Leukocytosis and eosinophilia: an approach

Neutropenia is a reduced absolute neutrophil count that raises infection risk sharply once the count falls below 500/microL, most often from chemotherapy or another marrow-suppressing or idiosyncratic drug. Diagnosis rests on a repeat CBC with differential and smear review followed by a directed search for cause, and management centers on stopping the offending agent, treating any underlying disease, and using G-CSF and neutropenic precautions when the count is low or the patient is febrile.

Chronic myeloid leukemia is a myeloproliferative neoplasm driven by the Philadelphia chromosome t(9;22), which produces the constitutively active BCR-ABL1 tyrosine kinase and marked, left-shifted granulocytosis with a low leukocyte alkaline phosphatase score. Diagnosis is confirmed by cytogenetics or molecular testing for BCR-ABL1, and a BCR-ABL tyrosine kinase inhibitor such as imatinib is first-line, continued indefinitely with molecular-response monitoring, reserving allogeneic transplant for TKI failure or blast crisis.

Essential thrombocythemia is a clonal myeloproliferative neoplasm driven by Janus kinase 2 (JAK2), calreticulin (CALR), or MPL mutations that produces a sustained platelet count above 450x10^9/L. Diagnosis rests on marrow megakaryocytic hyperplasia after excluding reactive thrombocytosis and other myeloproliferative neoplasms. High-risk patients are treated with low-dose aspirin plus hydroxyurea cytoreduction.

Polycythemia (erythrocytosis) is a true increase in red cell mass that must be sorted into primary polycythemia vera, a JAK2-mutated myeloproliferative neoplasm with a low erythropoietin level, versus secondary erythrocytosis driven by hypoxia or ectopic erythropoietin, versus relative erythrocytosis from plasma volume contraction. Diagnosis rests on the hemoglobin threshold plus JAK2 V617F testing and a serum erythropoietin level, and management of polycythemia vera centers on therapeutic phlebotomy to a hematocrit target below 45%, low-dose aspirin, and cytoreduction in higher-risk patients.

Primary myelofibrosis is a BCR-ABL-negative myeloproliferative neoplasm driven by JAK2, CALR, or MPL mutations that produces marrow fibrosis, extramedullary hematopoiesis, massive splenomegaly, and a leukoerythroblastic smear with teardrop cells. Diagnosis rests on bone marrow biopsy showing fibrosis with a clonal marker or exclusion of reactive causes, and management is risk-stratified with the JAK inhibitor ruxolitinib for symptomatic disease and allogeneic transplant as the only cure.

Myelodysplastic syndromes are clonal stem cell disorders producing ineffective hematopoiesis: a dysplastic, usually hypercellular bone marrow with peripheral cytopenias and a variable risk of transformation to acute myeloid leukemia. Diagnosis requires bone marrow biopsy showing dysplasia after excluding reversible mimics, risk is stratified with the IPSS-R, and treatment ranges from supportive transfusions and lenalidomide in lower-risk disease to hypomethylating agents and allogeneic transplant, the only cure, in higher-risk disease.

Acute myeloid leukemia is a clonal proliferation of myeloid precursors that fails to differentiate, defined by myeloblasts at or above 20% of the bone marrow or blood, and it presents with cytopenias from marrow replacement plus, in acute promyelocytic leukemia, a coagulopathic emergency. Diagnosis rests on marrow blast count, immunophenotype, and cytogenetic and molecular testing that set both classification and risk, while treatment is intensive induction chemotherapy or ATRA-arsenic trioxide for APL, followed by risk-adapted consolidation.

Eosinophilic granulomatosis with polyangiitis (EGPA) is the rarest antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, defined by a three-phase course of late-onset asthma and rhinosinusitis, then peripheral and tissue eosinophilia, then small- and medium-vessel vasculitis with mononeuritis multiplex. ANCA is positive in only 40 to 60 percent of patients, cardiac involvement drives most mortality, and treatment is glucocorticoids alone for non-organ-threatening disease, glucocorticoids plus cyclophosphamide or rituximab for organ-threatening disease, and mepolizumab as steroid-sparing therapy.

Eosinophilic pneumonia is eosinophil-driven lung injury presenting as two distinct syndromes, acute eosinophilic pneumonia causing rapid hypoxemic respiratory failure and chronic eosinophilic pneumonia causing weeks to months of relapsing symptoms, both confirmed by bronchoalveolar lavage eosinophilia and both dramatically responsive to corticosteroids.

Eosinophilic fasciitis is a rare inflammatory disorder of the deep fascia that mimics systemic sclerosis with symmetric woody induration and peau d'orange skin of the extremities, but classically spares the fingers and face and lacks Raynaud phenomenon, nailfold capillary changes, and scleroderma-specific autoantibodies. Peripheral eosinophilia and a full-thickness skin-to-fascia biopsy establish the diagnosis. First-line treatment is high-dose prednisone, with methotrexate added as a steroid-sparing agent for an inadequate response.

DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is a severe delayed drug hypersensitivity presenting 2 to 6 weeks after the culprit drug with fever, a morbilliform rash with facial edema, lymphadenopathy, eosinophilia, and internal-organ involvement, especially hepatitis. Diagnosis uses the RegiSCAR criteria, and treatment is immediate drug withdrawal and systemic corticosteroids with a slow taper.

Strongyloides stercoralis is a soil-transmitted nematode uniquely capable of autoinfection, so it can persist for decades and, in a host started on glucocorticoids or otherwise immunosuppressed, progress to hyperinfection with gram-negative bacteremia; diagnosis is by stool larvae or serology and treatment is ivermectin.

Trichinellosis is infection with Trichinella spiralis larvae acquired from undercooked meat, especially pork or wild game, producing an initial intestinal illness followed by larval encystment in striated muscle causing myositis, periorbital edema, and eosinophilia. Diagnosis rests on eosinophilia and elevated creatine kinase confirmed by serology or muscle biopsy, and treatment combines an antihelminthic with corticosteroids for severe systemic disease.

Toxocariasis is human infection with the dog or cat roundworm Toxocara canis or Toxocara cati, acquired by ingesting embryonated eggs, producing visceral larva migrans with hepatic, pulmonary, and eosinophilic disease or ocular larva migrans mimicking retinoblastoma. Diagnosis rests on compatible exposure and clinical findings plus Toxocara-specific serology, and treatment combines an antihelminthic with corticosteroids for organ-threatening inflammation.

Fever of unknown origin is a defined clinical syndrome, not a single diagnosis, in which fever of at least 38.3C persists for weeks despite an appropriate initial evaluation. Management is a staged, ordered search across infectious, malignant, rheumatologic, and miscellaneous causes, followed by treatment of whatever is found.