Hematology

Leukocyte Disorders

Benign Leukocyte Disorders and Reactive Blood Patterns

Absolute leukocyte counts, the differential, cell maturity, and blood-film morphology guide interpretation. Marrow release, redistribution between circulating and marginated pools, altered cell survival, infection, inflammation, medication effects, and specimen aging can change the result. Persistent unexplained findings, blasts, or a uniform abnormal population require targeted evaluation for a clonal disorder.1,2

Absolute counts and reference intervals

A relative differential divides a fixed total among the leukocyte lines. An absolute count shows the measured concentration of each line and prevents a change in one population from being mistaken for a change in another. The ASCP BOC examination reference ranges provide composite values for examination review. Patient interpretation uses the reporting laboratory’s verified interval for the patient’s age and population.3,4

Common teaching thresholds help describe a pattern. Patient interpretation still uses the local interval:

Cell lineIncreased absolute countDecreased absolute count
NeutrophilsAdult neutrophilia is often taught as an absolute neutrophil count (ANC) above about 7.0 × 109/L. Demargination produces a rapid mature neutrophilia; infection, inflammation, tissue injury, corticosteroids, and growth-factor exposure are other causes.Severe neutropenia is an ANC below 0.5 × 109/L. Infection risk depends on depth, duration, mucosal integrity, marrow reserve, and the clinical setting. Prolonged severe neutropenia carries the greatest risk.
EosinophilsAn absolute eosinophil count of at least 0.5 × 109/L is a common definition of eosinophilia. Persistent counts of at least 1.5 × 109/L meet the quantitative definition of hypereosinophilia. Helminth infection, atopy, drug reactions, and clonal disorders are major categories.A low or zero result has little meaning in isolation. Corticosteroids and acute stress can lower the count.
BasophilsPersistent basophilia can accompany hypersensitivity, chronic inflammation, and myeloid neoplasia. The magnitude, duration, other CBC findings, and film determine the next test.A low count usually has little independent diagnostic value.
MonocytesMonocytosis occurs during recovery from marrow suppression or acute infection and with chronic infection, inflammatory disease, tissue injury, and neoplasia. Persistent unexplained monocytosis requires evaluation for a clonal process.Monocytopenia can accompany marrow suppression, corticosteroid exposure, severe infection, or hemodialysis.
LymphocytesAdult lymphocytosis is commonly taught as an absolute lymphocyte count above 5.0 × 109/L. Pediatric upper limits are higher and change rapidly through infancy and childhood.Adult lymphocytopenia is commonly taught as a count below 1.0 × 109/L. Pediatric lower limits are age-specific. Infection, immune deficiency, systemic disease, and cytotoxic or immunosuppressive treatment are common settings.

Current consensus definitions support the severe-neutropenia and eosinophilia thresholds shown here.5,6

Age-partitioned pediatric intervals are especially important during the neonatal period and early childhood. A single child cutoff can misclassify a normal developmental count.4

The Duffy-null erythrocyte phenotype caused by ACKR1 variation is associated with a lower baseline ANC without increased infection risk. Race is an unreliable substitute for phenotype or genotype. A 2026 multinational study found a central 95% adult ANC interval of 1.21 to 5.39 × 109/L in its United States Duffy-null cohort, with variation among study sites. These values support phenotype-aware intervals. Each laboratory establishes its own interval. A falling count, symptoms, other cytopenias, or discordant clinical findings still require investigation.7,8

Left shift and marked reactive leukocytosis

A left shift is an increase in immature neutrophil-lineage cells in blood, usually bands and sometimes metamyelocytes, myelocytes, or promyelocytes. It can occur with neutrophilia, a normal ANC, or neutropenia. Report immature stages by name. CLSI H20 separates bands and segmented neutrophils in its reference visual differential and recognizes that some instruments combine them. The laboratory should document which cells its ANC includes so serial results remain comparable.2,9

Worked ANC. A CBC has a WBC count of 10.0 × 109/L, 55% segmented neutrophils, 4% bands, 2% metamyelocytes, and 1% myelocytes. Under an ANC definition that includes segmented neutrophils and bands, the ANC is (0.55 + 0.04) × 10.0 = 5.9 × 10⁹/L. Metamyelocytes and myelocytes are reported separately.

