upper and lower GI endoscopy if GI loss suspected (stool occult blood test first)
• Dietary history and counseling
• Deworm if parasitic infestation (hookworm) is suspected

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PART 2: PYREXIA UNDER EVALUATION (PUE)

Definition

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Causes of FUO - The "Big 5" Domains

In India / South Asia, TB is always the #1 priority to rule out in PUE/FUO.

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Diagnostic Workup for PUE (Initial Tier)

• CBC with differential - already relevant (severe IDA found)
• CRP and ESR - inflammation markers
• Comprehensive metabolic panel - LFT, RFT
• Blood cultures x3 (spaced at least 2 hours apart) - rule out bacteremia, endocarditis
• HIV Ag/Ab (4th generation)
• CMV IgM/IgG
• TB: IGRA (interferon-gamma release assay) or Mantoux test - critical in India
• Widal test / blood culture for Salmonella typhi - enteric fever
• Malaria thick and thin smear + RDT - essential in endemic regions like Telangana
• LDH - elevated in lymphoma, hemolysis
• TSH - hyperthyroidism can cause fever
• ANA, rheumatoid factor - autoimmune screen
• Serum ferritin - markedly elevated in hemophagocytic lymphohistiocytosis (HLH), Still's disease

• Urinalysis with microscopy + culture - rule out UTI/pyelonephritis

• Chest X-ray - TB, pneumonia, mediastinal lymphadenopathy (lymphoma)
• Ultrasound abdomen - hepatosplenomegaly, lymphadenopathy, abscess
• CECT chest/abdomen/pelvis if initial workup unrevealing

• AFB smear and culture if TB suspected

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Key Clinical Points for Evaluation

1. Take a thorough history:
   • Duration and pattern of fever (continuous? remittent? periodic?)
   • Travel history (malaria belt, endemic areas)
   • Contact with TB patients
   • Menstrual history (source of blood loss)
   • Weight loss, night sweats, cough (TB triad)
   • Joint pains, rash, oral ulcers (SLE/connective tissue disease)
   • Drug history (drug fever!)
   • Family history
2. Physical examination:
   • Lymphadenopathy (lymphoma, TB)
   • Hepatosplenomegaly (malaria, lymphoma, leishmaniasis)
   • Pallor, jaundice, signs of IDA (koilonychia, glossitis)
   • Heart murmurs (endocarditis)
   • Rash (SLE, adult Still's, viral)
   • Thyroid enlargement

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Treatment Approach for PUE

• Paracetamol (acetaminophen) 500-1000 mg every 6-8 hours PRN - safest antipyretic
• Keep well hydrated (oral/IV fluids)
• Physical cooling measures (tepid sponging)
• Avoid aspirin in fever (risk of Reye's syndrome if viral; also avoided in platelet disorders)
• Avoid NSAIDs if GI bleed is suspected (relevant here given possible GI source of IDA)

• TB → 4-drug ATT (HRZE for 2 months, then HR for 4 months)
• Typhoid → Ceftriaxone or ciprofloxacin
• Malaria → Artemisinin-based combination therapy (ACT)
• SLE → Hydroxychloroquine, steroids
• Lymphoma → Refer oncology

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PART 3: PUTTING IT TOGETHER - MANAGEMENT PLAN FOR SULTANA

Today's Priorities

Expected Course

• Post-transfusion: Hb should rise ~1 g/dL per unit transfused
• With oral iron: reticulocytosis in 5-7 days; Hb normalizes in 4-8 weeks
• Continue iron for 3-6 months after Hb normalizes to rebuild stores
• Fever cause must be identified and specifically treated

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Key Teaching Points to Remember

1. Severe IDA in a 47-year-old woman = always investigate for GI malignancy. Menorrhagia is common but never assume without excluding other causes.
2. The PBS image of IDA shows hypochromic microcytic cells with pencil cells - those brighter, fully-hemoglobinized cells you see are from the transfusion she just received.
3. Hepcidin is the master switch - infection/inflammation raises hepcidin → traps iron → worsens functional anemia.
4. 1 unit PRBC ≈ +1 g/dL Hb - transfuse slowly (3-4 hours) in chronic severe anemia.
5. PUE workup is structured: start with CBC, cultures, CRP/ESR, malaria smear, TB screen, chest X-ray. Do not start empiric therapy blindly.
6. In India, TB + malaria + typhoid must always be ruled out first in any fever of unknown cause.
7. IDA + fever in the same patient - think of one unifying diagnosis: TB causing both (malabsorption + iron loss + fever), lymphoma, or malignancy.
8. A 2025 systematic review (Bedan & Lottrup, PMID 40577932) confirms IV iron is a valid alternative to PRBC transfusion for IDA - both effective, but IV iron avoids transfusion complications.

