NeutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation are an important component of the immune systemImmune systemThe body's defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components.Primary Lymphatic Organs and play a significant role in the eradication of infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease. Low numbers of circulating neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation, referred to as neutropenia, predispose the body to recurrent infectionsRecurrent infectionsCommon Variable Immunodeficiency (CVID) or sepsisSepsisSystemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock.Sepsis and Septic Shock, though patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship can also be asymptomatic. Most causes of neutropenia are acquired, including neutropenia that is secondary to infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease, bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis disorders, and/or adverse effects of many drugs. The diagnosis is made using CBC and peripheral blood smears. Management is aimed at preventing and treating infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease.
Neutropenia is a decrease in the number of circulating neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation in the blood, which is typically defined as an absolute neutrophil count (ANC) of:
< 1500 cells/µL in adults and children > 1 year of age:
Mild neutropenia: 1000–1500 cells/µL
Moderate neutropenia: 500–1000 cells/µL
Severe neutropenia: < 500 cells/µL
AgranulocytosisAgranulocytosisA decrease in the number of granulocytes; (basophils; eosinophils; and neutrophils).Lincosamides: < 100–200 cells/µL
< 1000 cells/µL in children 2 weeks to 1 year of age
< 5000 cells/µL in infants during their 1st few days of life
NeutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation
NeutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation are the most common of all the leukocytesLeukocytesWhite blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes).White Myeloid Cells: Histology. LeukocytesLeukocytesWhite blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes).White Myeloid Cells: Histology are WBCs and are a major component of the immune systemImmune systemThe body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components.Primary Lymphatic Organs.
NeutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation respond rapidly to the site of infection.
NeutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation are granulocytic leukocytesLeukocytesWhite blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes).White Myeloid Cells: Histology:
Contain enzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, oxidants, and proteinsProteinsLinear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein.Energy Homeostasis, within 4 types of granules, all of which are formed during neutrophil differentiation:
Azurophil (primary) granules: contain antibacterialAntibacterialPenicillinsproteinsProteinsLinear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein.Energy Homeostasis like myeloperoxidaseMyeloperoxidaseAcute Myeloid Leukemia and CAP37; function primarily within the phagolysosomes
Specific granules: contain antibacterialAntibacterialPenicillinsproteinsProteinsLinear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein.Energy Homeostasis, such as lactoferrin, neutrophil gelatinase–associated lipocalin, cathelicidin, and lysozyme, and proteasesProteasesProteins and Peptides, such as collagenase
Secretory granules: contain transmembrane receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors (e.g., tumorTumorInflammationnecrosisNecrosisThe death of cells in an organ or tissue due to disease, injury or failure of the blood supply.Ischemic Cell Damage factor receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors and interferon-α receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors) that integrate into the plasma membranePlasma membraneA cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules.The Cell: Cell Membrane of neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation as exocytosisExocytosisCellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane.The Cell: Cell Membrane takes place
Can produce neutrophil extracellular traps (NETs):
Made up of networks of extracellular microfibers, mostly composed of DNADNAA deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).DNA Types and Structure from disrupted neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation
NETs bindBINDHyperbilirubinemia of the Newborn and degrade bacteriaBacteriaBacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology and other pathogens.
Other terms:
Often referred to as PMNs
Younger and immature neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation known as “bands” or “stab cells”
Typically reported on a CBC as a percentage of the WBC count
ANC:
The number of neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation (as opposed to the percentage of WBCs) circulating per µL of blood
ANC = WBC cells/µL × percent (segmented neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation + bands)
Example:
WBC = 5600 cells/µL; neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation = 5%; bands = 2%
ANC = 5600 × 7% = 392 cells/µL
Normal ANC levels: vary by age
Table: Normal ANC levels by age
Age group
Normal range (cells/µL)
Percent of WBCs that are neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation
At 1 day of life
5000–21,000
Approximately 60%
At 1 month of life
1000–9000
Approximately 35%
≥ 1 year of age
1500‒8500
Approximately 31%
≥ 10 years of age
1500–8000
Approximately 40%–70%
Scanning electron microscope images at different magnifications to demonstrate neutrophil extracellular traps (NETs): The sections are from Candida albicans–infected mouse lungs 24 hours after intranasal challenge. A: A bronchiole (b) colonized with C. albicans and infiltrated by host immune cells B: High-resolution image of boxed area from panel A shows respiratory epithelium of the bronchiole colonized with C. albicans yeast forms (arrow) and hyphae (arrowhead). C: High-resolution image of boxed area from panel B shows NETs covering fungal surfaces (arrow).
