Leukocytosis Differential Diagnosis in Primary Care: A Comprehensive Guide

Introduction

Leukocytosis, defined as an elevated white blood cell (WBC) count above the normal range, is a frequently encountered finding in primary care settings. While often indicative of the body’s natural response to infection or inflammation, leukocytosis can also signal more serious underlying conditions, including malignancies and myeloproliferative disorders. For primary care physicians, understanding the differential diagnosis of leukocytosis is crucial for timely and accurate patient management. This guide provides a comprehensive overview of leukocytosis, focusing on its differential diagnosis in primary care, enabling clinicians to effectively evaluate and manage this common hematological abnormality. Recognizing the various causes and understanding the nuances of WBC differentials are essential steps in guiding appropriate investigations and ensuring optimal patient outcomes in the primary care setting.

Etiology of Leukocytosis

Leukocytosis is not a disease itself but rather a sign of an underlying condition. In primary care, identifying the etiology of leukocytosis is paramount for effective patient management. The causes are diverse, ranging from benign reactive processes to life-threatening malignancies. A systematic approach, considering the specific type of white blood cell elevated (as indicated by the WBC differential), is vital.

Neutrophilia: Elevated Neutrophil Count

Neutrophilia, an increase in neutrophils, is the most common type of leukocytosis encountered in primary care. It frequently signals bacterial infection, but various non-infectious causes are also relevant in primary care.

Infections: Bacterial infections are the most frequent cause of neutrophilia. Common primary care scenarios include pneumonia, urinary tract infections (UTIs), skin and soft tissue infections (cellulitis, abscesses), and acute sinusitis. Viral infections, particularly in children, such as varicella, herpes simplex, and Epstein-Barr virus, can also induce neutrophilia, although lymphocytosis is more typical in many viral infections.
Inflammation: Non-infectious inflammatory conditions are significant causes of neutrophilia in primary care. These include:
- Acute inflammation: Trauma, surgery, burns, and acute gout flares can lead to transient neutrophilia.
- Chronic inflammatory diseases: Rheumatoid arthritis, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), and vasculitis can present with persistent neutrophilia.
Stress: Physiological stress, including strenuous exercise, emotional stress, pain, and even pregnancy, can temporarily elevate neutrophil counts.
Smoking: Chronic cigarette smoking is a well-known cause of mild to moderate neutrophilia.
Medications: Corticosteroids are a common medication class in primary care that can induce neutrophilia by increasing neutrophil release from the bone marrow and decreasing migration into tissues. Beta-agonists and lithium can also cause neutrophilia.
Myeloproliferative Neoplasms: While less common in the initial primary care presentation, myeloproliferative neoplasms (MPNs) like essential thrombocythemia, polycythemia vera, and primary myelofibrosis can present with neutrophilia. Chronic myeloid leukemia (CML) should also be considered, although it often presents with more pronounced leukocytosis.

Lymphocytosis: Elevated Lymphocyte Count

Lymphocytosis, an increase in lymphocytes, is another common finding in primary care. Viral infections are the most frequent cause, but other etiologies must be considered.

Viral Infections: Many viral infections common in primary care cause lymphocytosis. These include:
- Infectious mononucleosis (Epstein-Barr virus): Characterized by fatigue, fever, pharyngitis, and lymphadenopathy, often with atypical lymphocytes on peripheral smear.
- Cytomegalovirus (CMV) infection: Can cause a mononucleosis-like syndrome.
- Pertussis (Whooping cough): A bacterial infection classically associated with lymphocytosis, particularly in infants and children.
- Other viral infections: Influenza, adenovirus, rubella, rubeola, and varicella can also cause lymphocytosis.
Chronic Lymphocytic Leukemia (CLL): CLL is the most common leukemia in adults and often presents with asymptomatic lymphocytosis detected on routine CBC. In primary care, an unexpected, persistent lymphocytosis in an older adult should raise suspicion for CLL.
Other Malignancies: Lymphoma and acute lymphoblastic leukemia (ALL), although less common initial presentations in primary care for adults, can cause lymphocytosis.
Autoimmune and Inflammatory Conditions: Autoimmune diseases like systemic lupus erythematosus (SLE) and autoimmune lymphoproliferative syndrome (ALPS) can cause lymphocytosis.
Hyperthyroidism: Can sometimes be associated with lymphocytosis.

