Neutrophilia

Introduction:

• It is condition in which absolute neutrophil count is more than 7000/cmm in adults

Causes

• Increased production
  • Hereditary neutrophilia (Mutation of CSF3R gene which leads to constitutive activation of G-CSF receptor)
  • Trisomy 13 or 18
  • Chronic idiopathic neutrophilia
  • Inflammation- Burns, trauma, RA, osteomyelitis, Gout, IBD
  • Tissue necrosis- MI, PE, hepatic necrosis
  • Infections- Bacterial and fungal infections.
  • Viral- Acute phase of measles, chicken pox, infectious mononucleosis
  • Acute hemolysis/ hemorrhage
  • Malignancies elaborating G-CSF- Gastric, bronchogenic, breast, hepatic, pancreatic, uterine, Hodgkin's disease
  • Hematological malignancy- CML, CNL, CMML, PV, HL
  • Drugs- Corticosteroids, lithium, G-CSF, Beta agonists, minocycline
  • Ethylene glycol exposure
  • Sweet syndrome
  • Cigarette smoking
  • Cardiopulmonary bypass
  • Downs syndrome
  • Obesity
  • Recovery from neutropenia
  • Third trimester of pregnancy
  • Anorexia
  • Intoxications- Uremia, diabetic ketoacidosis, eclampsia, poisoning
  • Chronic idiopathic neutrophilia
• Decreased circulatory egress.
  • Drugs- Ex-Glucocorticoids
  • Neutrophil cell membrane defect- Deficiency of CD 11a/CD18
• Maldistribution of neutrophils.
  • Pseudoneutrophilia (Vigorous exercise, emotional stress etc).
  • Post splenectomy

Neutropenia

Introduction:

• It is condition in which absolute neutrophil count is less than 1500/cmm.
• Agranulocytosis is a condition in which ANC is less than 100/cmm.
• Neutropenia can be a part of pancytopenia, which has been discussed separately.
• It is a medical emergency, as without prompt treatment, mortality due to septicemia is high.