Scale bar in A = 100 µm, in B = 10 µm, and in C = 2 µm
Image: “A scanning electron microscope” by Urban CF et al. License: CC BY 2.5
Wright stain of a peripheral blood smear showing 5 normal, mature neutrophils (polymorphonuclear cells): Note that each neutrophil has a dense nucleus arranged into 2–5 lobes and pale pink-blue cytoplasm. The fine granularity of the cytoplasm can only be appreciated at higher magnification. The life span of neutrophils in the blood is 6–10 hours.
Image: “hematoxylin eosin stain” by Berkshire Community College Bioscience Image Library. License: Public Domain
Clinical significance of neutropenia
The correlationCorrelationDetermination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable.Causality, Validity, and Reliability between ANC and infectious risk applies only to conditions in which the bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis neutrophil reserve is diminished, such as hematologic toxicityToxicityDosage Calculation from chemotherapyChemotherapyOsteosarcoma.
With non–chemotherapy-related mild neutropenia (ANC, 1000–1500 cells/µL), there is no significantly increased risk of infection.
With severe neutropenia (ANC, < 500/µL), there is a significant risk of infection; feverFeverFever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever should be managed on an inpatient basis with parenteral antibiotics, even with few clinical signs of infection.
Epidemiology
PrevalencePrevalenceThe total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time.Measures of Disease Frequency:
1%–10% in healthy, asymptomatic individuals
Higher in those with certain medical conditions:
Autoimmune disorders: systemic lupus erythematosusSystemic lupus erythematosusSystemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected.Systemic Lupus Erythematosus (SLESLESystemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected.Systemic Lupus Erythematosus), rheumatoid arthritisArthritisAcute or chronic inflammation of joints.Osteoarthritis
Connective tissueConnective tissueConnective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix.Connective Tissue: Histology diseases
Varies by ethnicity:
Blacks: 4.5%–10.5%
Whites: 0.79%
Mexican Americans: 0.38%
Neutropenia may occur as an isolated feature or in association with other hematologic abnormalities and/or bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis defects (e.g., megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies.Megaloblastic Anemia or leukemia).
Pathophysiology
Normal physiology review
Mature neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation are produced by precursors in the bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis. NeutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation can be found in three compartments:
Bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis; neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation here can be classified as:
Proliferative: developing
Stored: mature neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation
Blood; neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation here can be classified as:
Circulating
Marginated: adherent to the vascular endotheliumEndotheliumA layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body.Arteries: Histology or located within the spleenSpleenThe spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
Tissues: NeutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation leave the blood randomly after about 6–10 hours to enter the tissues, where they act to destroy pathogens or undergo apoptosisApoptosisA regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.Ischemic Cell Damage.
Mechanisms that lead to neutropenia
Decreased production/differentiation in bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis:
Damaged hematopoietic precursors (e.g., chemotherapyChemotherapyOsteosarcoma, radiationRadiationEmission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles).Osteosarcoma, infection)
Ineffective granulopoiesis (e.g., megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies.Megaloblastic Anemia)
Shift of circulating PMNs to the vascular endotheliumEndotheliumA layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body.Arteries: Histology or spleenSpleenThe spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
Example: endotoxinEndotoxinToxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells.Proteus can cause margination → ↓ circulating neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation (sometimes referred to as pseudoneutropenia)
Neutropenia is most commonly acquired, often after infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease or as a side effect of a number of different medications. Rarely, neutropenia may be “primary” or congenitally inherited as part of a less common syndrome.