Eosinophilia: Elevated Eosinophil Count

Eosinophilia, an increase in eosinophils, is less common than neutrophilia or lymphocytosis but important to recognize in primary care due to its association with specific conditions.

Allergic Reactions: Allergic diseases are the most common cause of mild eosinophilia in primary care. These include:
- Allergic rhinitis (hay fever)
- Asthma
- Atopic dermatitis (eczema)
- Drug allergies: Numerous medications can cause eosinophilia.
Parasitic Infections: Helminthic infections (intestinal worms) are a significant cause of eosinophilia, especially in patients with a history of travel to endemic areas.
Asthma and Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss Syndrome): EGPA is a rare vasculitis associated with asthma and eosinophilia, which may initially present in primary care.
Hypereosinophilic Syndromes (HES): HES are a group of disorders characterized by persistently elevated eosinophils and organ damage. These are less common but require specialist referral.

Monocytosis: Elevated Monocyte Count

Monocytosis, an increase in monocytes, is less frequently isolated but can be seen in various primary care scenarios.

Chronic Infections: Tuberculosis, bacterial endocarditis, and some protozoal infections can cause monocytosis.
Inflammatory Bowel Disease (IBD): Both Crohn’s disease and ulcerative colitis can be associated with monocytosis.
Recovery from Neutropenia: Monocytosis can be seen during recovery from neutropenia as monocytes repopulate the blood.
Malignancies: Monocytic leukemia and some lymphomas can present with monocytosis.

Basophilia: Elevated Basophil Count

Basophilia, an increase in basophils, is the least common type of leukocytosis. Its presence often warrants further investigation, although transient basophilia can occur with infections.

Myeloproliferative Neoplasms (MPNs): Basophilia is strongly associated with MPNs, particularly chronic myeloid leukemia (CML) and essential thrombocythemia. Persistent basophilia should prompt consideration of MPNs.
Hypersensitivity Reactions: Rarely, basophilia can occur in immediate hypersensitivity reactions.
Myxedema (Severe Hypothyroidism): Can be associated with basophilia.

Diagnostic Approach to Leukocytosis in Primary Care

The evaluation of leukocytosis in primary care requires a systematic and thoughtful approach. The following steps are crucial for effective differential diagnosis:

Confirm Leukocytosis and Review WBC Differential: The first step is to confirm the leukocytosis on repeat testing if the initial finding was unexpected or borderline. Crucially, review the WBC differential to determine which cell lines are elevated (neutrophils, lymphocytes, eosinophils, monocytes, basophils). This differential is key to narrowing down the potential causes.
Detailed History and Physical Examination: A thorough history and physical exam are paramount. Key aspects include:
- Symptoms: Inquire about symptoms suggestive of infection (fever, cough, dysuria, skin changes), inflammation (joint pain, abdominal pain, diarrhea), allergy (itching, rash, wheezing), or malignancy (fatigue, weight loss, night sweats, bleeding, bruising).
- Duration of Symptoms: Acute leukocytosis often suggests infection or acute inflammation, while chronic leukocytosis may indicate chronic inflammation, smoking, or myeloproliferative disorders.
- Medication History: Carefully review all medications, including over-the-counter drugs and supplements, to identify potential drug-induced leukocytosis. Corticosteroids, lithium, and beta-agonists are common culprits.
- Past Medical History: Note any pre-existing conditions like autoimmune diseases, inflammatory bowel disease, asthma, allergies, history of malignancy, or myeloproliferative disorders.
- Smoking History: Document smoking status, as smoking is a common cause of neutrophilia.
- Travel History: Inquire about recent travel, especially to areas with endemic parasitic infections, if eosinophilia is present.
- Occupational Exposures: Consider occupational exposures to chemicals like benzene, which can increase leukemia risk, although this is less directly related to acute leukocytosis diagnosis.
- Family History: Family history of hematologic malignancies or autoimmune disorders may be relevant.
- Physical Examination: Perform a complete physical exam, focusing on:
  - Vital signs: Fever, tachycardia, and hypotension may suggest infection.
  - Lymph nodes: Lymphadenopathy may indicate infection, lymphoma, or leukemia.
  - Spleen and liver: Splenomegaly or hepatomegaly can be seen in infectious mononucleosis, leukemia, lymphoma, and myeloproliferative disorders.
  - Signs of infection: Examine for signs of localized infection (e.g., skin, lungs, urinary tract).
  - Skin: Rashes, urticaria, and angioedema may suggest allergic reactions or eosinophilic disorders.
Initial Laboratory Investigations: Based on the clinical presentation and WBC differential, initial laboratory tests may include:
- Peripheral Blood Smear Review: If the automated differential is abnormal or blasts are suspected, a manual review of the peripheral blood smear is essential. This can identify atypical lymphocytes (viral infections, CLL), blasts (leukemia), or other morphological abnormalities.
- Inflammatory Markers: CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) can help assess for inflammation, although they are non-specific.
- Infectious Disease Workup: If infection is suspected, order appropriate cultures (blood, urine, sputum, wound), rapid antigen tests (e.g., influenza, strep), or viral serology (e.g., EBV, CMV, HIV).
- Allergy Testing: If allergic eosinophilia is suspected, consider allergy testing. Stool ova and parasite examination should be considered in eosinophilia, especially with travel history.
- Liver and Renal Function Tests: Baseline metabolic panel to assess overall organ function.
- Chest X-ray: If pneumonia or other pulmonary infection is suspected.
Risk Stratification for Malignancy: Assess the risk of underlying hematologic malignancy. Factors that increase suspicion include:
- High WBC Count: Markedly elevated WBC counts (e.g., > 50,000/µL, especially > 100,000/µL) are more concerning for leukemia or myeloproliferative neoplasms.
- Persistent Leukocytosis: Leukocytosis that persists for weeks to months without a clear benign explanation warrants further investigation.
- Presence of Blasts or Immature Cells on Peripheral Smear: Blasts are abnormal immature white blood cells and are a hallmark of acute leukemia.
- Accompanying Cytopenias: Leukocytosis associated with anemia (low hemoglobin) or thrombocytopenia (low platelets) is more suggestive of bone marrow pathology, including leukemia or myelodysplasia.
- Unexplained Symptoms: Constitutional symptoms like fatigue, weight loss, night sweats, and unexplained bleeding or bruising raise concern for malignancy.
- Splenomegaly or Hepatomegaly: These findings can be associated with hematologic malignancies.
- Age: Leukemia risk increases with age, particularly for CLL and AML in adults.
Referral to Hematology/Oncology: Prompt referral to a hematologist/oncologist is indicated in the following situations:
- High Suspicion for Malignancy: Presence of blasts, unexplained cytopenias, persistent leukocytosis without benign cause, concerning symptoms (weight loss, night sweats), splenomegaly, or markedly elevated WBC count.
- Persistent Basophilia: Persistent basophilia is highly suggestive of myeloproliferative neoplasm and requires hematology evaluation.
- Hypereosinophilia: Absolute eosinophil count > 1500/µL persisting on repeat testing, especially with organ involvement or symptoms, should be referred for evaluation of hypereosinophilic syndromes and other causes.
- Diagnostic Uncertainty: If the cause of leukocytosis remains unclear after initial primary care workup, hematology referral is appropriate for further expert evaluation and specialized testing (e.g., bone marrow biopsy, flow cytometry, molecular studies).
Management in Primary Care: For leukocytosis deemed likely benign and reactive, primary care management may include:
- Treating the Underlying Cause: Address identified infections, inflammatory conditions, or allergies.
- Monitoring: Repeat CBC with differential in 2-4 weeks to ensure resolution of leukocytosis, especially for mild to moderate elevations thought to be reactive.
- Smoking Cessation Counseling: For smokers with neutrophilia, provide smoking cessation advice and resources.
- Medication Review and Adjustment: If medication-induced leukocytosis is suspected, consider alternative medications if clinically appropriate and monitor CBC after medication change.
- Patient Education: Educate patients about the likely benign cause of their leukocytosis, the plan for monitoring, and when to seek further medical attention if symptoms worsen or new symptoms develop.

Differential Diagnosis Categories in Primary Care

To further aid in the differential diagnosis in primary care, consider these categories based on the WBC differential:

A. Predominant Neutrophilia:

Infections (Bacterial): Pneumonia, UTI, cellulitis, sinusitis, abscess, sepsis.
Inflammation (Non-infectious): Acute injury, surgery, burns, gout, rheumatoid arthritis, IBD, vasculitis.
Stress/Physiological: Exercise, emotional stress, pain, pregnancy.
Smoking.
Medications (Corticosteroids, Beta-agonists).
Leukemoid Reaction: Severe infection or inflammation, extreme neutrophilia (> 50,000/µL) without leukemia.
Myeloproliferative Neoplasms (less common initial presentation).