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CASE SUMMARY

1. Acute Ischemic Stroke with Right Hemiplegia
2. Right UMN Palsy - Acute infarct in Left Frontal Capsulo-Ganglionic Region

• Thrombolysis with Inj. Tenecteplase 40mg on 31/5/26 (uncomplicated)
• 1 unit Whole Blood + 1 unit PRBC transfusion on 1/7/26 (for GI bleed-related anemia)

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PART 1: STROKE - COMPLETE THEORETICAL FOUNDATION

1.1 Definition

• Ischemic stroke (~85%) - thrombotic or embolic occlusion of cerebral artery
• Hemorrhagic stroke (~15%) - intracerebral or subarachnoid hemorrhage

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1.2 Blood Supply to the Brain - Know This Cold

Shamalamma's infarct is in the left frontal capsulo-ganglionic region, fed by lenticulostriate arteries (branches of the proximal MCA). This explains her right-sided hemiplegia. The left brain controls the right body.

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1.3 Why Left Lesion → Right Hemiplegia?

• Anterior limb: frontopontine fibers
• Genu: corticobulbar fibers (face, tongue, throat)
• Posterior limb: corticospinal fibers (arm, leg) + sensory fibers

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1.4 UMN vs LMN - A Must-Know Table

In Shamalamma: Right UMN palsy means right-sided spasticity, hyperreflexia, upgoing plantar reflex, and facial weakness sparing the forehead (because the forehead muscles receive bilateral cortical input, so only one hemisphere being damaged doesn't paralyze the forehead - this distinguishes UMN from LMN facial weakness).

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1.5 NIHSS - National Institutes of Health Stroke Scale

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1.6 Pathophysiology of Ischemic Stroke

1. Arterial occlusion → blood flow falls below threshold
2. Within minutes: ATP depletion → failure of Na/K ATPase pump
3. Cellular depolarization → Na and water enter cells → cytotoxic edema
4. Glutamate release → excitotoxicity → calcium influx → cell death
5. The ischemic core (irreversibly dead within minutes) is surrounded by the penumbra (ischemic but salvageable if reperfused quickly)
6. The penumbra is the target of thrombolysis and thrombectomy

• Cytotoxic edema: minutes to hours (gray matter predominant)
• Vasogenic edema: hours to days (white matter predominant)
• Peak edema: 72-120 hours after stroke

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1.7 Risk Factors for Ischemic Stroke

• Hypertension (most important - present in Shamalamma)
• Atrial fibrillation (cardioembolic strokes)
• Diabetes mellitus (present in Shamalamma)
• Hyperlipidemia
• Smoking
• Carotid artery stenosis
• Prior TIA/stroke
• Cardiac disease (valvular, IHD, heart failure)

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1.8 OCSP (Bamford/Oxford Community Stroke) Classification

Shamalamma's case - left frontal capsulo-ganglionic infarct with right hemiplegia and no cortical signs = LACI (Lacunar Anterior Circulation Infarct).

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PART 2: TENECTEPLASE THROMBOLYSIS - WHAT YOU MUST KNOW

2.1 Mechanism of Thrombolytics

In Shamalamma's case, Inj. Tenecteplase 40mg was used. At 0.25 mg/kg, this corresponds to a body weight of ~80 kg (40/0.25 = 160 kg... actually at this dose 40mg = weight ~160kg which seems high; more likely she received tenecteplase dosed for stroke: 0.25 mg/kg max 25mg for stroke, but 40mg may reflect MI dosing). This detail should be verified at bedside. The note states it was uncomplicated.