Acquired neutropenia: non–drug-induced
InfectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease (most common form of acquired neutropenia):
Viral, including:
CMV
EBVEBVEpstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency.Epstein-Barr Virus
InfluenzaInfluenzaInfluenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza
BacteriaBacteriaBacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, including:
Bacterial sepsisSepsisSystemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock.Sepsis and Septic Shock
TuberculosisTuberculosisTuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
Rickettsial infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease
Parasitic:
ToxoplasmosisToxoplasmosisToxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host’s immune status. Toxoplasma/Toxoplasmosis
MalariaMalariaMalaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis.Plasmodium/Malaria
Hematologic malignancies (typically present with pancytopeniaPancytopeniaDeficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets.Aplastic Anemia):
Bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and HematopoiesissuppressionSuppressionDefense Mechanisms:
Aplastic anemiaAplastic AnemiaAplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia
Ionizing radiationRadiationEmission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles).Osteosarcoma
Malignant infiltration
Medications (see below)
HypersplenismHypersplenismCondition characterized by splenomegaly, some reduction in the number of circulating blood cells in the presence of a normal or hyperactive bone marrow, and the potential for reversal by splenectomy.Splenomegaly
Nutritional causes:
Vitamin B12 or folate deficiencyFolate deficiencyA nutritional condition produced by a deficiency of folic acid in the diet. Many plant and animal tissues contain folic acid, abundant in green leafy vegetables, yeast, liver, and mushrooms but destroyed by long-term cooking. Alcohol interferes with its intermediate metabolism and absorption. Folic acid deficiency may develop in long-term anticonvulsant therapy or with use of oral contraceptives. This deficiency causes anemia, macrocytic anemia, and megaloblastic anemia. It is indistinguishable from vitamin B12 deficiency in peripheral blood and bone marrow findings, but the neurologic lesions seen in B12 deficiency do not occur.Megaloblastic Anemia (megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies.Megaloblastic Anemia; may be seen in alcoholismAlcoholismA primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic.Wernicke Encephalopathy and Korsakoff Syndrome)
CopperCopperA heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55.Trace Elements deficiency
Autoimmune process and/or associated with rheumatologic disorders:
SLESLESystemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected.Systemic Lupus Erythematosus
Granulomatosis with polyangiitisGranulomatosis with PolyangiitisA multisystemic disease of a complex genetic background. It is characterized by inflammation of the blood vessels (vasculitis) leading to damage in any number of organs. The common features include granulomatous inflammation of the respiratory tract and kidneys. Most patients have measurable autoantibodies (antineutrophil cytoplasmic antibodies) against myeloblastin.Granulomatosis with Polyangiitis
Transfusion reactionsTransfusion reactionsTransfusion-related complications occur during or after a blood product is given. These complications can be classified as immunologic, non-immunologic and acute, and delayed. Non-immunologic reactions are caused by the transmission of disease in blood products, and immunologic reactions are antigen-antibody-mediated. Transfusion Reactions
Complement activationComplement ActivationThe sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides.Systemic Lupus Erythematosus:
HemodialysisHemodialysisProcedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys.Crush Syndrome using nonbiocompatible membranes
Acute respiratory distress syndromeAcute Respiratory Distress SyndromeAcute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome (ARDS)
Some medications, including many chemotherapyChemotherapyOsteosarcoma agents, produce predictable dose-dependent myelosuppressionMyelosuppressionOxazolidinones. Many other medications are associated with severe isolated neutropenia (known as idiosyncratic drug reactions (IDRs)), typically occurring within 3 months after starting the medication.
