In an 80‑year‑old man presenting with generalized weakness, neutrophilic leukocytosis, markedly elevated C‑reactive protein, mild anemia of chronic disease, low albumin and impaired renal function (estimated glomerular filtration rate 55 mL/min/1.73 m²), what is the most likely diagnosis and recommended initial management?

Likely Diagnosis: Infection with Anemia of Chronic Disease

In an 80-year-old presenting with weakness, neutrophilic leukocytosis (absolute neutrophils 11.7 × 10³/μL), markedly elevated CRP (119 mg/L), and mild anemia, the most likely diagnosis is an underlying infection with secondary anemia of chronic disease, and initial management should prioritize identifying and treating the infectious source with broad-spectrum antibiotics while investigating for occult malignancy or inflammatory conditions.

Diagnostic Reasoning

Primary Concern: Infection vs. Inflammatory Disease

The laboratory pattern strongly suggests an active infectious or inflammatory process:

• Neutrophilic leukocytosis (WBC 14.6, neutrophils 81%, absolute 11.7 × 10³/μL) indicates bone marrow response to infection or inflammation, though values >12,000/mm³ can occur in both bacterial infections and systemic inflammatory diseases 1, 2
• Markedly elevated CRP (119 mg/L) has 98.5% sensitivity for probable or definite sepsis when ≥50 mg/L, though specificity is only 75% 1. CRP >100 mg/L suggests bacterial infection in approximately 66% of cases, but systemic diseases (vasculitis, Still's disease, malignancy) can produce similar elevations 3
• Low albumin (3.7 g/dL) combined with elevated CRP indicates an acute phase response and is independently associated with bacteremia 1, 4
• Elevated BUN/creatinine ratio (26, with BUN 34 mg/dL) suggests prerenal azotemia, consistent with dehydration from infection or reduced oral intake 1

Anemia Pattern: Chronic Disease vs. Other Causes

The anemia characteristics point toward anemia of chronic disease (ACD):

• Mild normocytic anemia (Hgb 13.8 g/dL, MCV 98 fL) with normal RDW (13.1%) suggests ACD rather than iron deficiency 5
• Low iron (34 μg/dL) with low TIBC (206 μg/dL) is the hallmark pattern of ACD, caused by defective iron release from macrophages and hepatocytes due to inflammatory mediators 5
• Iron saturation 17% is borderline low but combined with low TIBC distinguishes ACD from iron deficiency anemia (which shows high TIBC) 5
• Normal B12 (474 pg/mL) and folate (14.1 ng/mL) exclude nutritional deficiencies 1

The anemia results from long-term elaboration of inflammatory mediators (interleukin-1/leukocyte endogenous mediator) causing hypoferremia, reduced erythrocyte survival, and impaired erythropoietin response 5.

Critical Differential Diagnoses to Exclude

Adult-Onset Still's Disease (AOSD) must be considered given:

• Marked neutrophilia with monocytosis (1.6 × 10³/μL, elevated) 1
• Extremely elevated CRP (119 mg/L) 1
• Low albumin and anemia of chronic disease pattern 1
• However, ferritin is not reported—ferritin >1000 ng/mL has 74.7% sensitivity and 88.9% specificity for AOSD 1. Glycosylated ferritin ≤20% increases specificity to 83.2% 1

Occult malignancy requires investigation:

• Age 80 with new-onset weakness and anemia 6
• Elevated ESR (13 mm/hr) and CRP suggest chronic inflammation 1
• Mild renal impairment (eGFR 55) could indicate multiple myeloma or other hematologic malignancy 1

Sepsis is the most urgent consideration:

• Neutrophilia, hypoalbuminemia, and renal dysfunction are independent predictors of bacteremia 1
• CRP >50 mg/L has high sensitivity for sepsis 1

Initial Management Algorithm

Step 1: Immediate Infection Workup (Within Hours)