2.2 Time Windows

• Within 3 hours: Strongest evidence, all eligible patients (≥18 years, no exclusions)
• 3 to 4.5 hours: Also recommended but with additional criteria:
  • Age ≤80
  • No history of BOTH DM AND prior stroke
  • NIHSS ≤25
  • No oral anticoagulants
  • Infarct <1/3 of MCA territory on imaging

Shamalamma is 70 (≤80) but has T2DM - the 3-4.5h window restriction applies only if there is both prior stroke AND DM together. DM alone does not exclude the 3-4.5h window.

2.3 Blood Pressure for Thrombolysis

2.4 Exclusion Criteria for Thrombolysis (Must Know for Rounds!)

• Active internal bleeding (this is critical - she now has lower GI bleed)
• Significant head trauma or stroke within 3 months
• Intracranial neoplasm, AVM, or aneurysm
• BP >185/110 mmHg not responsive to treatment
• Symptoms of subarachnoid hemorrhage
• Current use of anticoagulants with elevated INR or aPTT
• Platelet count <100,000
• Blood glucose <50 or >400 mg/dL

• Minor or rapidly improving stroke symptoms
• Seizure at onset
• Prior ischemic stroke within 3 months
• Major surgery within 14 days
• GI or urinary hemorrhage within 21 days (relevant to this patient!)

Key clinical point: Shamalamma developed lower GI bleed AFTER thrombolysis. The GI bleed is likely a complication of the thrombolysis or her underlying condition, and this is why she was transfused. This is one of the feared complications of tPA/tenecteplase.

2.5 Complications of Thrombolysis

• Stop any anticoagulants/antiplatelets
• Fresh frozen plasma (FFP) + cryoprecipitate
• Transfuse blood as done (PRBC/whole blood already given)

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PART 3: ACUTE STROKE MANAGEMENT PROTOCOL

3.1 The "Stroke Chain" - Time-Based

3.2 Initial Assessment and Stabilization

• Airway: risk of aspiration (especially with hemiplegia + dysphagia) - keep HOB >30°
• Breathing: Pulse oximetry; supplement O2 only if SpO2 <94%
• Circulation: Cardiac monitoring for 48h (AF is common trigger), 12-lead ECG, troponin

• CBC, PT/INR, aPTT
• Blood glucose (hypoglycemia mimics stroke; hyperglycemia worsens outcome)
• Electrolytes, renal function
• Cardiac biomarkers

3.3 Imaging

• Done immediately on arrival
• Rules out hemorrhagic stroke (absolute contraindication to thrombolysis)
• May show early ischemic changes (hypodensity, loss of gray-white differentiation, dense MCA sign)
• Early changes of large MCA infarct: ASPECTS score (Alberta Stroke Program Early CT Score)

• Restricted diffusion (bright on DWI, dark on ADC) = acute infarct
• Can detect lesions within minutes (vs CT which may miss early infarcts)

3.4 Blood Pressure Management in Acute Stroke

• In acute ischemic stroke, BP is often deliberately allowed to stay elevated (permissive hypertension)
• Optimal SBP: 160-200 mmHg in the first 24-48h
• Why? The ischemic penumbra depends on cerebral perfusion pressure (CPP). Lowering BP too aggressively can extend the infarct
• Exception: If thrombolysis is given → BP must be <180/105 mmHg

• BP >220/120 (if no thrombolysis)
• BP >185/110 (if thrombolysis planned)
• Hypertensive emergency with end-organ damage

• IV labetalol (5-20mg IV, repeat as needed)
• IV nicardipine infusion
• Avoid: sublingual nifedipine (precipitous drop), hydralazine (reflex tachycardia)

3.5 Glucose Management

• Hyperglycemia → worse neurological outcome (avoid glucose-containing IV fluids)
• Target glucose: 140-180 mg/dL in acute phase
• Hypoglycemia (<50 mg/dL) must be corrected immediately (can mimic stroke)
• SHINE trial: intensive glucose control did NOT improve outcomes
• Shamalamma has T2DM - monitor blood glucose closely, use normal saline not D5W