MethotrexateMethotrexateAn antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.Antimetabolite Chemotherapy
CyclophosphamideCyclophosphamidePrecursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.Immunosuppressants
CisplatinCisplatinAn inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These cross links appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the g2 phase of the cell cycle.Alkylating Agents and Platinum, carboplatinCarboplatinAn organoplatinum compound that possesses antineoplastic activity.Alkylating Agents and Platinum
EtoposideEtoposideA semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the g2 and s phases of the cell cycle.Microtubule and Topoisomerase Inhibitors
Doxorubicin
ColchicineColchicineA major alkaloid from colchicum autumnale l. And found also in other colchicum species. Its primary therapeutic use is in the treatment of gout.Gout Drugs
AzathioprineAzathioprineAn immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen.Immunosuppressants
GanciclovirGanciclovirAn acyclovir analog that is a potent inhibitor of the herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from aids-associated cytomegalovirus infections.Antivirals for Herpes Virus
Medications associated with IDR neutropenia (partial list, most common are in bold):
Antibiotics: PenicillinsPenicillinsBeta-lactam antibiotics contain a beta-lactam ring as a part of their chemical structure. Drugs in this class include penicillin G and V, penicillinase-sensitive and penicillinase-resistant penicillins, cephalosporins, carbapenems, and aztreonam. Penicillins (especially penicillinPenicillinRheumatic Fever G), cephalosporinsCephalosporinsCephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with “cef-” or “ceph-.” Cephalosporins, sulfonamidesSulfonamidesA group of compounds that contain the structure so2nh2.Sulfonamides and Trimethoprim, macrolidesMacrolidesMacrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides,vancomycinVancomycinAntibacterial obtained from streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear.Glycopeptides, dapsoneDapsoneA sulfone active against a wide range of bacteria but mainly employed for its actions against Mycobacterium leprae. Its mechanism of action is probably similar to that of the sulfonamides which involves inhibition of folic acid synthesis in susceptible organisms. It is also used with pyrimethamine in the treatment of malaria.Antimycobacterial Drugs
Antimalarials: chloroquineChloroquineThe prototypical antimalarial agent with a mechanism that is not well understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses.Antimalarial Drugs, quinineQuinineAn alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood.Antimalarial Drugs
Antifungals: amphotericin BAmphotericin BMacrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela.Polyenes, flucytosineFlucytosineFlucytosine is a pyrimidine analog that disrupts fungal DNA and RNA synthesis. Flucytosine is always used in combination with other antifungal agents and is primarily used to treat cryptococcal meningitis.Flucytosine, Griseofulvin, and Terbinafine
Antivirals: acyclovirAcyclovirA guanosine analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes.Herpes Zoster (Shingles), oseltamivirOseltamivirAn acetamido cyclohexene that is a structural homolog of sialic acid and inhibits neuraminidase.Antivirals for Influenza, ganciclovirGanciclovirAn acyclovir analog that is a potent inhibitor of the herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from aids-associated cytomegalovirus infections.Antivirals for Herpes Virus
Antiinflammatories: NSAIDsNSAIDSPrimary vs Secondary Headaches, sulfasalazineSulfasalazineA drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid released in the colon.Sulfonamides and Trimethoprim, penicillaminePenicillamine3-mercapto-d-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in wilson’s disease.Wilson Disease
ThionamidesThionamidesOrganic compounds containing the radical -CSNH2.Antithyroid Drugs (thyroidThyroidThe thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck.Thyroid Gland: Anatomy medications): methimazoleMethimazoleA thioureylene antithyroid agent that inhibits the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin. This is done by interfering with the oxidation of iodide ion and iodotyrosyl groups through inhibition of the peroxidase enzyme.Antithyroid Drugs, propylthiouracilPropylthiouracilA thiourea antithyroid agent. Propylthiouracil inhibits the synthesis of thyroxine and inhibits the peripheral conversion of thyroxine to triiodothyronine. It is used in the treatment of hyperthyroidism.Antithyroid Drugs (PTUPTUA thiourea antithyroid agent. Propylthiouracil inhibits the synthesis of thyroxine and inhibits the peripheral conversion of throxine to triiodothyronine. It is used in the treatment of hyperthyroidism.Antithyroid Drugs)
Cardiovascular drugs: ticlopidine, procainamideProcainamideA class ia antiarrhythmic drug that is structurally-related to procaine.Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers), propranololPropranololA widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs.Antiadrenergic Drugs, digoxinDigoxinA cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small.Cardiac Glycosides, ACE inhibitorsACE inhibitorsTruncus Arteriosus, hydralazineHydralazineA direct-acting vasodilator that is used as an antihypertensive agent.Heart Failure and Angina Medication
DiureticsDiureticsAgents that promote the excretion of urine through their effects on kidney function.Heart Failure and Angina Medication: thiazides, acetazolamideAcetazolamideOne of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition.Carbonic Anhydrase Inhibitors, spironolactoneSpironolactoneA potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects.Potassium-sparing Diuretics
Psychotropics: clozapineClozapineA tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2a/2c receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.Second-Generation Antipsychotics, phenothiazines, tricyclic antidepressantsTricyclic antidepressantsTricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain.Tricyclic Antidepressants
Antiepileptics: phenytoinPhenytoinAn anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.First-Generation Anticonvulsant Drugs, carbamazepineCarbamazepineA dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties.First-Generation Anticonvulsant Drugs, valproic acidValproic acidA fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels.First-Generation Anticonvulsant Drugs
Nonmyelosuppressive anticancer agents: rituximabRituximabA murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis.Immunosuppressants, tyrosineTyrosineA non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin.Synthesis of Nonessential Amino Acids kinase inhibitors
PatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with neutropenia will either be asymptomatic, present with infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease, or present with symptoms associated with the underlying cause of their neutropenia.
InfectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease
The primary symptoms related directly to neutropenia involve infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease. Viral infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease may cause neutropenia, while patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with moderate to severe neutropenia are more likely to develop a bacterial or fungal infection. PatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with neutropenia may present with:
Serious infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease with severe neutropenia (ANC < 200 cells/µL):
SepsisSepsisSystemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock.Sepsis and Septic Shock
Life-threatening GI and pulmonary infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease
Most common organisms causing recurrent, opportunistic, and/or serious infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease:
Gram-negative rods:
Escherichia coliEscherichia coliThe gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli
KlebsiellaKlebsiellaKlebsiella are encapsulated gram-negative, lactose-fermenting bacilli. They form pink colonies on MacConkey agar due to lactose fermentation. The main virulence factor is a polysaccharide capsule. Klebsiella pneumoniae is the most important pathogenic species.Klebsiella spp.
Pseudomonas aeruginosaPseudomonas aeruginosaA species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. Aeruginosa is a major agent of nosocomial infection.Pseudomonas
StaphylococcusStaphylococcusStaphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora.Staphylococcusspp.
Streptococcus viridansStreptococcus viridansA large heterogeneous group of mostly alpha-hemolytic streptococci. They colonize the respiratory tract at birth and generally have a low degree of pathogenicity. This group of species includes Streptococcus mitis; Streptococcus mutans; Streptococcus oralis; Streptococcus sanguis; Streptococcus sobrinus; and the Streptococcus milleri group. The latter are often beta-hemolytic and commonly produce invasive pyogenic infections including brain and abdominal abscesses.Brain Abscess
CandidaCandidaCandida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis spp., especially after neutropenic patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship receive treatment with broad-spectrumBroad-SpectrumFluoroquinolones antibiotics
Clinical findings will depend on the location of infection and causative organism and most commonly may include:
FeverFeverFever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
FatigueFatigueThe state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.Fibromyalgia
LymphadenopathyLymphadenopathyLymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
SkinSkinThe skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue.Skin: Structure and Functions findings:
CellulitisCellulitisCellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis, ulcers, and/or abscesses
JaundiceJaundiceJaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice (may suggest liverLiverThe liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease secondary to viral hepatitis)
Lung findings (if pneumoniaPneumoniaPneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.Pneumonia is present):
Cough
DyspneaDyspneaDyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
Dullness to percussionPercussionAct of striking a part with short, sharp blows as an aid in diagnosing the condition beneath the sound obtained.Pulmonary Examination
Note:PatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship are not at increased risk for viral or parasitic infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease, as these infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease are not neutralized by neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation.
