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BHS Educational Course 2012 Leukopenia & Leukocytosis

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10 November 2012 …

10 November 2012
Belgium

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  • Zoals altijd moet deze gesteld worden uitgaande van anamnese, gaande naar het fysisch onderzoek en rekening houdend met laboratoriumonderzoekingen. De eerste oriënterende laboratoriumonderzoekingen zijn gewoonlijk een perifeer bloedbeeld en een stollingsonderzoek (APTT, PT, fibrinogeen). Een lijst van mogelijke combinaties van klachten en bevindingen bij fysisch en laboratoriumonderzoek vind je hieronder:
  • Witte bloedcellen (WBC) of leukocyten: Fagocyten: deze cellen hebben zich gespecialiseerd om partikels en micro-organismen ‘op te eten’. Granulocyten : zijn witte bloedcellen die korrels (granules) vertonen. Deze granules nemen verschillende kleuren aan in een standaard May-Grünwald-Giemsa kleuring en worden aldus geklasseerd: Neutrofiele granulocyten : de granules zijn blauw of blauwgrijs; de kern is staafkernig gebogen (staafkernige granulocyt) of bestaat uit 2 tot 5 met elkaar verbonden gecondenseerde kwabben (segmentkernige granulocyt). De functie van de neutrofiele granulocyten (vaak ‘segmentkernige granulocyten’ genoemd) bestaat erin bacteriën op te eten en te doden. Zij vormen de eerste verdedigingslijn van de huid en de slijmvliesbarrières (mond, maag, darmen,…). Eosinofiele granulocyten : de granules zijn oranjerood. Eosinofiele granulocyten spelen een rol in de bestrijding van parasitaire infecties en in allergische aandoeningen. Basofiele granulocyten : de granules zijn grof en donkerblauw. Histamine komt vrij door binding van IgE. In de weefsels worden basofiele granulocyten mastcellen genoemd. Zij spelen een rol bij allergische aandoeningen. Monocyten: hebben een niervormige kern en blauwgrijs cytoplasma. Monocyten die naar de weefsels migreren worden macrofagen genoemd. Monocyten en macrofagen vernietigen micro-organismen en ontstekingslittekenweefsel. Zij verwijderen ook oude bloedcellen. Monocyten worden Kupfercellen in de lever, microgliacellen in de hersenen en osteoclasten in het bot. Dendritische cellen: zijn afgeleid van monocyten en hebben vele en lange uitlopers. In de huid worden ze Langerhanscellen genoemd. Ze spelen een belangrijke rol in antigenopname en presentatie aan T-cellen. Immunocyten: immunologisch competente cellen die samen werken T-lymfocyten (ook wel ‘T-cellen’ genoemd): spelen een rol in de cellulaire immuniteit. Men onderscheidt helper T lymfocyten , dodende T lymfocyten en regulerende T lymfocyten (Tregs). Tregs onderdrukken te hevige immuunresponsen. T-lymfocyten herkennen antigenen door hun receptoren op het membraan (T-celreceptor; TCR). B-lymfocyten : spelen een rol in de humorale immuniteit, dwz door productie van immunoglobulines. Ze kunnen zich omvormen tot plasmacellen die grote hoeveelheden immunoglobulines produceren. Natural Killer Cellen (NK-cellen): vertonen grove blauwe korrels (vandaar hun andere naam ‘large granular lymphocytes) en kunnen helemaal alleen bepaalde cellen (tumoren of virussen) stuk maken.