B. Predominant Lymphocytosis:

Viral Infections: Infectious mononucleosis (EBV), CMV, pertussis, influenza, adenovirus, rubella, rubeola, varicella.
Chronic Lymphocytic Leukemia (CLL): Especially in older adults with persistent lymphocytosis.
Lymphoma (less common initial presentation).
Autoimmune Disorders (SLE, ALPS).
Hyperthyroidism.

C. Predominant Eosinophilia:

Allergic Disorders: Allergic rhinitis, asthma, atopic dermatitis, drug allergies.
Parasitic Infections (Helminths).
Asthma and EGPA (Churg-Strauss).
Hypereosinophilic Syndromes (HES) (rare, specialist referral).

D. Predominant Monocytosis:

Chronic Infections: Tuberculosis, bacterial endocarditis.
Inflammatory Bowel Disease (IBD).
Recovery from Neutropenia.
Malignancies (Monocytic leukemia, some lymphomas).

E. Predominant Basophilia:

Myeloproliferative Neoplasms (MPNs): CML, essential thrombocythemia.
Hypersensitivity Reactions (rare).
Myxedema (Hypothyroidism).

Pearls for Primary Care Practice

Always review the WBC differential: The differential is crucial for narrowing the differential diagnosis.
Consider the clinical context: Integrate the leukocytosis finding with the patient’s symptoms, medical history, and physical examination findings.
Think about common primary care scenarios: Infections, inflammation, allergies, and medication effects are frequent causes of leukocytosis in primary care.
Don’t dismiss persistent leukocytosis: Unexplained, persistent leukocytosis, especially with concerning features, warrants further investigation, including hematology referral.
Peripheral smear review is valuable: If the automated differential is abnormal or malignancy is suspected, review the peripheral blood smear.
Risk stratify for malignancy: Assess for risk factors and red flags suggestive of hematologic malignancy to guide timely referral.
Educate and monitor: For benign reactive leukocytosis, educate patients and arrange appropriate follow-up with repeat CBC to ensure resolution.

Conclusion

Leukocytosis is a common laboratory finding in primary care. By systematically evaluating the WBC differential, considering the clinical context, and utilizing a stepwise diagnostic approach, primary care physicians can effectively differentiate benign reactive leukocytosis from more serious underlying conditions, including hematologic malignancies. Prompt recognition of high-risk features and timely referral to hematology/oncology when indicated are essential for optimizing patient care and outcomes. This comprehensive guide aims to empower primary care clinicians with the knowledge and tools necessary to confidently navigate the differential diagnosis of leukocytosis in their daily practice.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare professional for diagnosis and treatment of medical conditions.

References:

Chabot-Richards DS, George TI. Leukocytosis. Int J Lab Hematol. 2014 Jun;36(3):279-88. [PubMed: 24750674]
Riley LK, Rupert J. Evaluation of Patients with Leukocytosis. Am Fam Physician. 2015 Dec 01;92(11):1004-11. [PubMed: 26760415]
Cerny J, Rosmarin AG. Why does my patient have leukocytosis? Hematol Oncol Clin North Am. 2012 Apr;26(2):303-19, viii. [PubMed: 22463829]
Gulati G, Uppal G, Gong J. Unreliable Automated Complete Blood Count Results: Causes, Recognition, and Resolution. Ann Lab Med. 2022 Sep 01;42(5):515-530. [PMC free article: PMC9057813] [PubMed: 35470271]
Naqvi S, Awasthi NP, Das PK, Husain N. Leukoerythroblastosis – An unsusal presentation of COVID 19 infection. Clin Epidemiol Glob Health. 2022 May-Jun;15:101026. [PMC free article: PMC8931990] [PubMed: 35317212]
Kovalszki A, Weller PF. Eosinophilia. Prim Care. 2016 Dec;43(4):607-617. [PMC free article: PMC5293177] [PubMed: 27866580]
Ramirez GA, Yacoub MR, Ripa M, Mannina D, Cariddi A, Saporiti N, Ciceri F, Castagna A, Colombo G, Dagna L. Eosinophils from Physiology to Disease: A Comprehensive Review. Biomed Res Int. 2018;2018:9095275. [PMC free article: PMC5829361] [PubMed: 29619379]
Itzykson R, Fenaux P, Bowen D, Cross NCP, Cortes J, De Witte T, Germing U, Onida F, Padron E, Platzbecker U, Santini V, Sanz GF, Solary E, Van de Loosdrecht A, Malcovati L. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet. Hemasphere. 2018 Dec;2(6):e150. [PMC free article: PMC6745959] [PubMed: 31723789]
Hensel M, Grädel L, Kutz A, Haubitz S, Huber A, Mueller B, Schuetz P, Hügle T. Peripheral monocytosis as a predictive factor for adverse outcome in the emergency department: Survey based on a register study. Medicine (Baltimore). 2017 Jul;96(28):e7404. [PMC free article: PMC5515748] [PubMed: 28700476]
Valent P, Sotlar K, Blatt K, Hartmann K, Reiter A, Sadovnik I, Sperr WR, Bettelheim P, Akin C, Bauer K, George TI, Hadzijusufovic E, Wolf D, Gotlib J, Mahon FX, Metcalfe DD, Horny HP, Arock M. Proposed diagnostic criteria and classification of basophilic leukemias and related disorders. Leukemia. 2017 Apr;31(4):788-797. [PMC free article: PMC7115817] [PubMed: 28090091]
Abramson N, Melton B. Leukocytosis: basics of clinical assessment. Am Fam Physician. 2000 Nov 01;62(9):2053-60. [PubMed: 11087187]
Çehreli C. Diagnostic Problems in Chronic Basophilic Leukemia. Turk J Haematol. 2018 Nov 13;35(4):283-289. [PMC free article: PMC6256821] [PubMed: 30401657]
Pepper C, Thomas A, Hoy T, Tighe J, Culligan D, Fegan C, Bentley P. Leukemic and non-leukemic lymphocytes from patients with Li Fraumeni syndrome demonstrate loss of p53 function, Bcl-2 family dysregulation and intrinsic resistance to conventional chemotherapeutic drugs but not flavopiridol. Cell Cycle. 2003 Jan-Feb;2(1):53-8. [PubMed: 12695689]
Stieglitz E, Loh ML. Genetic predispositions to childhood leukemia. Ther Adv Hematol. 2013 Aug;4(4):270-90. [PMC free article: PMC3734905] [PubMed: 23926459]
Barron HV, Harr SD, Radford MJ, Wang Y, Krumholz HM. The association between white blood cell count and acute myocardial infarction mortality in patients > or =65 years of age: findings from the cooperative cardiovascular project. J Am Coll Cardiol. 2001 Nov 15;38(6):1654-61. [PubMed: 11704377]
Yeh YT, Liu CW, Li AH, Ke SR, Liu YH, Chen KC, Liao PC, Wu YW. Rapid Early Triage by Leukocytosis and the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: An Observational Study. Medicine (Baltimore). 2016 Feb;95(7):e2857. [PMC free article: PMC4998652] [PubMed: 26886652]
Brandt L, Nilsson PG, Mitelman F. Occupational exposure to petroleum products in men with acute non-lymphocytic leukaemia. Br Med J. 1978 Mar 04;1(6112):553. [PMC free article: PMC1603268] [PubMed: 630218]
Levine EG, Bloomfield CD. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Semin Oncol. 1992 Feb;19(1):47-84. [PubMed: 1736370]
Khan AA, Ahuja S, Zaheer S, Das S. Epithelioid Hemangioma of the Nasal Cavity: a Diagnostic Challenge. Indian J Surg Oncol. 2024 Mar;15(1):181-184. [PMC free article: PMC10948671] [PubMed: 38511032]
Proytcheva MA. Issues in neonatal cellular analysis. Am J Clin Pathol. 2009 Apr;131(4):560-73. [PubMed: 19289592]
Lim EM, Cembrowski G, Cembrowski M, Clarke G. Race-specific WBC and neutrophil count reference intervals. Int J Lab Hematol. 2010 Dec;32(6 Pt 2):590-7. [PubMed: 20236184]
Korkmaz S. The management of hyperleukocytosis in 2017: Do we still need leukapheresis? Transfus Apher Sci. 2018 Feb;57(1):4-7. [PubMed: 29477941]
Radulescu D, Cuiban E, Vacaroiu IA. Unusual Extreme Leukocytosis in Metformin Overdose. Maedica (Bucur). 2023 Jun;18(2):357-362. [PMC free article: PMC10427101] [PubMed: 37588821]
Viner E, Berger J, Bengualid V. Etiologies of Extreme Leukocytosis. Cureus. 2023 Apr;15(4):e38062. [PMC free article: PMC10208012] [PubMed: 37228523]