Other findings on history and physical exam
May be asymptomatic
History of medications that may cause neutropenia
Symptoms related to the primary cause, for example:
SLESLESystemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected.Systemic Lupus Erythematosus:
BoneBoneBone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and TypespainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
FatigueFatigueThe state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.Fibromyalgia and dyspneaDyspneaDyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea due to concurrent anemiaAnemiaAnemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
Diagnosis
Laboratory studies
CBC with differential:
Determines the severity of neutropenia
Determines whether neutropenia is isolated or associated with other hematologic abnormalities (helps narrow differential diagnosis); examples include:
EosinophiliaEosinophiliaAbnormal increase of eosinophils in the blood, tissues or organs.Autosomal Dominant Hyperimmunoglobulin E Syndrome → drug reactions/allergiesAllergiesA medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder.Selective IgA Deficiency or parasitic infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease
LymphocytosisLymphocytosisWBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Lymphocytosis → leukemias, lymphomas
Megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies.Megaloblastic Anemia → folateFolateFolate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 or vitamin B12 deficiency
Confirm the reduced number of neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation
Hypersegmented neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation → folateFolateFolate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 or vitamin B12 deficiency
Abnormalities consistent with leukemias (e.g., smudge lymphocytesLymphocytesLymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage.Lymphocytes: Histology, hair-like projections, or azurophilic granulesAzurophilic granulesMyeloperoxidase Deficiency)
Erythrocyte sedimentation rateErythrocyte Sedimentation RateSoft Tissue Abscess (ESRESRSoft Tissue Abscess) and CRP: since classic findings of infection or inflammationInflammationInflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation may be inapparent
Other laboratory tests to consider based on history and exam findings:
Blood and urine cultures if febrile
Stool testing if patient has infectious diarrheaDiarrheaDiarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
Testing for rheumatologic causes:
Antinuclear antibodiesAntibodiesImmunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution.Immunoglobulins: Types and Functions
Anti-DNA antibodiesAntibodiesImmunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution.Immunoglobulins: Types and Functions
Complement levels
Screen for nutritional deficiencies:
Serum copperCopperA heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55.Trace Elements
FolateFolateFolate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 and vitamin B12 levels
Genetic testingGenetic TestingDetection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing.Myotonic Dystrophies if congenitalCongenitalChorioretinitis syndromes are suspected
Peripheral blood smear for a patient with systemic lupus erythematosus (SLE) showing a paucity of neutrophils
Image: “Peripheral blood smear” by Melissa Zhao. License: CC BY 4.0
Peripheral blood smear of hypersegmented neutrophils seen in folate or vitamin B12 deficiency
Image: “Hypersegmented Neutrophils (36831145373)” by Ed Uthman. License: CC BY 2.0
Other tests
Other tests to consider based on clinical presentation include:
Chest X-rayX-rayPenetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source.Pulmonary Function Tests to evaluate for infection or malignancyMalignancyHemothorax
Ultrasound or CT of abdomen for liverLiverThe liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and spleenSpleenThe spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy imaging
Management depends on the cause and degree of the neutropenia.
Discontinue causative drugs.
Replete causative vitamin deficiencies (vitamin B12Vitamin B12A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12.Folate and Vitamin B12, folateFolateFolate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12, and/or copperCopperA heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55.Trace Elements).
Monitor ANC on serial CBCs:
For a majority of patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship, the neutropenia will be due to an infection or medication.
Repeat the CBC to ensure resolution of the neutropenia following improvement of infection/discontinuation of offending agents.
If neutropenia persists, further workup is indicated.
InfectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease:
Treat infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease with appropriate agents.
Autoimmune-associated neutropenia: Consider IV immunoglobulinIv ImmunoglobulinDermatomyositis (IVIGIVIGDermatomyositis) and/or steroidsSteroidsA group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus.Benign Liver Tumors if neutropenia is severe and because of their autoimmune condition.
Granulocyte-colony stimulating factors (G-CSFs):
Naturally stimulates neutrophil production
Examples: filgrastimFilgrastimA recombinant granulocyte colony-stimulating factor (G-CSF) that is used in the treatment and prevention of neutropenia, preparation and collection of blood progenitor cells, and for use in peripheral blood stem cell transplantation.Hematopoietic Growth Factors, pegfilgrastimPegfilgrastimHematopoietic Growth Factors
Prophylactic use in chemotherapyChemotherapyOsteosarcomapatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship at risk for neutropenia
Bone marrow transplantationBone marrow transplantationTransfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms.Organ Transplantation: may be curative for children with Kostmann syndromeKostmann syndromeSevere Congenital Neutropenia
Indications for immediate hematology referral:
BlastsBlastsInjuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary contusion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system.Blunt Chest Trauma or other findings suggesting hematologic malignancyMalignancyHemothorax seen on peripheral blood smearPeripheral Blood SmearAnemia: Overview and Types
ANC < 200
PancytopeniaPancytopeniaDeficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets.Aplastic Anemia
Management of neutropenic feverNeutropenic feverNeutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy.Neutropenic Fever in cancer patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship
Neutropenic feverNeutropenic feverNeutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy.Neutropenic Fever is the most common life-threatening complication of cancer therapy.