3.6 Temperature

• Hyperthermia worsens ischemic outcome - treat fever aggressively
• Paracetamol for fever
• Look for underlying cause (UTI - already treated in Shamalamma, pneumonia, DVT)

3.7 Prevention of Complications

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PART 4: SECONDARY PREVENTION - LONG-TERM MANAGEMENT

4.1 Antiplatelet Therapy

• Aspirin 75-100mg/day - first-line
• Clopidogrel 75mg/day - better than aspirin alone; use if aspirin intolerant
• Dual antiplatelet therapy (DAPT): Aspirin + Clopidogrel for 21 days after minor stroke/TIA (POINT/CHANCE trials) then switch to mono
• Aspirin + Dipyridamole (Aggrenox) - another alternative

4.2 Statin Therapy

• High-intensity statin (Atorvastatin 40-80mg) for all ischemic stroke patients regardless of baseline cholesterol
• Reduces recurrent stroke by ~20-25%

4.3 Anticoagulation (if AF detected)

• If AF (paroxysmal or persistent) is identified → OAC (oral anticoagulants) preferred over antiplatelets
• Direct oral anticoagulants (DOACs): apixaban, rivaroxaban, dabigatran preferred over warfarin
• Timing after stroke: generally start after 4-14 days depending on infarct size

4.4 Risk Factor Control

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PART 5: REHABILITATION

• Early mobilization (within 24-48h if stable) - reduces DVT, pneumonia, improves outcomes
• Physiotherapy - passive then active ROM exercises, gait training
• Occupational therapy - ADL retraining
• Speech and language therapy - for aphasia and dysphagia
• Stroke unit care - proven to reduce mortality and disability more than any single drug

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PART 6: ROUND QUESTIONS & MODEL ANSWERS

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1. Antiplatelet: Aspirin 75-100mg/day (or clopidogrel 75mg if aspirin intolerant) - started 24h post-thrombolysis. Caution: review given her GI bleed history; add a PPI (omeprazole) if using aspirin
2. Statin: Atorvastatin 40-80mg (high-intensity) regardless of cholesterol level
3. Antihypertensive: Continue/optimize - target <130/80 long-term
4. Anti-diabetic: Optimize glycemic control (HbA1c <7%)
5. Screen for AF: 24-72h Holter; if AF detected → anticoagulation (DOAC preferred)
6. Physiotherapy, speech therapy, OT: Early rehabilitation

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• Pure motor hemiplegia (internal capsule/pons)
• Pure sensory stroke (thalamus)
• Sensorimotor stroke (thalamus + internal capsule)
• Ataxic-hemiparesis (pons)
• Dysarthria-clumsy hand syndrome (pons/internal capsule)

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CURRENT MANAGEMENT PRIORITIES FOR SHAMALAMMA

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EVERYTHING ABOUT FEVER — FROM HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 22E (2025)

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PART 1: NORMAL BODY TEMPERATURE

1. Peripheral nerve input from warmth/cold receptors in the skin
2. Temperature of blood bathing the hypothalamic neurons

• Diurnal variation: Low at 8 AM and in summer; higher at 4 PM and in winter
• Age: Lower by 0.02°C for every 10-year increase in age (the elderly may NOT mount a fever!)
• Race/sex: African-American women have temperatures 0.052°C higher than white men
• Comorbidities: Cancer raises baseline by 0.02°C; hypothyroidism lowers it by 0.01°C
• Menstrual cycle: AM temperature rises ~0.6°C (1°F) with ovulation and stays elevated until menses

• Rectal > oral by 0.4°C (0.7°F) - oral is lower due to mouth breathing
• Tympanic membrane thermometers: unadjusted mode reads ~0.8°C lower than rectal
• Lower-esophageal temperatures best reflect true core temperature

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PART 2: FEVER vs HYPERTHERMIA - THE CRITICAL DISTINCTION

"Hyperpyrexia" = fever >41.5°C (>106.7°F). Occurs with severe infections OR most commonly with CNS hemorrhage.