  • Zoals altijd moet deze gesteld worden uitgaande van anamnese, gaande naar het fysisch onderzoek en rekening houdend met laboratoriumonderzoekingen. De eerste oriënterende laboratoriumonderzoekingen zijn gewoonlijk een perifeer bloedbeeld en een stollingsonderzoek (APTT, PT, fibrinogeen). Een lijst van mogelijke combinaties van klachten en bevindingen bij fysisch en laboratoriumonderzoek vind je hieronder:
  • Infants and young children  — The differential diagnosis of neutropenia in infants and young children includes isoimmune neonatal neutropenia, autoimmune neutropenia, severe congenital neutropenia (SCN), Shwachman Diamond-Oski syndrome, and cyclic neutropenia. Transient mild to moderate neutropenia can be caused by a variety of common viral infections during childhood, including respiratory syncytial virus (RSV), influenza A and B, parvovirus, Epstein-Barr virus (EBV), and human herpes virus 6 (HHV6). In most cases, neutropenia occurs during the first few days of the viral illness and persists for three to eight days. Isoimmune neutropenia occurs only in newborns and presents as moderate to severe neutropenia. The disorder is due to antineutrophil antibodies transferred from the mother. Autoimmune neutropenia (“benign neutropenia”) is not associated with recurrent severe infections and typically occurs between the ages 5 to 15 months, although the range extends from one month to adulthood. Although unusual, a small number of patients with autoimmune neutropenia present with features characteristic of SCN and the differential diagnosis is ultimately made by bone marrow aspiration and genetic studies. Severe congenital neutropenia (SCN) is very rare and characterized by severe infections in the first month of life, the absence of spontaneous remissions, and maturation arrest of myelopoiesis at the promyelocyte stage Shwachman Diamond-Oski syndrome is very rare and is characterized by pancreatic insufficiency, metaphyseal dysostosis, neutropenia with or without thrombocytopenia, and/or anemia. Cyclic neutropenia is very rare and classically occurs as neutropenic periods of three to six days approximately every 21 days. The diagnosis is made by monitoring the ANC three times per week for six to eight weeks. Children or adults  — If anemia, particularly normocytic or macrocytic anemia, or thrombocytopenia is found in the child or adult with neutropenia, hematological consultation should be requested immediately and examination of the peripheral smear along with a bone marrow aspiration should be performed unless the cause is clear. Moderate to severe neutropenia with recurrent infection — Bone marrow aspiration with evaluation of cellularity and morphology should permit identification of late myeloid arrest or myeloid hypoplasia. Late arrest is seen in idiopathic or autoimmune neutropenia, most often associated with antineutrophil antibodies, and in collagen vascular diseases, some drug-induced neutropenias, and chronic infection. Myeloid hypoplasia characterizes toxic drug-induced neutropenias, pure white cell aplasia, T-gamma lymphocytosis (large granular lymphocyte syndrome), severe congenital neutropenia, and myelodysplastic syndrome. The diagnostic evaluation of isolated neutropenia. While bone marrow aspiration is often thought of as the first step, we prefer to delay this test unless there is a clear indication to do it immediately. It is only diagnostic in the case of the progranulocyte maturation arrest seen in the rare case of Kostmann syndrome or marrow infiltration. Most other disorders require other confirmatory testing. Thus, we prefer to do tests for collagen vascular disease and nutritional disorders first, prior to marrow examination. Patients who have episodic infections should have twice weekly measurement of the ANC for at least six weeks to confirm the diagnosis of cyclic neutropenia. Patients with cyclic neutropenia have decreased marrow cellularity one week before the nadir of their neutropenia. This is a rare syndrome and usually associated with symptoms every 21 days and should not be considered unless there is good clinical reason or family history. Bone marrow aspiration is not helpful in this disorder; tests for the ELANE gene are positive over 90 percent of the time. Antinuclear antibodies and complement to screen for collagen vascular disease Antineutrophil antibodies to screen for immune neutropenia Immunoglobulins and immune evaluation to screen for defects of cellular or humoral immunity Screen for HIV infection Methylmalonic acid and homocysteine levels to assess vitamin B12 and folate status Serum copper and ceruloplasmin levels to assess for copper deficiency
