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PA18.1 | Reactive Leucocytosis, Leucopenia & Lymphocytosis — SDL Guide (Part 3)

Lymphocytosis: Reactive vs Neoplastic

A three-panel diagram comparing reactive and neoplastic lymphocytosis, highlighting Downey lymphocytes in infectious mononucleosis and common causes of reactive lymphocytosis. — **Panel A:** Infectious mononucleosis smear showing atypical Downey lymphocyte, abundant pale-blue cytoplasm, indented/lobulated nucleus, nuclear molding against RBCs, large cell size, surrounding RBCs. **Panel B:** Comparison of reactive lymphocytosis with pleomorphic atypical lymphocytes versus neoplastic lymphocytosis with monotonous small mature lymphocytes and smudge cells. **Panel C:** Reactive lymphocytosis causes and clues: adult ALC threshold > 4.8 x 10^9/L, EBV, CMV, rubella, viral hepatitis, adenovirus, pertussis, tuberculosis, toxoplasmosis, brucellosis.

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.

Blood smear showing atypical lymphocytes in infectious mononucleosis alongside comparison table of reactive versus neoplastic lymphocytosis features. — **Panel A:** Peripheral blood smear at 100× showing Downey lymphocytes with labeled features: abundant pale-blue cytoplasm, lobulated nuclei, nuclear molding against RBCs, large cell size. **Panel B:** Comparison table distinguishing reactive (infectious mononucleosis) from neoplastic lymphocytosis (CLL/lymphoma) based on morphology, count, smudge cells, and clinical findings.

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

A four-panel medical diagram explains EBV infectious mononucleosis pathogenesis, atypical lymphocytes on blood film, hematological findings, diagnostic tests, and major complications. — **Panel A:** EBV via saliva, oropharynx, B lymphocyte, CD21 receptor, infected B-cell proliferation, CD8+ cytotoxic T-cell response, lifelong EBV latency. **Panel B:** Peripheral blood film, atypical lymphocytes, Downey cells, abundant basophilic cytoplasm, irregular lymphocyte nuclei. **Panel C:** Leucocytosis 10-20 x 10^9/L, predominant lymphocytosis, atypical lymphocytes >10%, mild thrombocytopenia, mild haemolytic anaemia, anti-i cold agglutinins. **Panel D:** Monospot heterophile antibodies, horse/sheep RBC agglutination, VCA IgM, VCA IgG, EA, EBNA, splenic rupture risk, tonsillar hypertrophy with airway obstruction, Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma.

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.