What is the indication for a Complete Blood Count (CBC) with Differential (DIFF) in patients with suspected infection, anemia, or blood disorders, particularly in the elderly, young children, or those with a history of blood disorders or previous infections?

Indications for CBC with Differential

A CBC with differential is indicated when there is clinical suspicion of infection, anemia, blood disorders, or hematologic malignancy, and should be performed within 12-24 hours of symptom onset in patients with suspected infection. 1

Primary Clinical Indications

Suspected Infection

• Obtain CBC with differential for all long-term care facility residents suspected of having infection within 12-24 hours of symptom onset (or sooner if seriously ill), as this provides critical diagnostic information about bacterial infection. 1
• An elevated WBC count (≥14,000 cells/mm³) or left shift (band neutrophils ≥16% or total band count ≥1,500 cells/mm³) warrants careful assessment for bacterial infection, even without fever. 1
• In the absence of fever, leukocytosis, left shift, or focal infection signs, additional diagnostic tests have low yield and may not be indicated. 1

Evaluation of Anemia

• CBC with differential is the foundational diagnostic test for any patient with anemia, providing critical information about red blood cell indices and peripheral blood morphology that directly guides diagnosis and management. 2
• The test classifies anemia by MCV into microcytic, normocytic, or macrocytic categories, directing the diagnostic pathway. 2
• Manual differential and blood smear morphology detect dysplastic changes, blasts, or abnormal cell populations that may indicate myelodysplastic syndrome or leukemia. 2
• The reticulocyte count distinguishes decreased RBC production from increased production, helping identify the underlying cause. 2

Suspected Congenital Syphilis in Newborns

• Complete blood count with differential and platelet count is required for all infants with proven or highly probable congenital syphilis, along with CSF analysis and other tests as clinically indicated. 1
• This evaluation should include assessment for abnormalities consistent with congenital disease. 1

High-Risk Hematologic Conditions Requiring Surveillance

Leukemia-Predisposing Syndromes

• For highest-risk diseases (Fanconi anemia, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L mutations), perform CBC with differential every 3-4 months, even with stable counts. 1, 3
• For moderate-risk conditions (DDX41, RUNX1, ANKRD26, ETV6, telomere biology disorders), perform CBC with differential every 6-12 months. 1, 3
• For lower-risk conditions (TP53, Lynch syndrome genes, PAX5, CEBPA, chromosome 21, ATM, NBN, NF1, CBL-1, RASopathies, IKZF1, BLM), perform CBC with differential as clinically indicated. 1

Critical Components to Evaluate in High-Risk Patients

• Examine for leukemic blasts or dysplastic changes on peripheral smear. 1, 2
• Enumerate platelet count for those at risk for thrombocytopenia. 1
• Assess MCV, as macrocytosis can be an early manifestation of myelodysplastic syndrome. 1, 2
• Use manual differential to assess bands and other immature forms, as this is superior to automated differentials for detecting early abnormalities. 1

When to Repeat CBC with Differential

New or Worsening Cytopenias

• If a patient develops new cytopenia of one or more lineages, repeat CBC within 2-4 weeks. 1, 3
• If the CBC worsens or remains abnormal over two or more measurements, proceed to bone marrow evaluation rather than continued CBC monitoring. 1, 3

Stable High-Risk Patients

• For patients with initially abnormal counts that stabilize, lengthen monitoring intervals from every 3-4 months to every 6-12 months. 1, 3
• Do not continue frequent monitoring indefinitely once stability is established. 3

Urgent Indications Requiring Immediate Action

Life-Threatening Findings

• Urgent hematology consultation is required when CBC reveals severe neutropenia (<500/mm³), multiple cell line abnormalities suggesting bone marrow failure, presence of blasts, or significant dysplastic changes on peripheral smear. 2, 4
• Severe cytopenias (Grade 3-4) affecting any cell line require immediate specialist referral. 4
• Persistent unexplained cytopenias despite initial evaluation mandate hematology consultation. 4

Common Clinical Pitfalls to Avoid

• Do not skip peripheral blood smear review, as automated CBC parameters alone may miss critical morphologic findings like blasts or dysplasia. 2
• Do not overlook medication history, as drug-induced cytopenias are a frequently missed cause of abnormalities. 2, 4
• Do not assume iron deficiency based solely on microcytosis; confirm with ferritin and RDW. 2
• Do not order CBC with differential for asymptomatic screening in the general population, as it has no value in this setting. 5

When CBC with Differential is NOT Indicated

• Asymptomatic residents of long-term care facilities should not have urinalysis or urine cultures performed routinely, and similarly, CBC with differential should be reserved for those with clinical suspicion of infection or other specific indications. 1
• Screening asymptomatic members of the general population has no value. 5
• Repeat testing should be limited to situations where clinical course is unclear and at intervals long enough that results might affect clinical decision making. 5