  • Infants and young children  — The differential diagnosis of neutropenia in infants and young children includes isoimmune neonatal neutropenia, autoimmune neutropenia, severe congenital neutropenia (SCN), Shwachman Diamond-Oski syndrome, and cyclic neutropenia. Transient mild to moderate neutropenia can be caused by a variety of common viral infections during childhood, including respiratory syncytial virus (RSV), influenza A and B, parvovirus, Epstein-Barr virus (EBV), and human herpes virus 6 (HHV6). In most cases, neutropenia occurs during the first few days of the viral illness and persists for three to eight days. Isoimmune neutropenia occurs only in newborns and presents as moderate to severe neutropenia. The disorder is due to antineutrophil antibodies transferred from the mother. Autoimmune neutropenia (“benign neutropenia”) is not associated with recurrent severe infections and typically occurs between the ages 5 to 15 months, although the range extends from one month to adulthood. Although unusual, a small number of patients with autoimmune neutropenia present with features characteristic of SCN and the differential diagnosis is ultimately made by bone marrow aspiration and genetic studies. Severe congenital neutropenia (SCN) is very rare and characterized by severe infections in the first month of life, the absence of spontaneous remissions, and maturation arrest of myelopoiesis at the promyelocyte stage Shwachman Diamond-Oski syndrome is very rare and is characterized by pancreatic insufficiency, metaphyseal dysostosis, neutropenia with or without thrombocytopenia, and/or anemia. Cyclic neutropenia is very rare and classically occurs as neutropenic periods of three to six days approximately every 21 days. The diagnosis is made by monitoring the ANC three times per week for six to eight weeks. Children or adults  — 
  • Infants and young children  — The differential diagnosis of neutropenia in infants and young children includes isoimmune neonatal neutropenia, autoimmune neutropenia, severe congenital neutropenia (SCN), Shwachman Diamond-Oski syndrome, and cyclic neutropenia. Transient mild to moderate neutropenia can be caused by a variety of common viral infections during childhood, including respiratory syncytial virus (RSV), influenza A and B, parvovirus, Epstein-Barr virus (EBV), and human herpes virus 6 (HHV6). In most cases, neutropenia occurs during the first few days of the viral illness and persists for three to eight days. Isoimmune neutropenia occurs only in newborns and presents as moderate to severe neutropenia. The disorder is due to antineutrophil antibodies transferred from the mother. Autoimmune neutropenia (“benign neutropenia”) is not associated with recurrent severe infections and typically occurs between the ages 5 to 15 months, although the range extends from one month to adulthood. Although unusual, a small number of patients with autoimmune neutropenia present with features characteristic of SCN and the differential diagnosis is ultimately made by bone marrow aspiration and genetic studies. Severe congenital neutropenia (SCN) is very rare and characterized by severe infections in the first month of life, the absence of spontaneous remissions, and maturation arrest of myelopoiesis at the promyelocyte stage Shwachman Diamond-Oski syndrome is very rare and is characterized by pancreatic insufficiency, metaphyseal dysostosis, neutropenia with or without thrombocytopenia, and/or anemia. Cyclic neutropenia is very rare and classically occurs as neutropenic periods of three to six days approximately every 21 days. The diagnosis is made by monitoring the ANC three times per week for six to eight weeks. Children or adults  — 
  • Transcript

    • 1. 1Ann Van de VeldeBHS Educational Course Seminar, 10 Nov 2012Seminar 8 – Non-malignant Hematology EINDE
    • 2. 2
    • 3. 3 Release of neutrophils from the marrow storage pool• 2 fold increase in the neutrophil count < 4 h• > 1/2 of neutrophils in peripheral circulation attached to vascular endothelium• “Marginated" neutrophils released immediately ("demarginated") at times of stress
    • 4. 4 WBC• 9 days in marrow• 3 to 6 hours in blood• 1 to 4 days in tissues• Total neutrophil count, as measured from peripheral blood, represents a population that comprises only 5 % of the total pool sampled during a fleeting 2 % of its total transit time.
