In a 71‑year‑old woman with persistent fever, elevated C‑reactive protein and erythrocyte sedimentation rate, isolated thrombocytopenia, normal leukocyte count, chest computed tomography showing only atelectasis, and urinalysis revealing minimal pyuria, what is the most likely diagnosis and appropriate initial management?

Clinical Impression: Hematologic Malignancy or Systemic Inflammatory Disease

In a 71-year-old woman with persistent fever, isolated thrombocytopenia, markedly elevated inflammatory markers (CRP 45 mg/L, ESR 112 mm/h), normal WBC, and minimal imaging findings, the most likely diagnoses are hematologic malignancy (particularly lymphoma or myelodysplastic syndrome) or a systemic inflammatory disease (such as polymyalgia rheumatica, giant cell arteritis, or adult-onset Still's disease).

Diagnostic Reasoning

Key Clinical Features Pointing Away from Infection

• Normal WBC count with high CRP argues against typical bacterial infection 1, 2. While bacterial infections can present with normal WBC and elevated CRP in elderly patients, the combination of persistent fever, thrombocytopenia, and extremely elevated ESR (112 mm/h) without a clear infectious source makes infection less likely 1, 2.

• Minimal pyuria with negative chest imaging makes urinary tract infection and pneumonia unlikely primary diagnoses 3. The guideline states that pyuria ≥10 WBCs/high-power field is needed to pursue UTI workup, and "minimal pyuria" does not meet this threshold 3.

• ESR of 112 mm/h is extremely elevated and suggests either malignancy, systemic inflammatory disease, or chronic infection 4, 5. Research shows that all FUO patients with malignancy had ESR >40 mm/h, and a normal ESR essentially excludes malignancy 5.

Hematologic Malignancy Considerations

• Isolated thrombocytopenia with normal WBC is concerning for bone marrow pathology 5. The research demonstrates that WBC <4,000/μL significantly increased the rate of malignancy in FUO patients (p=0.015), but even normal WBC doesn't exclude hematologic malignancy when thrombocytopenia is present 5.

• ESR >100 mm/h has 92.2% specificity for giant cell arteritis but also indicates high risk for malignancy 4, 6. ESR >100 mm/h is an independent prognostic factor for mortality 4.

• Hodgkin lymphoma with ESR ≥50 mm/h is considered an unfavorable prognostic factor 6, and this patient's ESR of 112 mm/h warrants urgent hematologic evaluation.

Systemic Inflammatory Disease Considerations

• Polymyalgia rheumatica (PMR) commonly presents with ESR >40 mm/h (this patient has ESR 112 mm/h), bilateral shoulder/hip girdle pain, and morning stiffness >45 minutes 4, 6. However, the question doesn't mention musculoskeletal symptoms, making this less likely unless specifically queried.

• Giant cell arteritis requires urgent evaluation with ESR >100 mm/h having 92.2% specificity and positive likelihood ratio of 3.11 4, 6. This is an ophthalmologic emergency requiring same-day evaluation to prevent irreversible vision loss 4.

• Adult-onset Still's disease demonstrates ESR elevation in 95-98% of cases and can present with persistent fever, elevated inflammatory markers, and cytopenias 4.

Immediate Diagnostic Workup

Essential First-Line Tests

• Complete blood count with manual differential to assess for anemia, abnormal cell populations, and confirm thrombocytopenia 3, 6. Manual differential is superior to automated counts for detecting immature forms and abnormal cells 3.

• Peripheral blood smear review to evaluate for atypical lymphocytes, blasts, or dysplastic features suggesting hematologic malignancy 4.

• Comprehensive metabolic panel including glucose, creatinine, liver function tests, and albumin 4, 6. Azotemia can artificially elevate ESR, and hypoalbuminemia suggests chronic inflammation 4.

• Serum ferritin is elevated in Still's disease, malignancy, and infection 4. Extremely elevated ferritin (>1,000 ng/mL) with glycosylated ferritin <20% is highly specific for Still's disease 4.

• Lactate dehydrogenase (LDH) is elevated in lymphoma, hemolysis, and tissue destruction 4.

Second-Line Targeted Testing

• Blood cultures (two sets from different sites) to exclude occult bacteremia or endocarditis 6, 7. Obtain before any antibiotic administration 7.

• Rheumatoid factor, anti-CCP antibodies, and ANA panel if musculoskeletal symptoms are present or develop 4. These help differentiate inflammatory arthritis from PMR.

• Serum protein electrophoresis and immunofixation to evaluate for monoclonal gammopathy or multiple myeloma 4.

• Bone marrow aspiration and biopsy should be strongly considered given isolated thrombocytopenia with persistent fever and markedly elevated inflammatory markers 5. This is the definitive test for hematologic malignancy and can also identify granulomatous disease or infection.

Imaging Studies

• CT chest/abdomen/pelvis with contrast to evaluate for lymphadenopathy, splenomegaly, or occult malignancy 3, 6. The chest CT showing only atelectasis is insufficient; abdominal imaging is essential.

• Temporal artery ultrasound or biopsy if any symptoms of giant cell arteritis are present (headache, jaw claudication, visual symptoms, scalp tenderness) 4, 6. This is urgent given the ESR of 112 mm/h.

• PET-CT scan may be considered if initial workup is unrevealing, as it can identify occult lymphoma, vasculitis, or inflammatory foci 3.

Management Approach

Do NOT Start Empiric Antibiotics Unless Specific Indications Present

• Avoid empiric antibiotics in stable patients without clear infectious source 3, 7. The normal WBC, minimal pyuria, and negative chest imaging argue against bacterial infection requiring immediate antibiotics 3, 1.

• Empiric antibiotics are indicated only if: fever >38.3°C with hemodynamic instability, suspected neutropenic sepsis, or high clinical suspicion for bacterial infection with positive cultures pending 7.

Hospitalization Criteria

• This patient meets criteria for hospitalization based on persistent fever, thrombocytopenia, and markedly elevated inflammatory markers requiring urgent diagnostic workup 3, 6.

• Major risk factors for hospitalization include: fever >38°C, large pericardial effusion or tamponade, failure of NSAIDs, and subacute course 3. This patient has fever and likely subacute course.

Monitoring Strategy

• Daily CBC to monitor platelet trend 6. Worsening thrombocytopenia suggests progressive bone marrow pathology.

• Repeat CRP and ESR in 2-4 weeks if diagnosis remains unclear after initial workup 4. CRP falls more rapidly than ESR with inflammation resolution 4.

• Serial temperatures and clinical assessment for development of new symptoms (rash, lymphadenopathy, organomegaly, musculoskeletal complaints) 3, 6.

Common Pitfalls to Avoid

• Do not attribute elevated inflammatory markers solely to age 4, 6. While ESR increases with age, ESR of 112 mm/h is pathologic and requires explanation.

• Do not delay hematology consultation when isolated thrombocytopenia is present with persistent fever 5. Bone marrow evaluation may be diagnostic.

• Do not miss giant cell arteritis 4, 6. Specifically ask about new headache, jaw claudication, visual changes, and scalp tenderness. Temporal artery examination is mandatory.

• Do not overlook drug-induced fever or thrombocytopenia 4. Review all medications including over-the-counter drugs and supplements.

• Do not assume infection based solely on elevated CRP 1, 2. CRP >10 mg/L can reflect obesity, chronic inflammation, or malignancy 4.