1. Set point rises (e.g., 37°C → 39°C)
2. Vasomotor center activates → vasoconstriction (hands and feet feel cold)
3. Shivering begins (increases heat production from muscles)
4. Non-shivering thermogenesis from liver adds to heat production
5. Behavioral adjustment (adding clothing)
6. Once blood temperature matches new set point → hypothalamus maintains it
7. When set point resets downward (pyrogens reduced OR antipyretic given) → vasodilation + sweating → heat loss → fever breaks

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PART 3: PATHOGENESIS OF FEVER

The Complete Pathway (Harrison's Figure 20-1):

Step-by-step:

• Most are microbial products, toxins, or whole microorganisms
• Classic example: LPS (lipopolysaccharide/endotoxin) from gram-negative bacteria
  • Injected IV at 2-3 ng/kg → causes fever, leukocytosis, acute-phase proteins, malaise
• Gram-positive organisms: less pyrogenic LPS but produce superantigens causing fever
  • e.g., S. aureus TSST-1, staphylococcal enterotoxins, streptococcal pyrogenic exotoxins
  • These cause fever at 1-10 μg/kg IV in animals

• Exogenous pyrogens activate monocytes/macrophages and endothelial cells to produce pyrogenic cytokines
• Key pyrogenic cytokines: IL-1, IL-6, TNF, ciliary neurotropic factor, IFN-α
• Doses needed to produce fever in humans:
  • IL-1 and TNF: 10-100 ng/kg
  • IL-6: much higher dose needed (1-10 μg/kg)
• Important: Fever can also occur WITHOUT infection! Pericarditis, trauma, stroke, immunizations all induce IL-1, TNF, and/or IL-6 → fever

• Pyrogenic cytokines do NOT cross the blood-brain barrier directly
• They act on the endothelium of circumventricular vascular organs (organum vasculosum of lamina terminalis) - networks of enlarged capillaries around the hypothalamic regulatory centers
• This interaction is the first step in raising the set point

• The interaction triggers PGE₂ (prostaglandin E₂) synthesis by hypothalamic endothelium
• PGE₂ levels rise in hypothalamic tissue and the third cerebral ventricle
• PGE₂ acts on the EP-3 receptor (most critical for fever) on glial cells
• This triggers rapid release of cyclic AMP (cAMP) from glial cells
• cAMP is the actual neurotransmitter that raises the set point

• PGE₂ is also produced in peripheral tissues → accounts for the myalgias and arthralgias of fever
• Some systemic PGE₂ escapes lung destruction and reaches the hypothalamus via the internal carotid

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PART 4: FEVER PATTERNS AND THEIR SIGNIFICANCE

• Typhoid fever
• Brucellosis
• Leptospirosis
• Drug-induced fevers
• Factitious fever

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PART 5: DISEASE CATEGORIES PRESENTING WITH FEVER

1. Infectious diseases (most common worldwide)
2. Autoimmune and noninfectious inflammatory disorders
3. Cancer
4. Medication-related (vaccines, drug fever)
5. Endocrine disorders (e.g., hyperthyroidism)
6. Intrinsic hypothalamic malfunction

• Newborns
• Elderly patients
• Chronic hepatic or renal failure
• Patients taking glucocorticoids
• Patients on anticytokine therapy (anti-TNF, anti-IL-1, anti-IL-6, anti-IL-17)
• Patients on NSAIDs

Harrison's explicitly warns: "physicians should be aware that these patients may have active disease in the absence of fever."

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PART 6: APPROACH TO THE PATIENT WITH FEVER

History

• Chronology of events preceding the fever
• Exposure to symptomatic individuals
• Exposure to disease vectors (insects, animals)
• Travel history
• Medications (drug fever!)
• Immunization status
• HIV risk factors

Physical Examination

• Look for localizing signs (rash, lymphadenopathy, heart murmurs, organomegaly, tenderness)
• Pulse-temperature relationship
• Signs of end-organ involvement

Laboratory Tests

• CBC with differential - manual preferred for detecting:
  • Neutrophil band forms (bacterial infection)
  • Toxic granulations (bacterial infection)
  • Döhle bodies (bacterial infection)
  • Neutropenia (some viral infections)
• CRP and ESR - most valuable for detecting occult disease in low-grade fever
• IL-6 measurement - can be useful (levels remain elevated longer than IL-1/TNF which may be below detection limits)
• Note: circulating IL-1 and TNF are often below detection limit - measuring them is not helpful clinically