    • 5. 5• Mechanisms controlling release of neutrophils from bone marrow only partially understood - Endotoxin - Glucocorticoids - Leukocyte-mobilizing factor derived from the third component of complement (C3e) - Chemoattractants such as C5a - Cytokines as tumor necrosis factor (TNF)-alpha - Androgens
    • 6. 6
    • 7. 7 Keep in mind• As is true for the approach to any medical problem, there is no substitute for an accurate history and physical examination.• However, before this process is started, the clinician must make sure that there is no laboratory error involved. Blood counts that do not make sense within the context of the clinical findings should be repeated before extensive evaluation is undertaken.
    • 8. Vrouw Man 8Hematocriet 37 – 44 % 40 – 54 %Hemoglobine 12 – 16 g/dl 14 – 18 g/dlRode bloedcellen 4,2 – 5,5 x 10E12/l 4,4 – 6 x 10E12/lMCV 76 – 96 flMCH 27- 32 pgMCHC 30 – 35 g/dlReticulocyten 0 – 2 % RBC (10-100 x 10E9/lWitte bloedcellen 4 – 10 x 10E9/lNeutrofiele granulocyten 0–5%- Staafkernige granulocyten 40 – 75 %- Segmentkernige granulocytenEosinofiele granulocyten 1–6%Basofiele granulocyten 0 -1 %Lymfocyten 20 – 45 %Monocyten 2 – 10 %Bloedplaatjes 140 – 440 x 10E9/l
    • 9. 9Leukocytes
    • 10. 10
    • 11. 11 Definitions: Absolute Neutrophil Count (ANC)• ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100• Neutrophilic metamyelocytes and younger forms NOT included in this calculation
    • 12. 12
    • 13. 13 PART 1: LEUKOPENIAKerkyra island, Greece
    • 14. 14 ANC <1500/microL (<1.5 x 109/L)• Generally accepted DEFINITION of neutropenia• TRESHOLD for neutrophil toxicity and infectious risk following chemotherapy. - Mild: 1000 and 1500/microL, - Moderate: 500 and 1000/microL - Severe: less than 500/microL.• Leukopenia and granulocytopenia are generally used interchangeably with neutropenia, although somewhat different.
    • 15. 15 Leukopenia• Refers to a low total white blood cell count that may be due to any cause - lymphopenia and/or neutropenia• Almost all leukopenic patients are NEUTROPENIC since the number of neutrophils is so much larger than the number of lymphocytes.
    • 16. Vrouw Man 16Hematocriet 37 – 44 % 40 – 54 %Hemoglobine 12 – 16 g/dl 14 – 18 g/dlRode bloedcellen 4,2 – 5,5 x 10E12/l 4,4 – 6 x 10E12/lMCV 76 – 96 flMCH 27- 32 pgMCHC 30 – 35 g/dlReticulocyten 0 – 2 % RBC (10-100 x 10E9/lWitte bloedcellen 4 – 10 x 10E9/lNeutrofiele granulocyten 0–5%- Staafkernige granulocyten 40 – 75 %- Segmentkernige granulocytenEosinofiele granulocyten 1–6%Basofiele granulocyten 0 -1 %Lymfocyten 20 – 45 %Monocyten 2 – 10 %Bloedplaatjes 140 – 440 x 10E9/l
    • 17. 17 Granulocytopenia• Reduced absolute number of ALL circulating cells of the granulocyte series - neutrophils, eosinophils, and basophils• Almost all granulocytopenic patients are NEUTROPENIC since the number of neutrophils is so much larger than the number of eosinophils and basophils.
    • 18. 18 Agranulocytosis• Literally means ABSCENCE of granulocytes• Often incorrectly used to indicate severe neutropenia (ie, ANC <500/microL)
    • 19. 19 Two fundamental issues1. Is the patient at increased RISK for infection because of neutropenia?2. Does the presence of neutropenia indicates a SERIOUS UNDERLYING DISORDER that is secondarly effecting the neutrophil count?