A leukemoid reaction is marked reactive neutrophilic leukocytosis, traditionally a WBC count above 50 × 109/L with a left shift. This threshold is an operational convention. Severe infection or inflammation, metabolic stress, growth-factor exposure, and cytokine-secreting tumors can produce the pattern. The blood film and clinical setting guide testing for chronic myeloid leukemia (CML) and other myeloid neoplasms.1,10

FindingLeukemoid reaction patternCML pattern
Neutrophil morphologyToxic granulation, Döhle bodies, and vacuoles may accompany a left shiftA broad granulocytic maturation spectrum is typical; dysplastic forms can occur
Basophils and eosinophilsUsually lack the persistent combined increase typical of CMLBasophilia is characteristic; eosinophils can also increase
Hemoglobin and plateletsResults follow the underlying illness and can be normal or abnormalAnemia and thrombocytosis or abnormal platelet morphology can support the pattern
Leukocyte alkaline phosphatase (LAP)Usually increasedOften decreased in untreated disease
Defining studyReactive cause established and clonal testing selected when indicatedBCR::ABL1 fusion demonstrated by a validated molecular or cytogenetic method

CML diagnosis requires a BCR::ABL1 result interpreted in the full clinicopathologic setting.11

LAP scoring is now mainly a historical cytochemistry exercise. One hundred bands and segmented neutrophils are graded from 0 to 4+, and the score is the sum of each grade multiplied by the number of cells at that grade. A count with 18 cells at 4+, 28 at 3+, 32 at 2+, 14 at 1+, and 8 at 0 gives (18 × 4) + (28 × 3) + (32 × 2) + (14 × 1) = 234. Interpret any score with the laboratory’s own interval. LAP can support a reactive pattern. Molecular testing carries the diagnostic decision for CML.10,12

A leukoerythroblastic blood film contains immature myeloid cells together with nucleated red cells; that combination alone defines the pattern. Anemia, neutrophilia, and teardrop cells may accompany it, and prominent teardrop cells strongly support marrow fibrosis or infiltration. Marrow infiltration or fibrosis, severe infection, shock or trauma, brisk hemolysis, and recovery from marrow suppression are recognized settings. The hypoproliferative anemia topic explains the myelophthisic pattern in marrow replacement.13

Reactive neutrophil morphology

Reactive morphology provides evidence of accelerated production, cell activation, phagocytosis, or degeneration. Each finding is nonspecific and should agree with the specimen age, CBC, analyzer flags, and clinical setting.9,14

ChangeBlood-film appearanceInterpretation
Toxic granulationCoarse dark blue-purple cytoplasmic granulesCommon with infection, inflammation, tissue injury, and granulocyte colony-stimulating factor exposure
Döhle bodiesPale blue-gray inclusions near the cytoplasmic edgeAggregates of rough endoplasmic reticulum associated with infection, inflammation, burns, pregnancy, and growth-factor exposure
Cytoplasmic vacuolesSmall pinholes or larger clear spaces; organisms may be visible in phagocytic vacuolesSupports activation or phagocytosis when fresh; prolonged EDTA exposure and alcohol toxicity can produce similar vacuolation
PyknosisDense, shrunken chromatin with nuclear filaments between lobes still visibleDegenerative change that can precede cell death
Nuclear fragmentation (necrobiosis)Rounded nuclear fragments without filaments or recognizable chromatin patternCell death; numerous affected cells should prompt review of collection time and film-preparation delay
Variable neutrophil sizeMarked size variation within the same filmCan accompany activated-cell swelling or slide adhesion and has limited value alone
Three schematic blood-film panels show a reactive neutrophil with coarse granules, a pale blue Döhle body, and vacuoles; a large reactive lymphocyte with abundant blue cytoplasm molded around red cells; and a degenerating neutrophil with dense nuclear fragments and vacuoles.
Reactive and degenerative changes can overlap on one film. Specimen age, population pattern, and the CBC determine their significance.

