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PA18.1-2 | Reactive Leucocytosis, Leucopenia & Lymphocytosis — Part 3
Lymphocytosis: Reactive vs Neoplastic
Lymphocytosis is defined as an absolute lymphocyte count > 4.8 × 10⁹/L in adults (higher thresholds apply in children).
Reactive (benign) lymphocytosis — the key causes:
1. Viral infections — the dominant cause:
- Epstein-Barr virus (EBV) causing infectious mononucleosis (IM): absolute lymphocytosis with highly characteristic atypical (Downey) lymphocytes — large cells with abundant, pale blue cytoplasm, indented or lobulated nuclei that mould against adjacent red cells. See figure below.
- CMV mononucleosis: clinically similar to EBV IM but monospot-negative; heterophile antibody absent.
- Pertussis (whooping cough): profound lymphocytosis (up to 40–50 × 10⁹/L) with small, mature lymphocytes — one of the highest reactive lymphocyte counts encountered.
- Other viruses: rubella, viral hepatitis, adenovirus.
2. Tuberculosis — chronic lymphocytosis accompanies primary and miliary TB.
3. Toxoplasmosis, brucellosis — bacterial causes of reactive lymphocytosis.
Atypical Lymphocytes in Infectious Mononucleosis and Differential Features
Distinguishing reactive from neoplastic lymphocytosis:
| Feature | Reactive | Neoplastic (CLL, lymphoma) |
|---|---|---|
| Cell morphology | Heterogeneous, atypical | Monotonous, mature small lymphocytes |
| Count | Usually < 20 × 10⁹/L | Often > 30 × 10⁹/L, can be > 100 |
| Smudge cells | Absent | Present (fragile CLL cells) |
| Lymphadenopathy | Soft, tender | Firm, non-tender |
| Splenomegaly | Mild if present | Common |
| Immunophenotype (flow) | Polyclonal | Monoclonal |
| Duration | Self-limited weeks | Persistent |
The definitive test for neoplastic lymphocytosis is flow cytometry demonstrating surface immunoglobulin light-chain restriction (kappa or lambda alone = clonal = neoplastic).
SELF-CHECK
A 19-year-old college student has sore throat, cervical lymphadenopathy, WBC 16 × 10⁹/L, lymphocytes 72% with many large atypical forms. Monospot is positive. Which statement about his lymphocytes is MOST accurate?
A. They are malignant B cells transformed by EBV
B. They are reactive CD8+ T cells responding to EBV-infected B cells
C. They are the EBV-infected B cells themselves
D. They represent CLL cells with smudge cell artefact
Reveal Answer
Answer: B. They are reactive CD8+ T cells responding to EBV-infected B cells
The atypical (Downey) lymphocytes of infectious mononucleosis are reactive CD8+ cytotoxic T lymphocytes responding to EBV-infected B cells — they are NOT the infected B cells. EBV infects B cells (via CD21/CR2 receptor), but it is the T-cell response that produces the large atypical morphology and the clinical syndrome. This distinction is tested repeatedly.
Eosinophilia, Monocytosis, and Basophilia
Eosinophilia (absolute count > 0.4 × 10⁹/L) is remembered with the mnemonic NAACP:
- Neoplastic — Hodgkin lymphoma, CML, hypereosinophilic syndrome
- Allergic — asthma, hay fever, urticaria, atopic eczema (most common cause in urban India)
- Addison's disease (adrenal insufficiency)
- Collagen vascular diseases — polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
- Parasites — tissue-invasive helminths: ascariasis, strongyloidiasis, toxocariasis, filariasis, schistosomiasis (most common cause globally)
Important addition: drugs (sulfonamides, aspirin, allopurinol) cause eosinophilia, and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is a potentially life-threatening example.
Monocytosis (absolute count > 1.0 × 10⁹/L):
Causes follow the pattern of chronic granulomatous disease:
- Chronic infections: TB (classically), infective endocarditis, brucellosis, malaria
- Autoimmune: SLE, inflammatory bowel disease, rheumatoid arthritis
- Recovery phase after neutropenia (marrow regeneration — monocytes recover before neutrophils, a prognostically favourable sign)
- Neoplastic: chronic myelomonocytic leukaemia (CMML — defined by persistent monocytosis > 1.0 × 10⁹/L)
Basophilia (absolute count > 0.1 × 10⁹/L) is always a flag for myeloproliferative disease:
- CML (most important — basophilia > 2% is highly characteristic)
- Polycythaemia vera, primary myelofibrosis, essential thrombocythaemia
- Rarely: hypothyroidism, allergic reactions
Teaching point: basophilia in the peripheral blood is almost never reactive. When you see it, think myeloproliferative neoplasm until proven otherwise.
SELF-CHECK
A 28-year-old returned from Bihar with recurrent fever and hepatosplenomegaly. CBC: WBC 9 × 10⁹/L, eosinophils 18% (absolute 1.62 × 10⁹/L). Which of the following is the MOST likely cause?
A. Atopic asthma
B. Visceral leishmaniasis (kala-azar)
C. Tissue-invasive helminth infection
D. CML with eosinophilia
Reveal Answer
Answer: C. Tissue-invasive helminth infection
Travel history, fever, and hepatosplenomegaly in a Bihar resident strongly suggest a tropical infection. Tissue-invasive helminths (hookworm, ascariasis, filariasis) are the leading global cause of eosinophilia. Note: kala-azar actually causes neutropenia and pancytopenia (from hypersplenism), not eosinophilia. CML would present with a much higher WBC and basophilia. Asthma is the most common allergic cause but the clinical context doesn't fit.
Infectious Mononucleosis — A Clinical-Pathological Vignette
Infectious mononucleosis (IM) caused by EBV deserves special attention because it perfectly illustrates reactive white-cell changes and their clinical consequences.
Pathogenesis in brief:
1. EBV (herpesvirus) enters via saliva and infects B lymphocytes through the CD21 (complement receptor 2) receptor.
2. Infected B cells proliferate; CD8+ cytotoxic T cells (the atypical lymphocytes you see on the smear) mount a vigorous response.
3. The T-cell response controls, but does not eradicate, the infection. EBV establishes lifelong latency.
Haematological features:
- Leucocytosis 10–20 × 10⁹/L, predominantly lymphocytosis
- Atypical lymphocytes > 10% (Downey cells, described above)
- Mild thrombocytopenia (immune-mediated) in ~50%
- Mild haemolytic anaemia (anti-i cold agglutinins) in ~10%
Diagnostics:
- Monospot (Paul-Bunnell) test: detects heterophile antibodies (IgM that agglutinate horse/sheep RBCs). Positive in 85–90% of cases after week 1.
- EBV-specific serology (VCA IgM/IgG, EA, EBNA) for monospot-negative cases.
- Blood film: classic morphology is often diagnostic.
Complications to know:
- Splenic rupture (rare but catastrophic — avoid contact sports for 4 weeks)
- Airway obstruction from massive tonsillar hypertrophy
- EBV-associated malignancies (Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma) — long-term risk, not acute.