    • 20. 20Febrile neutropenia
    • 21. 21
    • 22. 22 Infection propensity• Only 3% of neutrophils circulating in peripheral blood• Vast majority in BONE MARROW RESERVE POOL and remainder is in TISSUE and MARGINATED POOL attached to lining of blood vessels• Standard complete blood count (CBC) is sampling very smallest compartment of neutrophils and does not accurately reflect body’s capacity to protect against bacterial infection.• Most important issue is whether adequate neutrophils get to the site of infection.• No good clinical laboratory test available to quantitate tissue neutrophil delivery.• Adequacy of the marrow reserve pool is most critical determinant of propensity to infection. - NORMAL MARROW CELLULARITY - NORMAL MATURATION OF THE NEUTROPHIL SERIES
    • 23. 23 Bone marrow reserve status• If the bone marrow reserve pool is completely adequate, there is no relationship between the degree of neutropenia and propensity to infection.• Most physicians are aware of the extreme danger present in patients with significant fever and very low absolute neutrophil counts based upon their experiences during training with patients who have received chemotherapy or who have bone marrow failure syndromes. These patients have NO bone marrow reserve.• Patients with immune mediated neutropenia but normal bone marrow reserve are on the other end of the spectrum and are at NO increased risk of infection because of the neutropenia.
    • 24. 24 Bone marrow reserve status• If a neutropenic patient has a frank abscess or purulent exudate, he or she can get neutrophils to tissue and likely has a normal marrow.• The presence of mucosal ulcerations and severe gingivitis suggests inability to deliver neutrophils. However, immune disorders can directly cause similar lesions in the presence of normal reserve neutropenia.
    • 25. 25
    • 26. 26
    • 27. 27 Etiology of isolated neutropenia• Neutropenia results from four basic mechanisms: - decreased production - ineffective granulopoiesis - shift of circulating PMNs to vascular endothelium or tissue pools - enhanced peripheral destruction.• Confirmation of one of these mechanisms requires leukokinetic studies employing bone marrow cultures, radionuclide tagging of blood PMNs, and other monitoring devices not readily available outside the research laboratory.• Various interactions between subtle genetic differences and environmental factors. Apoptosis of marrow precursors is now recognized as a common mechanism for many acquired and congenital neutropenias.
    • 28. 28 Acquired neutropenias• There are many acquired causes of neutropenia - Infection - Drugs - Immune disorders
    • 29. 29 Infectious neutropenias• Most common cause of acquired isolated neutropenia• Bacterial, viral, parasitic and rickettsial infections.• Short-lived - rarely results in bacterial superinfection• Mechanisms - Redistribution - Sequestration and aggregation - Destruction by circulating antibodies.• More severe and protracted neutropenia - Hepatitis B virus - Epstein-Barr virus - Human immunodeficiency virus:
    • 30. 30 Drug-induced neutropenia and agranulocytosis• Adverse idiosyncratic reaction• Second most common cause of neutropenia• Requires that the drug have been administered within 4 weeks of onset neutropenia.• Drugs with highest risk of inducing severe neutropenia - clozapine - thionamides (antithyroid drugs) - sulfasalazine• Mechanism - Immune-mediated destruction of circulating neutrophils by drug-dependent or drug-induced antibodies - Direct toxic effects upon marrow granulocytic precursors
    • 31. 31
    • 32. 32 Nutritional neutropenia• B12 and folate deficiency, as well as inborn errors of B12 metabolism• B12 and folate deficiency best detected by measuring methylmalonic acid (MMA) and homocysteine (HcY). Both are elevated with B12 deficiency and HcY alone is elevated in folate deficiency.• Copper deficiency and subsequent low ceruloplasmin. - Malabsorption - post-gastric bypass surgery - Critically ill patients who have prolonged hospitalizations
    • 33. 33 Primary immune disorders• ANTINEUTROPHIL ANTIBODIES mediate neutrophil destruction - by splenic sequestration of opsonized cells - by complement-mediated neutrophil lysis• Antineutrophil antibodies - Infections - drug exposure - immune deficiencies. - specific PRIMARY immune disorders• Propensity to infection may be more related to the underlying immune disorder than to the neutropenia !• Vasculitis, leading to mucosal ulcers. - Oral symptoms completely resolve with treatment of the underlying vasculitis with no change in the ANC, proving that the mucositis and the neutropenia are not related.
