What are the differential diagnoses for an elevated neutrophil (polymorphonuclear leukocyte) count?

Differential Diagnosis for Elevated Polymorphonuclear Leukocytes (Neutrophils)

An elevated polymorphonuclear leukocyte (neutrophil) count most commonly indicates acute bacterial infection, but the differential diagnosis varies significantly based on the clinical context—including whether the elevation is in peripheral blood versus body fluid compartments, and the presence of accompanying cell population abnormalities. 1, 2

Primary Differential Diagnoses by Clinical Context

Peripheral Blood Neutrophilia

Infectious Causes (Most Common)

• Acute bacterial infections are the most common cause of neutrophilia and mild leukocytosis, with an absolute neutrophil count >6.70 K/uL warranting careful assessment even without fever 1
• Suppurative infections particularly when neutrophil differential count exceeds 50% 3
• Sepsis or systemic infection, especially when accompanied by left shift (≥16% band neutrophils increases likelihood ratio to 4.7 for bacterial infection) 2
• Note that in elderly patients, 50% of documented bacterial infections present without fever, so absence of fever does not exclude infection 1

Non-Infectious Inflammatory Causes

• Acute lung injury or aspiration pneumonia when neutrophil differential >50% 3, 4
• Trauma or burns, which produce characteristic patterns of PMN upregulation with increased expression of high-affinity receptors 5
• Myocardial ischemia, where PMNs can exacerbate tissue damage 6
• Adult respiratory distress syndrome (ARDS) 6

Systemic Disease States

• Diabetes mellitus, which produces distinct patterns of PMN functional abnormalities and increased infection risk 5
• Renal failure, associated with acquired PMN functional defects 5
• Inflammatory rheumatic diseases and autoimmune conditions 7
• Cardiovascular diseases through PMN interaction with platelets and endothelial cells 7

Hematologic Malignancies

• Acute myelogenous leukemia (AML), where 97% of patients have cytochemically abnormal PMNs that are progeny of leukemic blasts 8
• Chronic myeloid leukemia (CML), though this typically presents with additional abnormalities (basophilia, eosinophilia, splenomegaly) rather than isolated neutrophilia 2
• Myeloproliferative disorders when WBC ≥12,000/mm³ 2
• Peripheral smear showing blast cells, immature forms, or dysplastic features requires immediate hematology referral regardless of absolute WBC count 2

Body Fluid Compartment Neutrophilia

Ascitic Fluid

• Spontaneous bacterial peritonitis (SBP) when PMN count >250 cells/mm³ in cirrhotic patients, with PMN ≥500 cells/μL yielding positive likelihood ratio of 10.6 3
• Secondary bacterial peritonitis from perforation or inflammation of intra-abdominal organs 3
• Pancreatic ascites, where raised PMN count may occur alongside amylase >1000 IU/L 3
• Culture-negative neutrocytic ascites (PMN >250 cells/mm³ with negative cultures) has similar morbidity and mortality to culture-positive SBP 3

Bronchoalveolar Lavage (BAL) Fluid

• Idiopathic pulmonary fibrosis (IPF), where neutrophil increase >5% occurs in 70-90% of patients 3
• Fibrosing alveolitis associated with rheumatological disease 3
• Asbestosis or fibrotic sarcoidosis 3
• Acute interstitial pneumonias when neutrophil differential >50% 3
• Diffuse alveolar damage 3
• Note: A neutrophil differential >50% in BAL strongly supports acute lung injury, aspiration pneumonia, or suppurative infection 3

Cervical/Urethral Specimens

• Mucopurulent cervicitis (MPC) characterized by increased polymorphonuclear leukocytes on endocervical Gram stain, though this has low positive predictive value 3
• Urethritis with objective signs of inflammation 3

Critical Risk Stratification Thresholds

Emergency Situations Requiring Immediate Intervention

• WBC >100,000/μL represents a medical emergency due to risk of leukostasis, brain infarction/hemorrhage, disseminated intravascular coagulation, and tumor lysis syndrome, requiring aggressive IV hydration, allopurinol or rasburicase, hydroxyurea, and consideration of leukapheresis 2

High-Risk Features Beyond Absolute Count

• Absolute band count ≥1,500 cells/mm³ has the highest likelihood ratio (14.5) for documented bacterial infection 1, 2
• Neutrophil percentage >90% has likelihood ratio of 7.5 for bacterial infection 1, 2
• Left shift ≥16% band neutrophils increases likelihood ratio to 4.7 for bacterial infection, even with normal total WBC 2
• Total WBC ≥14,000 cells/mm³ has likelihood ratio of 3.7 for bacterial infection 1

Diagnostic Algorithm for Elevated PMNs

Step 1: Determine the Compartment

• Peripheral blood: Consider systemic causes (infection, inflammation, malignancy, physiologic stress)
• Body fluid (ascites, BAL, CSF): Consider localized infection or inflammation in that compartment

Step 2: Assess Accompanying Cell Populations

• Isolated neutrophilia: Bacterial infection, physiologic stress, or early myeloproliferative disorder 1, 2
• Neutrophilia with lymphopenia: Acute bacterial infection or sepsis (high segmented neutrophils with low lymphocytes strongly suggests acute bacterial infection) 1
• Neutrophilia with eosinophilia: IPF (40-60% of patients), drug reaction, or parasitic infection 3
• Neutrophilia with basophilia/eosinophilia and splenomegaly: CML 2
• Neutrophilia with blast cells or dysplastic features: Acute leukemia requiring immediate hematology referral 2, 8

Step 3: Evaluate for Infection Based on Clinical Context

• Respiratory symptoms: Obtain chest imaging, consider sputum culture, evaluate for pneumonia or aspiration 1
• Urinary symptoms: Perform urinalysis and urine culture (but do not treat asymptomatic bacteriuria) 1
• Abdominal symptoms in cirrhotic patients: Perform diagnostic paracentesis with cell count and culture 3
• Systemic symptoms: Obtain blood cultures if fever or hemodynamic instability present 1

Step 4: Consider Non-Infectious Causes When Infection Excluded

• Recent trauma or surgery: Physiologic stress response 5
• Chronic diseases: Diabetes, renal failure, cardiovascular disease 5, 7
• Medications: Corticosteroids, G-CSF, GM-CSF 9
• Persistent unexplained neutrophilia with splenomegaly or lymphadenopathy: Immediate hematology referral for myeloproliferative disorder workup 2

Common Pitfalls to Avoid

• Do not dismiss mildly elevated WBC counts (11-14 K/uL) when accompanied by high neutrophil percentage or elevated absolute neutrophil count, as these still indicate significant infection risk 1
• Do not treat asymptomatic bacteriuria based solely on positive urine culture in the absence of urinary symptoms (prevalence 15-50% in certain populations), as this leads to unnecessary antibiotic use 1
• Do not overlook the significance of absolute neutrophil count elevation when total WBC count is only mildly elevated 1
• Do not assume absence of fever excludes bacterial infection, particularly in elderly patients where 50% of documented infections present without fever 1
• Do not attribute neutrophilia solely to "stress" or "inflammation" without excluding bacterial infection through appropriate clinical assessment and targeted testing 1, 2
• Do not delay hematology referral when peripheral smear shows blast cells, immature forms, dysplastic features, or when splenomegaly/lymphadenopathy is present on examination 2