During the first week of ehrlichiosis or anaplasmosis, a film may show purple intracytoplasmic microcolonies called morulae. Anaplasma phagocytophilum favors granulocytes, Ehrlichia chaffeensis favors monocytes, and Ehrlichia ewingii favors granulocytes. Morulae are a rapid presumptive clue with low sensitivity, and the infected cell type leaves species identification unresolved. Leukopenia and thrombocytopenia commonly accompany these infections. The vector-borne blood isolate topic covers specimen choice, PCR, serology, and reporting.15

Reactive lymphocyte patterns

Reactive lymphocytosis commonly accompanies viral infection, including Epstein-Barr virus (EBV), cytomegalovirus, hepatitis viruses, and acute HIV. Pertussis and selected other infections, drug reactions, vaccination, endocrine disease, and acute physiologic stress can also raise the absolute count. Lymphocytopenia occurs with infection, immune deficiency, systemic illness, marrow failure, and immunosuppressive or cytotoxic treatment. The absolute count, patient age, duration, and film pattern determine the next step.1,4

ICSH recommends reactive lymphocyte when morphology supports a benign stimulus and abnormal lymphocyte with a description when a clonal process is suspected. The older terms atypical, variant, Downey cell, Türk cell, and immunoblast are historical and inconsistent. Morphology guides follow-up; flow cytometry or another clonality study establishes clonality.9

Population patternTypical featuresLaboratory action
ReactiveHeterogeneous cell size, nuclear shape, chromatin density, nucleoli, and cytoplasmic basophilia; abundant cytoplasm can mold around adjacent red cellsCorrelate with the clinical setting and targeted infectious or drug testing
Persistent uniform abnormal populationSimilar cells repeated across the film, sometimes with a disease-associated morphologyReview prior counts and analyzer flags; select flow cytometry or hematopathology review according to laboratory policy
Blasts or blast-like cellsHigh nucleus-to-cytoplasm ratio, fine chromatin, and nucleoli, with variable size and cytoplasmUrgent confirmation and escalation under the laboratory’s critical or urgent-review procedure

A plasmacytoid lymphocyte is a reactive form with eccentric nuclear placement and deeply basophilic cytoplasm. Numerous plasmacytoid forms or circulating plasma cells require correlation and possible immunophenotyping because reactive and clonal processes can share this appearance.

Infectious mononucleosis

EBV infects B lymphocytes through interactions that include viral gp350/220 binding to CD21. The large reactive lymphocytes in infectious mononucleosis are mainly activated EBV-specific CD8-positive T cells responding to infected B cells, with contributions from NK and CD4-positive T cells. The CBC commonly shows absolute lymphocytosis with a heterogeneous reactive population. Mild thrombocytopenia and increased aminotransferases can accompany the pattern.1,16

Test or patternInterpretation
Heterophile antibodyCan support a typical mononucleosis syndrome. False-positive and false-negative results occur, and young children often remain negative. CDC advises against Monospot testing for general use.
Viral capsid antigen (VCA) IgMAppears early and usually disappears within 4 to 6 weeks. VCA IgM with absent EBV nuclear antigen antibody supports primary infection.
VCA IgGAppears during the acute phase, peaks within several weeks, and then persists for life. It requires VCA IgM and EBNA context.
EBV nuclear antigen (EBNA) antibodyStandard immunofluorescence detects it after the acute phase, commonly 2 to 4 months after symptom onset. VCA IgG and EBNA antibodies with absent VCA IgM support past infection.

