Leukemoid Reaction
1. Dr. Samatbek Turdaliev
2. Mohammed Mansoor S. S
Ahmed bin Abdullah Juman Askool
(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic
2. Students, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
ABSTRACT
Persistent neutrophilic leukocytosis above 50,000 cells/μL when the cause is other than leukemia defines a leukemoid reaction. The diagnostic work-up consists of the exclusion of chronic myelogenous leukemia (CML) and chronic neutrophilic leukemia (CNL) and the detection of an underlying cause. The major causes of leukemoid reactions are severe infections, intoxications, malignancies, severe hemorrhage, or acute hemolysis. The present article points out the difficulties in the differential diagnosis of a leukemoid reaction and suggests an algorithm for a rational clinical and laboratory evaluation of this problematic entity.
INTRODUCTION
A leukemoid reaction (LR) is a hematological disorder, defined by a leukocyte count greater than 50,000 cells/μL, caused by reactive causes outside the bone marrow. It is characterized by a significant increase in mature neutrophils in the peripheral blood and a differential count showing marked left shift. The diagnosis of LR is based on the exclusion of chronic myelogenous leukemia (CML) and chronic neutrophilic leukemia (CNL). The absence of immature cells, basophilia or monocytosis, increased leukocyte alkaline phosphatase (LAP), and the absence of the bcr/abl translocation distinguishes LR from CML. CNL is a rare, distinct myeloproliferative syndrome with a poor prognosis . The differential diagnosis between LR and CNL may be difficult or even impossible because both conditions share identical morphological features, including a raised LAP score and the absence of the bcr/abl translocation. The current review discusses the different causes of LR, pointing out the difficulties in the differential diagnosis. Moreover, a diagnostic approach to a rational clinical and laboratory evaluation that mainly refers to an isolated LR is proposed.
ETIOLOGY
1. Severe Infections (Most Common Cause)
Leukemoid reactions frequently occur in response to severe or overwhelming infections, especially those causing systemsic inflammation. Mechanism: Excessive release of endogenous cytokines (IL-1, IL-6, TNF-α, G-CSF) leads to rapid bone marrow mobilization of mature and immature granulocytes.
Examples of infections include bacterial infections such as Clostridium difficile colitis, sepsis, pneumonia (especially pneumococcal), tuberculosis, and pyelonephritis, alongside fungal infections like histoplasmosis and disseminated candidiasis. Additionally, severe viral infections such as CMV, EBV, and acute HIV seroconversion may occur, along with parasitic infections including malaria and toxoplasmosis.
2. Severe Inflammation and Tissue Stress
Strong inflammatory stimuli or extensive tissue injury can provoke an intense marrow response, leading to a significant increase in the production and release of blood cells. This reaction is commonly seen in cases of major trauma or severe burns, as well as during episodes of severe hemolysis or acute blood loss. Additionally, conditions such as pancreatitis, rhabdomyolysis, and pregnancy-related complications like eclampsia or HELLP syndrome can serve as powerful triggers. Furthermore, postoperative stress—especially following major abdominal or thoracic surgeries—frequently results in this heightened bone marrow activity as the body attempts to recover and maintain homeostasis.
3. Malignancies (Non-Hematologic)
Many solid tumors secrete colony-stimulating factors (especially G-CSF, GM-CSF) that drive extreme neutrophilic leukocytosis.
Various malignancies can trigger a significant marrow response, with notable examples including lung cancer (particularly squamous cell carcinoma), renal cell carcinoma, hepatocellular carcinoma, melanoma, gastrointestinal cancers, and advanced sarcomas. The underlying mechanism for this response typically involves tumor-related cytokine production or marrow infiltration, both of which can cause reactive granulopoiesis as the body reacts to the presence and spread of the cancer.
4. Asplenia or Functional Hyposplenism
The absence of normal splenic filtration allows for higher circulating leukocyte counts, a phenomenon commonly observed in post-splenectomy patients or those with functional hyposplenism, such as individuals with sickle cell disease or celiac disease. This occurs through a specific physiological mechanism where the spleen’s usual capacity to filter the blood is diminished, leading to a reduced removal of aged or immature granulocytes from the systemic circulation.
DIAGNOSIS
The diagnosis of a leukemoid reaction involves confirming that the marked leukocytosis is reactive and benign, rather than due to a primary hematologic malignancy such as leukemia or CML. Evaluation requires clinical correlation, laboratory testing, and exclusion of neoplastic causes.
1. Clinical Assessment
A careful history and examination provide the first clues toward a diagnosis, with several key clinical pointers helping to differentiate the underlying cause. These include the presence of a triggering condition such as severe infection, inflammation, trauma, malignancy, or specific drug exposure. Additionally, symptoms suggesting a reactive process, such as fever, pain, signs of sepsis, dehydration, or physical stress, can further guide the assessment. Crucially, the absence of leukemia-specific findings often points away from malignancy; this includes the lack of significant splenomegaly, as while mild enlargement may occur, massive splenomegaly is unusual. Furthermore, the absence of constitutional “B-symptoms” without an identifiable underlying cause, as well as the absence of anemia or thrombocytopenia of marrow origin, helps confirm that the process is likely reactive rather than primary bone marrow disease.
