In the discussion, the authors focused on the probable etiopathogenesis. They cited the Hill and Duncan classification that attributed leukemoid reaction to three mechanisms; (i) bone marrow irritation or stimulation by physical, chemical or allergic agents; (ii) response of the bone marrow to an overwhelming demand for leukocytes; and (iii) ectopic hematopoesis due to destruction of or encroachment of the marrow space [2]. This was followed by possible illnesses attributable to each; (i) infections with bacteria like S. aureus, H. Influenzae, M. tuberculosis, S typhi and much less commonly viruses; (ii) hemolytic conditions or hemorrhage, increased bone marrow regeneration after hematinics or post bone marrow suppression; and (iii) lymphoma or neuroblastoma. The authors stated that leukemia should not be diagnosed merely by peripheral blood smear findings, and concluded by suggesting that the term leukemoid reaction be replaced by ‘Leuco-erythroblastic reaction’ as it had less ominous implications.

Till date the term ‘Leukemoid reaction’ still hold good. The definition, however has become more elaborate, and now reads as ‘a hematological disorder, characterized by a leukocyte count >50,000 cells/µL, significant increase in mature neutrophil counts in the peripheral blood, accompanied by a differential count showing marked left shift, signs of neutrophil activation in the absence of basophilia and dysplastic changes’. Over the last fifty years, most advances have been in terms of expanding the number of underlying causes as well as the use of alternative diagnostic modalities when standard hematological methods fail to establish the diagnosis.

It is well known that most cases are due to reactive causes operating outside the bone marrow [4,5]. Infective causes are still the commonest, especially bacteria like B. pertussis, C. difficile, Shigella, Mycoplasma and M. tuberculosis. Others include viruses (EBV, CMV, HIV and parvovirus B19), parasitic illnesses (trichinosis, visceral larva migrans, and malaria) and even fungal infections (mucormycosis, Tinea capitis), and scabies. An association of neonatal leukemoid reaction in low birth weight babies has been observed with maternal chorioamnionitis. When an infectious cause is not evident, it is essential to exclude hematological malignancies like CML and chronic neutrophilic leukemia (CNL), a rare myeloproliferative syndrome with poor prognosis. There is a long list of other malignancies associated with leukemoid reaction, which also secrete haematopoeitic stimulating cytokines. These include carcinomas (lung, oropharyngeal, gastro-intestinal, genitourinary, and nasopharyngeal), Hodgkin lymphoma, melanomas and sarcomas. Apart from severe hemorrhage and acute hemolysis (that was recognized earlier), drugs like corticosteroids, minocycline, recombinant hematopoietic growth factors and ethylene glycol intoxication are also known to cause leukemoid reaction.

To conclude, leukemoid reaction is a rare but challenging condition that may require a careful diagnostic work-up. The diagnosis is usually made by a combination of raised TLC, marked mature neutrophilia (but with a left shift), high LAP score and hypercellular bone marrow with intact maturation and morphology of all elements. Rarely, it may require demonstration of absence of cytogenetic abnormalities, mature granulocyte pattern by immunophenotyping and polyclonal neutrophils, or the absence of high levels of hemopoietic growth factors.

1. Chandra RK, Bhakoo ON. Leuco-erythroblastic (leukemoid) reaction in infants and children. Indian Pediatr. 1965;2:411-6.

2. Hill JM, Duncan CN. Am J Med Sci. 1941;201:847.

3. Krumbhaar EB. Am J Med Sci. 1926;172:519.

4. Nimieri HS, Makoni SN, Madziwa FH, Nemiary DS. Leukemoid reaction response to chemotherapy and radiotherapy in a patient with cervical carcinoma. Ann Hematol. 2003;82:316-7.

5. Curnutte JT, Coates TD. Disorders of phagocyte function and number. In: Hoffman R, Benz Jr EJ, Shattil SJ, editors. Hematology: Basic Principles and Practice. 3rd ed. Philadelphia: Churchill Livingstone; 2000. p. 740.

6. Chianese R, Brando B, Gratama JW. European Working Group on Clinical Cell Analysis. Diagnostic and prognostic value of flow cytometric immunophenotyping in malignant hematological diseases. J Biol Regul Homeost Agents. 2002;16:259-69.

7. Bohm J, Kock S, Schaefer HE, Fisch P. Evidence of clonality in chronic neutrophilic leukaemia. J Clin Pathol. 2003;56:292-5.

8. Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y, Ohyashiki K. Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer. 2001;92:2399-405.