Empirical antibiotic therapy on presentation is imperative to improve outcomes and decrease mortalityMortalityAll deaths reported in a given population.Measures of Health Status.
A causative organism is identified only ⅓ of the time, and therefore antibiotics are aimed at treating a broad spectrumBroad SpectrumMacrolides and Ketolides of expected pathogens.
Prophylactic antibiotics and growth factor support at the onset of neutropenia have been shown to benefit only a small subgroup of high-risk cancer patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship receiving chemotherapyChemotherapyOsteosarcoma.
Differential Diagnosis of Primary Neutropenias
BenignBenignFibroadenoma familial (ethnic) neutropenia: inherited cause of mild to moderate neutropenia, most commonly seen in individuals of African descent. These patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship may not generate leukocytosisLeukocytosisA transient increase in the number of leukocytes in a body fluid.West Nile Virus during infection but their presentation is otherwise normal. They do generate a feverFeverFever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and tachycardiaTachycardiaAbnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia.Sepsis in Children during infection (similar to controls), do not have an increased incidenceIncidenceThe number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time.Measures of Disease Frequency of infection, and do not have an increased risk for febrile neutropeniaFebrile neutropeniaFever accompanied by a significant reduction in the number of neutrophils.Neutropenic Fever secondary to myelosuppressive therapy. The bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis reserves of these patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship are normal.
Hereditary neutropenia/congenital neutropeniaCongenital neutropeniaSevere Congenital Neutropenia: condition resulting from mutations in 1 of several genesGenesA category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.DNA Types and Structure, typically inherited in an autosomal dominantAutosomal dominantAutosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance fashion and often leading to severe neutropenia. This condition is more common in infants and young children. The symptoms include mouth sores, frequent feverFeverFever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, pneumoniaPneumoniaPneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.Pneumonia, ear infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease, and rectal sores. If the condition is not treated immediately, a child may begin losing teethTeethNormally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement.Teeth: Anatomy as a result of severe gum infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease.
Kostmann syndromeKostmann syndromeSevere Congenital Neutropenia: inherited cause of severe congenital neutropeniaCongenital neutropeniaSevere Congenital Neutropenia (ANC is often < 200). It is inherited in an autosomal recessiveAutosomal recessiveAutosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited.Autosomal Recessive and Autosomal Dominant Inheritance pattern, though the causative genesGenesA category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.DNA Types and Structure are unknown. Kostmann syndromeKostmann syndromeSevere Congenital Neutropenia is an aggressive condition in which patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship are unable to effectively make neutrophilsNeutrophilsGranular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Innate Immunity: Phagocytes and Antigen Presentation. PatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship typically get very sick and may require bone marrow transplantationBone marrow transplantationTransfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms.Organ Transplantation, which is curative.
Cyclic neutropeniaCyclic neutropeniaSevere Congenital Neutropenia:autosomal dominantAutosomal dominantAutosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance cause of episodic neutropenia in both children and adults. Episodes occur approximately every 3 weeks (range, 12–35 days) and continue for 3–6 days in a single cycle. The symptoms include feverFeverFever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, infectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease, and ulcers. Many children improve after pubertyPubertyPuberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems.Puberty.
Shwachman-Diamond syndrome: very rare syndrome presenting in infancy, inherited in an autosomal recessiveAutosomal recessiveAutosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited.Autosomal Recessive and Autosomal Dominant Inheritance pattern. The syndrome is characterized by pancreatic insufficiency, metaphyseal dysostosis (flaring at the ends of long bonesLong bonesLength greater than width.Bones: Structure and Types with constriction and sclerosisSclerosisA pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve.Wilms Tumor of the diaphysisDiaphysisThe shaft of long bones.Bones: Structure and Types), growth retardationGrowth RetardationFailure of a fetus to attain expected growth.Fetal Alcohol Spectrum Disorder, and neutropenia with or without anemiaAnemiaAnemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types or thrombocytopeniaThrombocytopeniaThrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia.