What is the most likely further investigation to help establish a diagnosis for a patient with fever, night sweats, anemia, leukocytosis, and impaired renal function?

ANCA Testing is Most Likely to Establish the Diagnosis

The most appropriate further investigation for this patient with fever, night sweats, anemia, leukocytosis, and impaired renal function is ANCA testing.

Clinical Presentation Analysis

The patient presents with:

• 4-week history of fever (39.2°C), severe night sweats, anorexia, and muscle pains
• Persistent non-visible hematuria with negative urine cultures
• Laboratory abnormalities:
  • Anemia (Hb 87 g/L)
  • Leukocytosis (WBC 23.5 × 10^9/L) with neutrophilia (21.9 × 10^9/L)
  • Thrombocytosis (523 × 10^9/L)
  • Elevated creatinine (135 μmol/L)
  • Markedly elevated CRP (235 mg/L)
  • Urinary findings: red cells, granular casts
  • Normal abdominal ultrasound and transthoracic echocardiogram

Diagnostic Reasoning

Why ANCA Testing is Most Appropriate:

1. Multi-system Involvement Pattern: The combination of constitutional symptoms (fever, night sweats), renal involvement (hematuria, elevated creatinine, RBCs and granular casts in urine), and marked inflammation strongly suggests ANCA-associated vasculitis (AAV) 1.

2. Laboratory Profile: The patient's laboratory findings are highly consistent with AAV:

   • Elevated inflammatory markers (CRP 235 mg/L)
   • Renal involvement with hematuria and granular casts
   • Leukocytosis with neutrophilia
   • Negative blood cultures despite significant inflammation

3. Exclusion of Other Diagnoses:

   • Negative blood cultures rule out bacteremia
   • Normal transthoracic echocardiogram makes infective endocarditis less likely
   • Normal abdominal ultrasound excludes obvious intra-abdominal pathology

Assessment of Alternative Investigations:

• Transoesophageal echocardiography: Less likely to be helpful given the negative blood cultures and normal transthoracic echocardiogram.

• CT scan of abdomen: The normal abdominal ultrasound makes significant intra-abdominal pathology less likely.

• Mycobacterial culture of early-morning urine: While TB can present with similar symptoms, the rapid onset, marked leukocytosis with neutrophilia (rather than lymphocytosis), and urinary findings are more consistent with vasculitis than TB.

• Radiolabelled white cell scan: Less specific and sensitive than ANCA for diagnosing vasculitis in this clinical scenario.

Diagnostic Approach for Suspected Vasculitis

When evaluating patients with suspected vasculitis, a structured approach is recommended 1:

1. ANCA testing: Should be performed when there are clinical manifestations suggestive of AAV, such as:

   • Multisystem organ dysfunction
   • Acute kidney injury with hematuria and proteinuria
   • Constitutional symptoms (fever, night sweats, weight loss)

2. Tissue biopsy: May be necessary after ANCA testing to confirm the diagnosis, typically renal biopsy in cases with kidney involvement.

3. Evaluation of all potentially involved organs: Systematic assessment of pulmonary, renal, ENT, and other systems.

Important Clinical Considerations

• ANCA testing has high diagnostic utility when ordered in the appropriate clinical context. Studies show that among patients with at least one clinical manifestation of AAV, 25% were ANCA positive and 18.3% were diagnosed with AAV 2.

• The most common clinical presentations in patients with AAV include glomerulonephritis (81.8%), pulmonary hemorrhage (45.5%), and multiple lung nodules (31.8%) 2.

• ANCA specificity (proteinase 3-ANCA vs. myeloperoxidase-ANCA) has prognostic implications, with PR3-ANCA associated with higher mortality and relapse rates 3.

Conclusion

Given the constellation of symptoms (fever, night sweats), laboratory abnormalities (anemia, leukocytosis, elevated creatinine), and urinary findings (hematuria with granular casts), ANCA testing is the most appropriate next investigation to establish a diagnosis of ANCA-associated vasculitis, which would explain all the patient's findings and guide appropriate treatment.