Differential Diagnosis: Sepsis vs. Leukocyte Adhesion Defect vs. Chronic Myeloid Leukemia
This constellation of findings—leukocytosis with neutrophilia, basophilia, burr cells, poikilocytes, and vacuolated neutrophils—most urgently suggests severe bacterial infection/sepsis requiring immediate evaluation and treatment, though leukocyte adhesion defect (LAD) and myeloproliferative disorders must be excluded. 1, 2
Immediate Priority: Rule Out Sepsis
Critical Assessment Required Within 1 Hour
Check vital signs immediately: fever >38°C or hypothermia <36°C, hypotension <90 mmHg systolic, tachycardia, tachypnea, altered mental status—any of these with leukocytosis indicates sepsis requiring immediate intervention. 1, 2
Obtain lactate level urgently: if >3 mmol/L, this confirms severe sepsis and mandates immediate broad-spectrum antibiotics and aggressive fluid resuscitation. 1, 2
Vacuolated neutrophils are a critical red flag: this morphologic finding strongly suggests severe bacterial infection with toxic changes and should trigger immediate sepsis workup. 3
Monitor urine output: oliguria <30 ml/h indicates sepsis-related organ dysfunction. 1
Diagnostic Workup (Complete Before Antibiotics if Hemodynamically Stable)
Manual differential is mandatory: automated analyzers miss band forms and toxic granulations—you need absolute band count ≥1,500 cells/mm³ (likelihood ratio 14.5 for bacterial infection) and left shift ≥16% bands (likelihood ratio 4.7). 1, 4, 2
Blood cultures × 2 sets before antibiotics if any systemic signs present. 4, 2
Urinalysis with culture: UTI is the most common occult source in adults with unexplained leukocytosis. 2
Chest imaging if any respiratory symptoms (cough, dyspnea, chest pain). 4
Abdominal evaluation: examine for peritoneal signs, diarrhea suggesting intra-abdominal infection; consider imaging if indicated. 4
Management if Sepsis Confirmed
Initiate broad-spectrum empiric antibiotics within 1 hour of sepsis recognition—do not delay for culture results if patient is hemodynamically unstable. 1, 2
Aggressive IV fluid resuscitation for hypotension (30 mL/kg crystalloid bolus). 1, 2
Vasopressor support (norepinephrine first-line) if hypotension persists despite adequate fluid resuscitation. 1, 2
Source control measures: drain abscesses, remove infected catheters, debride necrotic tissue as indicated. 1, 2
Secondary Consideration: Leukocyte Adhesion Defect (LAD)
When to Suspect LAD
Marked leukocytosis (often >30,000-50,000/mm³) even without active infection is the hallmark of LAD—neutrophils cannot migrate to tissues, so they accumulate in blood. 5
History of recurrent severe bacterial and fungal infections affecting lungs, skin, or viscera since infancy/childhood with delayed umbilical cord separation. 5
Absence of pus formation at infection sites despite severe tissue destruction (neutrophils cannot exit bloodstream). 5
Poor wound healing and periodontal disease are characteristic. 5
Diagnostic Testing for LAD
Flow cytometry for CD11b/CD18 expression on neutrophils—absent or markedly reduced expression confirms LAD type 1. 5
Peripheral smear shows mature neutrophils without left shift despite extreme leukocytosis. 5
Tertiary Consideration: Myeloproliferative Disorder (CML or Other)
When to Suspect Hematologic Malignancy
Basophilia is highly specific for chronic myeloid leukemia (CML) when present with leukocytosis—this is a critical clue that distinguishes CML from reactive leukocytosis. 5, 3
Burr cells (echinocytes) and poikilocytes suggest underlying bone marrow disorder or metabolic derangement, not typical of simple infection. 3
Constitutional symptoms: fever, night sweats, weight loss, early satiety (splenomegaly), bruising, or fatigue suggest malignancy. 6, 7
Splenomegaly or hepatomegaly on examination strongly suggests myeloproliferative disorder. 7
WBC >100,000/mm³ represents medical emergency due to leukostasis risk (brain infarction, hemorrhage) and strongly suggests CML or acute leukemia. 7
Diagnostic Workup for Suspected Malignancy
Peripheral blood smear review by hematopathologist: look for immature granulocytes (myelocytes, metamyelocytes, promyelocytes), blasts, dysplasia, and basophilia distribution. 5, 3
BCR-ABL1 fusion gene testing (quantitative PCR or FISH) if CML suspected—this is diagnostic for CML. 5
Bone marrow aspiration and biopsy with cytogenetics, flow cytometry, and molecular studies if peripheral smear suggests myeloid malignancy. 5, 3
Complete metabolic panel: elevated LDH and uric acid suggest high cell turnover in malignancy. 5
Critical Pitfalls to Avoid
Do not dismiss elevated neutrophils when total WBC is only mildly elevated—left shift with normal WBC still indicates serious bacterial infection (likelihood ratio 4.7). 4, 2
Do not rely on automated differential alone—manual review is essential to identify toxic granulations, vacuolization, left shift, and dysplasia. 1, 2
Do not delay antibiotics in septic shock while awaiting culture results—mortality increases 7.6% for each hour of delay. 1, 2
Do not ignore basophilia—this finding dramatically increases suspicion for CML and warrants hematology referral even if infection is also present. 5, 3
Do not treat asymptomatic leukocytosis empirically—if patient is hemodynamically stable without fever or localizing signs, complete diagnostic workup first before antibiotics. 2
Algorithmic Approach
Assess hemodynamic stability and sepsis criteria immediately (vital signs, lactate, mental status). 1, 2
If sepsis present: initiate antibiotics within 1 hour, fluids, vasopressors as needed, source control. 1, 2
If stable: obtain manual differential, blood cultures, urinalysis, imaging as indicated by symptoms. 4, 2
Review peripheral smear personally: vacuolated neutrophils + left shift = infection; basophilia + immature granulocytes = CML; extreme leukocytosis without left shift = LAD. 5, 3
If basophilia or dysplasia present: refer to hematology for BCR-ABL1 testing and bone marrow evaluation. 5, 3
If recurrent infections with persistent extreme leukocytosis: consider LAD and order CD11b/CD18 flow cytometry. 5