Causes of isolated neutropenia

• Decreased production
  • Congenital
    • Kostman syndrome and related disorders.
    • Reticular dysgenesis (Congenital aleukocytosis)
    • Neutropenia and exocrine pancreas dysfunction (Shwachman-Diamond syndrome)
    • Neutropenia and immunoglobulin abnormality (Ex: Hyper IgM syndrome)
    • Neutropenia and disordered cellular immunity (Ex: Cartilage hair hypoplasia)
    • Neutropenia with mental retardation (Cohen syndrome)
    • X-Linked cardio skeletal myopathy and neutropenia (Barth syndrome)
    • Myelokathexis/ /neutropenia with tetraploid leukocytes
    • Warts, hypogammaglobulinemia, infection, myelokathexis (WHIM) syndrome
    • Neonatal neutropenia in maternal hypertension
    • Griscelli syndrome
    • Chediak- Higashi syndrome
    • Glycogen storage disease
    • Hermansky Pudlak syndrome
    • Wiskott Aldrich syndrome
  • Cyclic neutropenia
  • Maturation arrest (Ineffective neutropoiesis)- Precursors of neutrophils are found in bone marrow but they do not mature to form neutrophils: Ex: MDS. Myelokathexis, Congenitalneutropenia
  • Pure white cell aplasia
  • Neutropenia associated with metabolic disorders- Droticaciduria, Methylmalonicaciduria, Glycogen storage disease-type I b.
  • Drug induced neutropenia (Through dose related toxicity or idiosyncratic reaction):
    • Cancer chemotherapies including TKIs
    • Antibiotics: Ampicillin, cefotazime, cefuroxime, flucytosine, fusidic acid, imipenum-cilastatin, nafcillin, oxacillin,ticarcillin, dapsone,Chloramphenicol,   Sulphonamides, Co-trimoxazole, quinine
    • Antifungal: Amphotericin B, Flucytosine
    • Antiviral: Oseltamivir, Gancyclovir, Acyclovir
    • Antimalarials: pyrimethamine, dapsone, sulfadoxine, chloroquine, amodiaquine, quinine
    • Anti-convulsants: Diphenyl hydantoin, Phenytoin, ethosuximide, carbamazepine, valproate
    • Anti-inflammatory agents: Naproxen, Aminopyrin, Aspirin, Phenylbutazone, Leflunomide, Oxyphenbutazone, Indomethacin, Ibufen, Gold salts, sulfasalzine
    • Anti-thyroid drugs:  Propylthiouracil, Carbimazole, methimazole
    • Psychotropic agents:  All phenothiazines, but particularly, Cholrpromazine, Dosulepin, Amitriptaline, mianserin, Promazine, Prochlorperazine, Clozapine, Fluoxitine
    • Sedatives:  Chlordiazepoxide, Diazepam, Imipramine
    • Cardiovascular drugs- Clopidogrel, disopyramide, methyldopa, procainamide, flecainide, quinidine, spironolactone, dipyridamole, captopril, analapril, nifedipine, ticlopidine
    • Diuretics: Thaizides, Acetazolamide, Furosemide, Spironolactone
    • Others:  Deferiprone, Benzene, Phenindione, amygdalin, calcium dobesilate, infliximab, levamisole, metoclopramide, rituximab, chlorpropamide, zidovudine, ranitidine, famotidine, Chlorpheniramine, Deferiprone
  • Chronic idiopathic neutropenia
  • Genetic causes of benign neutropenia (Considered as normal. They are n ot associated with increased risk of infection.)
    • Duffy-null associated neutrophil count (benign ethnic neutropenia)- mild/moderate neutropenia in individuals of African descent. Associated with single nucleotide polymorphism of ACKR1gene.
    • Single nucleotide polymorphism of CXCL2/CXCR2 gene.
    • Single nucleotide polymorphism of TCIRG1gene
  • Familial neutropenia
  • Nutritional deficiency: Vitamin B12, folate, copper
  • Alcoholism
  • Bone marrow failure: aplastic anemia, leukemias, myelodysplastic syndrome etc
  • T/B Immunodeficiency, HIV
• Accelerated neutrophil destruction
  • Alloimmune neonatal neutropenia.
  • Autoimmune neutropenia- Idiopathic (autoimmune neutropenia), Drug induced, Feltry syndrome, SLE, RA, Other autoimmune diseases
  • Immune mediated destruction- LGL leukemia, thymoma
  • Acute bacterial infections-
    • Alcoholic patient with pneumococcal pneumonia (Alcohol suppresses bone marrow and pneumonia consumes available neutrophil supply)
    • Typhoid fever
    • Shigella enteritis
    • Tularemia
    • Brucellosis
    • Whooping cough
    • Gram negative sepsis
    • Tuberculosis.
  • Viral infections- Infections mononucleosis, infections hepatitis, HIV, COVID-19, Dengue, measles, CMV, hepatitis viruses, Rubella, Dengue, varicella, human herpesvirus 6.
  • Parasites- Bartonellosis, malaria, kala-azar
  • Fungal- Histoplasmosis
  • Rickettsia- Enrlichiosis, rickettsialpox, human granulocytic anaplasmosis, Rocky Mountain spotted fever
• Mal distribution of neutrophils
  • Pseudoneutropenia
  • Hemodialysis (Activation of plasma complement pathway by dialyzer cellophane membranes which leads to excessive generation of C5a causing reversible neutrophil aggregates. Similar mechanism seen with leukapharesis, cardiopulmonary bypass surgery)
  • Filtration leukapheresis
  • Acute respiratory distress syndrome

Clinical manifestations

• High fever,chills
• Gingivitis
• Necrotizing painful oral ulcers (Agranulocytic angina)
• Abdominal pain due to intestinal mucosal ulcertaions
• Prostration due to sepsis which can lead to headache, stupor, coma
• Signs of infection such as purulence may be less evident (But fever, pain, tenderness erythema are present)

Grading based on ANC:

• Mild- 1000-1500/cmm
• Moderate- 500- 1000/cmm
• Severe-  <500/cmm
• Agranulocytosis- <200/cmm

Investigations:

• Complete hemogram including peripheral smear
• ESR, CRP
• Serum B12 assay, Copper, ceruloplasmin
• Bone marrow aspiration and biopsy
• Bone marrow cytogenetics
• Serum copper assay
• Serum zinc level
• Flow cytometry if NHL/ T-LGL is suspected
• Anti neutrophils antibodies
• RA factor.
• HIV, EBV serology
• Serial CBC (For cyclic neutropenia)
• ANA, Anti DS DNA, C3, C4
• Test for PNH
• NGS for congenital immunodeficiency

Management:

• Refer to "Febrile neutropenia chapter" in emergencies and supportive care section