• Obtain blood cultures immediately before antibiotics, ideally during fever if present, as bacteria are rapidly cleared and fever follows bacteremia by 30-90 minutes 1
• Urinalysis with culture given elevated BUN/creatinine ratio and age-related UTI risk 1
• Chest X-ray to exclude pneumonia, tuberculosis, or malignancy 1
• Stool studies if diarrhea present, including Clostridioides difficile testing 1

Step 2: Empiric Antibiotic Therapy

Initiate broad-spectrum antibiotics immediately if sepsis suspected (fever, hypotension, or organ dysfunction):

• Cefepime 1-2 g IV every 12 hours (adjust for renal function: eGFR 55 requires dose reduction to 1 g every 12 hours or 2 g every 24 hours) provides coverage for gram-negative and gram-positive organisms 7
• Monitor for neurotoxicity (encephalopathy, myoclonus, seizures) in elderly patients with renal impairment receiving cefepime 7

Step 3: Additional Diagnostic Testing

• Ferritin level is essential to evaluate for AOSD (target >1000 ng/mL) or hemochromatosis 1, 8
• Glycosylated ferritin if ferritin elevated, as ≤20% supports AOSD diagnosis 1
• Serum protein electrophoresis (SPEP) with immunofixation to exclude multiple myeloma given age, anemia, and renal impairment 1
• Peripheral blood smear to assess for immature cells, dysplasia, or malignant cells 1, 9
• Rheumatoid factor (RF) and anti-CCP antibodies if joint symptoms present, as RA commonly causes anemia of chronic disease 10

Step 4: Imaging for Occult Malignancy

• Contrast-enhanced CT chest/abdomen/pelvis is the most reliable exam for diagnosing intra-abdominal disease and occult malignancy in this population 1, 6
• Consider PET-CT if CT non-diagnostic and malignancy remains suspected 6

Step 5: Anemia Management

Do NOT initiate erythropoiesis-stimulating agents (ESAs):

• ESAs provide no mortality or hospitalization benefit in mild-to-moderate anemia with cardiovascular comorbidity and may cause hypertension, thromboembolism, and increased cardiovascular events 8

Consider intravenous iron therapy if ferritin <500 ng/mL after infection treated:

• Ferric carboxymaltose 200 mg IV weekly until ferritin >500 ng/mL, then 200 mg monthly for maintenance 8
• IV iron bypasses hepcidin-mediated blockade of intestinal absorption, making it superior to oral iron in inflammatory states 8
• Oral iron has minimal benefit in ACD due to hepcidin-mediated absorption blockade 8

Transfusion strategy:

• Transfuse only if hemoglobin falls to 7-8 g/dL using restrictive thresholds, as liberal transfusion provides no benefit and may cause harm (transfusion-related acute lung injury, worsening heart failure) 8

Common Pitfalls and Caveats

• CRP >100 mg/L does NOT definitively distinguish infection from systemic disease—specificity is only 45-66% 3. Always correlate with clinical context
• Normal ESR (13 mm/hr) does NOT exclude inflammatory arthritis—CRP may be more sensitive in acute inflammation 10. However, anemia and azotemia can artificially elevate ESR independent of inflammatory activity 10
• Leukocytosis can result from non-infectious causes including corticosteroids, physical/emotional stress, or chronic inflammatory conditions 2, 9. Review medication list carefully
• Elderly patients with renal impairment are at high risk for cefepime neurotoxicity—dose adjustment is mandatory and monitor for encephalopathy, confusion, or seizures 7
• Ferritin interpretation requires caution—it is an acute phase reactant and may be elevated in infection/inflammation independent of iron stores 1, 8

Monitoring Protocol

• Recheck CBC, CRP, and renal function after 48-72 hours of antibiotic therapy to assess response 1
• Monitor hemoglobin every 3 months for first year if iron therapy initiated, then annually 8
• Reassess iron parameters (ferritin, TIBC, iron saturation) to guide ongoing IV iron maintenance 8
• Track inflammatory markers (CRP, ESR) if AOSD or other inflammatory condition suspected 1