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PART 7: FEVER IN PATIENTS ON ANTICYTOKINE THERAPY

• Lowered host defenses
• Risk of reactivating latent TB (anti-TNF)
• Risk of systemic candidiasis (anti-IL-17)
• Blunted febrile response - low-grade fever in these patients is of considerable concern
• Require early and rigorous diagnostic evaluation

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PART 8: TREATMENT OF FEVER

The Decision to Treat

• No significant clinical evidence that antipyretics delay resolution of viral or bacterial infections
• No evidence that fever facilitates recovery
• Treating fever with antipyretics does no harm in common viral/bacterial infections
• However: in bacterial infections, withholding antipyretics can help assess antibiotic effectiveness and avoid masking inadequately treated infection

Mechanisms of Antipyretics

Oral aspirin and acetaminophen are equally effective as antipyretics. Chronic high-dose antipyretics do NOT reduce normal body temperature - PGE₂ plays no role in normal thermoregulation.

Regimens

• Acetaminophen (paracetamol) is PREFERRED over aspirin/NSAIDs (avoids platelet effects and GI toxicity)
• In children: Acetaminophen or ibuprofen - aspirin is contraindicated due to risk of Reye syndrome with viral infections
• If patient cannot take oral antipyretics → IV acetaminophen or rectal suppositories
• Physical cooling measures (tepid sponging) facilitate heat loss
• Hyperthermia (not fever): antipyretics do NOT work → need active cooling (ice packs, cooling blankets, cold IV fluids)

Anticytokine therapy for fever in autoimmune/autoinflammatory disease

• Anakinra or canakinumab (IL-1 blockers) - dramatically reduce fevers in autoinflammatory diseases (Still's disease, FMF, hyper-IgD)
• Colchicine: highly effective in preventing FMF attacks; less effective once attack is underway

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PART 9: FEVER OF UNKNOWN ORIGIN (FUO)

Definition (Current, Revised from Petersdorf & Beeson 1961)

1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration of at least 3 weeks
3. No known immunocompromised state
4. Diagnosis remains uncertain after thorough history, physical exam, AND the following obligatory investigations completed:
   • ESR and CRP
   • Platelet count, leukocyte count + differential
   • Hemoglobin, electrolytes, creatinine, total protein, ALP, ALT, AST, LDH, creatine kinase
   • Ferritin (very important!)
   • ANA, rheumatoid factor
   • Protein electrophoresis
   • Urinalysis + urine culture
   • Blood cultures x3
   • Chest X-ray
   • Abdominal ultrasonography
   • TST (Mantoux) or IGRA for TB

"Inflammation of Unknown Origin (IUO)" = same definition but without fever - just elevated CRP/ESR. Harrison's states IUO and FUO have the same causes and same workup.

Epidemiology

"The FUO Paradox": Despite better technology, MORE patients remain undiagnosed now than 60 years ago. Why? Because easy diagnoses are caught before 3 weeks elapses, leaving only the most difficult cases qualifying as FUO.

Differential Diagnosis of FUO (Harrison's Table 22-2)

• Bacterial (nonspecific): Abdominal abscess, endocarditis, osteomyelitis, spondylodiscitis, lung abscess, renal abscess, septic arthritis, sinusitis, pyelonephritis, pelvic inflammatory disease...
• Bacterial (specific): Tuberculosis, brucellosis, bartonellosis, leptospirosis, typhoid fever, listeriosis, Q fever (Coxiella burnetii), Whipple disease (Tropheryma whipplei), Lyme disease, legionellosis, syphilis...
• Fungal: Histoplasmosis, cryptococcosis, aspergillosis, candidiasis, coccidioidomycosis...
• Parasitic: Malaria, visceral leishmaniasis, toxoplasmosis, amebiasis, schistosomiasis, echinococcosis...
• Viral: CMV, EBV, HIV, hepatitis A/B/C/D/E, dengue, chikungunya, herpes simplex, parvovirus, West Nile...