2. Complete Blood Count (CBC) with Differential
The Complete Blood Count (CBC) is central to the diagnosis of a leukemoid reaction, with several typical findings helping to characterize the condition. The white blood cell (WBC) count is usually elevated between 30,000 and 50,000/µL, though it can sometimes exceed 50,000/µL, and is characterized by a predominant neutrophilia. A notable feature is the presence of a left shift, which involves an increase in immature cells such as band forms, metamyelocytes, and myelocytes. However, a key distinction from leukemia is that blasts are rare or entirely absent in a reactive process.
3. Peripheral Blood Smear
A vital diagnostic step to differentiate reactive changes from hematologic malignancy is the careful examination of the peripheral blood smear. Characteristic smear features of a leukemoid reaction include mature neutrophils exhibiting toxic granulation, the presence of Döhle bodies, and cytoplasmic vacuolation, all of which indicate a stimulated immune response. Crucially, there is an absence of abnormal or dysplastic cells, and blasts are either entirely absent or extremely uncommon. Additionally, basophilia is usually absent in these cases; the presence of marked basophilia instead suggests Chronic Myeloid Leukemia (CML) rather than a reactive leukemoid process. Together, these specific microscopic findings strongly favor a diagnosis of reactive leukocytosis over a primary bone marrow disorder.
4. Inflammatory and Infectious Workup
Since leukemoid reactions are most commonly caused by infection or inflammation, appropriate laboratory tests are essential to confirm the specific trigger. These tests typically include inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which are usually elevated, as well as procalcitonin levels when a bacterial infection is suspected. Comprehensive diagnostic workups often involve blood, urine, and sputum cultures to identify pathogens, alongside imaging such as chest X-rays or CT scans if there is a suspicion of pneumonia, deep-seated abscesses, or malignancy. Furthermore, depending on the clinical presentation, organ-specific markers—including liver enzymes or amylase and lipase—may be ordered to pinpoint the localized source of the systemic inflammatory response.
TREATMENT
A leukemoid reaction is not a primary hematologic disease; therefore, there is no direct medication to “treat” leukemoid reaction itself. Management focuses on treating the underlying cause, after which the white blood cell (WBC) count normalizes.
1. Antibiotics (for bacterial infections — the most common cause)
If a leukemoid reaction is due to a bacterial infection, the primary treatment is the administration of appropriate antimicrobial therapy. Depending on the clinical situation, common empiric antibiotics may include intravenous Ceftriaxone for broad-spectrum coverage, Piperacillin-tazobactam for severe sepsis or abdominal infections, or Meropenem for resistant and hospital-acquired infections. In cases where MRSA is suspected, Vancomycin is utilized, while Metronidazole is administered either orally or intravenously for anaerobic infections or Clostridium difficile. As the underlying infection successfully improves with these treatments, the white blood cell count will naturally and automatically decrease toward normal levels.
2. Antivirals (if viral infection is the cause)
Antiviral therapy is utilized only when a specific viral pathogen is responsible for triggering the leukemoid reaction. Common examples include oseltamivir for influenza, acyclovir for HSV or VZV infections, and ganciclovir for severe CMV infections. These treatments work by effectively reducing the viral load, which in turn decreases the production of inflammatory cytokines and allows the white blood cell count to return to normal levels.
3. Antifungal Therapy (if fungal infection is the cause)
Antifungal therapy is required when a leukemoid reaction is triggered by a severe fungal infection, a scenario that is relatively rare but occasionally seen in immunocompromised patients. Common pharmacological agents used in these cases include fluconazole, amphotericin B, and voriconazole, with the specific choice of medication depending on the underlying fungal pathogen identified as the cause of the intense inflammatory response.
CONCLUSION
Leukemoid reaction is a transient, exaggerated, and non-malignant elevation of the white blood cell count that mimics leukemia but arises as a physiological response to severe infection, systemic inflammation, stress, drugs, or cytokine-producing tumors.
Accurate diagnosis requires careful correlation of clinical findings with laboratory data, including a differential leukocyte count, peripheral smear evaluation, inflammatory markers, and exclusion of hematologic malignancies through molecular and cytogenetic testing when necessary. The leukocyte alkaline phosphatase (LAP) score and the absence of blasts or basophilia on smear are key features distinguishing it from chronic myeloid leukemia.
Importantly, leukemoid reaction does not require direct hematologic treatment. Management focuses on identifying and treating the underlying precipitating condition, such as infection, inflammation, drug-induced changes, or malignancy. Upon correction of the primary cause, the leukocyte count typically returns to normal, confirming the reactive nature of the process. Early recognition is crucial, as misdiagnosis may lead to unnecessary investigations or inappropriate therapy. Thus, leukemoid reaction should be approached as a marker of severe physiological stress rather than a standalone disease entity, with clinical context guiding both diagnosis and treatment.
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