The serologic timing, persistence, and pattern interpretations in this table follow CDC guidance.17

More than 90% of adults have evidence of past EBV infection. A high VCA IgG concentration occurs in acute and past infection and leaves illness timing unresolved. Cytomegalovirus and other infections can produce a similar heterophile-negative mononucleosis pattern. Test selection and interpretation should follow the clinical presentation and the assay’s instructions.17

References

  1. Keohane EM, Preston MM, Mirza KM, Walenga JM, eds. Rodak's Hematology: Clinical Principles and Applications. 7th ed. Elsevier; 2025. Accessed August 29, 2026.
  2. Clinical and Laboratory Standards Institute. Reference Leukocyte Differential Count (Proportional) and Evaluation of Instrumental Methods. 3rd ed. CLSI standard H20. Published April 29, 2026. Accessed August 29, 2026.
  3. Electronic Code of Federal Regulations. 42 CFR §493.1253: Standard: establishment and verification of performance specifications. Accessed August 29, 2026.
  4. Bohn MK, Wilson S, Steele S, Adeli K. Comprehensive pediatric reference intervals for 79 hematology markers in the CALIPER cohort of healthy children and adolescents. Int J Lab Hematol. 2023;45(4):469-480. doi:10.1111/ijlh.14068.
  5. Fioredda F, Skokowa J, Tamary H, et al. The European guidelines on diagnosis and management of neutropenia in adults and children: a consensus between the European Hematology Association and the EuNet-INNOCHRON COST Action. HemaSphere. 2023;7(4):e872. doi:10.1097/HS9.0000000000000872.
  6. Wang SA, Orazi A, Gotlib J, et al. The international consensus classification of eosinophilic disorders and systemic mastocytosis. Am J Hematol. 2023;98(8):1286-1306. doi:10.1002/ajh.26966.
  7. Hibbs SP, Chipare I, Halawani AJ, et al. Multinational assessment of absolute neutrophil counts and white blood cell counts among healthy Duffy-null adults. Blood. 2026;147(3):290-298. doi:10.1182/blood.2025029359.
  8. Palmblad J, Sohlberg E, Nilsson CC, et al. Clinical and immunological features in ACKR1/DARC-associated neutropenia. Blood Adv. 2024;8(3):571-580. doi:10.1182/bloodadvances.2023010400.
  9. Palmer L, Briggs C, McFadden S, et al. ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features. Int J Lab Hematol. 2015;37(3):287-303. doi:10.1111/ijlh.12327.
  10. Abukhiran IA, Jasser J, Syrbu S. Paraneoplastic leukemoid reactions induced by cytokine-secreting tumours. J Clin Pathol. 2020;73(6):310-313. doi:10.1136/jclinpath-2019-206340.
  11. Apperley JF, Milojkovic D, Cross NCP, et al. 2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Leukemia. 2025;39(8):1797-1813. doi:10.1038/s41375-025-02664-w.
  12. American Society of Hematology. Leukocyte alkaline phosphatase scoring. ASH Image Bank. Published September 28, 2011. Accessed August 29, 2026.
  13. Tabares Calvache E, Tabares Calvache AD, Faulhaber GAM. Systematic review about etiologic association to the leukoerythroblastic reaction. Int J Lab Hematol. 2020;42(5):495-500. doi:10.1111/ijlh.13238.
  14. College of American Pathologists. 2025 Hematology, Clinical Microscopy, and Body Fluids Glossary. 2025. Accessed August 29, 2026.
  15. Biggs HM, Behravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis, United States. MMWR Recomm Rep. 2016;65(RR-2):1-44. doi:10.15585/mmwr.rr6502a1.
  16. Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: biology and clinical disease. Cell. 2022;185(20):3652-3670. doi:10.1016/j.cell.2022.08.026.
  17. Centers for Disease Control and Prevention. Laboratory testing for Epstein-Barr virus (EBV). Updated April 10, 2024. Accessed August 29, 2026.