• Systemic rheumatic/autoimmune: SLE, RA, Sjögren's, Behçet's, antiphospholipid syndrome, autoimmune hepatitis, inflammatory bowel disease (IBD)...
• Vasculitides: Giant cell arteritis (GCA) - very common in elderly FUO (up to 17%!), polyarteritis nodosa, Takayasu's, GPA (Wegener's)...
• Adult-onset Still's disease - consider in young adults with quotidian (daily) spiking fever + salmon-colored rash + arthritis
• Granulomatous diseases: Sarcoidosis, Crohn's disease
• Autoinflammatory: FMF, TRAPS, hyper-IgD, CAPS (NLRP3)

• Lymphoma (Hodgkin most classic, non-Hodgkin), leukemia
• Solid tumors: Renal cell carcinoma (classic "internist's tumor"), hepatocellular carcinoma, atrial myxoma
• Myelodysplastic syndrome

• Drug fever
• Factitious fever (self-induced)
• Pulmonary embolism/DVT
• Hemophagocytic lymphohistiocytosis (HLH) - very high ferritin (>500, often >10,000)
• Subacute thyroiditis
• Addison's disease
• Periodic fever syndromes (FMF, TRAPS, PFAPA)

Workup Strategy - PDC-Driven Approach

• Diagnostic yield: ~50% in FUO
• FDG accumulates in: malignant cells, activated leukocytes (infection, sterile inflammation)
• Outperforms gallium scintigraphy and leukocyte scintigraphy
• Best performed when ESR/CRP are elevated (increased yield)
• Identifies sites for biopsy even if not directly diagnostic
• Can diagnose large-vessel vasculitis directly (increased vascular FDG uptake - see Figure 22-2 from Harrison's)
• Limitations: High physiologic FDG uptake in brain, bowel, kidneys, bladder, and heart can obscure pathology (prevent cardiac uptake by low-carbohydrate diet before scan)
• Especially important in episodic/periodic FUO - scan during a febrile episode

• Liver biopsy (granulomas in sarcoidosis, TB, lymphoma, Q fever)
• Bone marrow biopsy (HLH, myelodysplasia, leukemia, miliary TB, disseminated fungal)
• Lymph node excision (lymphoma)
• Temporal artery biopsy (in patients ≥55 years with suspected GCA)

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Treatment of FUO

• Antibiotics/anti-TB: Only if hemodynamic instability, neutropenia, or strong TB suspicion (positive IGRA + endemic area + compatible picture). Always collect cultures first! If no response after 6 weeks of anti-TB treatment, reconsider diagnosis.
• NSAIDs: Colchicine + NSAIDs - dramatic response in Adult Still's disease to NSAIDs; colchicine prevents FMF attacks
• Glucocorticoids: Effective for GCA, Adult Still's, sarcoidosis, but mask many diagnoses - use only when confident of inflammatory cause
• IL-1 inhibitors (anakinra, canakinumab): For autoinflammatory diseases once other causes excluded

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PART 10: SPECIAL TOPICS

Fever and Rash

• Macules: flat, color change, blanchable
• Papules: raised, solid, <5 mm
• Plaques: >5 mm, plateau surface
• Vesicles/Bullae: fluid-filled (<5 mm / >5 mm)
• Petechiae: non-blanchable, flat, <3 mm (bleeding into skin)
• Purpura: >3 mm; palpable purpura = vasculitis
• Eschar: necrotic, black crust (tâche noire in rickettsial disease)

Neutropenic Fever

• Defined as ANC <500 cells/μL (or <1000 falling toward 500) with temperature ≥38.3°C
• Medical emergency: empirical broad-spectrum antibiotics immediately
• Gram-positive organisms most common but gram-negative bacteremia is life-threatening

Drug Fever

• Can occur at any time during drug therapy; no fixed time after starting
• Characterized by relative bradycardia (pulse-temperature dissociation)
• Skin rash may or may not accompany
• Common offenders: beta-lactam antibiotics, sulfonamides, phenytoin, carbamazepine, allopurinol, procainamide, hydralazine, methyldopa
• Diagnosis: fever resolves within 48-72 hours of stopping the offending drug
• May have eosinophilia

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QUICK-REFERENCE SUMMARY TABLE

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