    • 34. 34• Isoimmune neonatal neutropenia — Moderate to severe neutropenia in newborn infants secondary to transplacental passage of IgG antibodies directed against neutrophil specific antigens inherited from the father of the infant. ~ Rh hemolytic disease. Otherwise normal infant and patients do well.• Chronic AUTOIMMUNE neutropenia — primarily in infants and children under age four and is also called CHRONIC BENIGN NEUTROPENIA OF INFANCY AND CHILDHOOD. Specific treatment is not required. Many patients remain free of infections and maintain normal lifestyle with no or minimal medical intervention. Spontaneous remission with disappearance of autoantibodies is common.• Chronic IDIOPATHIC neutropenia — BENIGN CHRONIC NEUTROPENIA, no obvious cause. Serologic abnormalities and evidence of antibody production have been found in 30 to 40 %. Benign course despite degree of neutropenia. Presence of normal marrow reserve may explain the lack of significant infections.
    • 35. 35• Pure white cell aplasia — rare disorder characterized by complete disappearance of granulocytopoietic tissue from bone marrow. Often associated with thymoma and is due to presence of antibody mediated GM-CFU INHIBITORY ACTIVITY. No marrow reserve and at risk for infection.• Other autoimmune disorders — T-GAMMA LYMPHOCYTOSIS (large granular lymphocyte syndrome) and FELTYS SYNDROME. Often associated with RHEUMATOID ARTHRITIS. LGL has markedly decreased marrow reserve as well as autoimmune vasculitic components.• Complement activation — Exposure of blood to artificial membranes, as in dialysis and extracorporeal membrane oxygenation, may result in complement activation in vivo. Neutrophil aggregation and adherence to endothelial surfaces, often in the lung. Neutropenia and cardiopulmonary symptoms typically occur shortly after exposure to the membrane. Can be prevented during hemodialysis by using BIOCOMPATIBLE MEMBRANES.
    • 36. 36 Hypersplenism• Enlargement of the spleen from any etiology• Splenic trapping• Severity of neutropenia is related to the size of the spleen• Rarely sufficient to result in severe infection
    • 37. 37 Cyclic neutropenia• Recurrent mouth infections• Regular oscillations in numbers of blood neutrophils, monocytes, eosinophils, lymphocytes and reticulocytes at approximately 21-day intervals.• Usually in childhood, as a familial syndrome• Treatment is largely supportive and G-CSF has been effective in preventing infection and reducing symptoms.
    • 38. 38 (Bone marrow disorders)• Aplastic anemia• Leukemias• Myelodysplasia• Post-chemotherapy - not an isolated defect - associated with varying degrees of anemia and thrombocytopenia.• Examination of peripheral smear and bone marrow aspirate/biopsy are indicated when more than one cell line is involved.
    • 39. 39
    • 40. 40 Diagnostic approach• First step in the approach to the patient with neutropenia is CONFIRMATION OF THE DIAGNOSIS.• Review of a Wright—Giemsa stained peripheral blood smear will confirm reduced number of neutrophils.• In all cases in which the white blood cell differential count has been generated by automatic counters, it should be repeated manually.• Pseudoneutropenia - If blood is left standing for a prolonged period of time - Paraproteinemia - Anticoagulants that can cause cellular clumping
    • 41. 41 Diagnostic approach• Monitoring of blood counts for 8 to 12 weeks if there are no other important clinical factors present.• According to this schema, if the patient develops clinical symptoms related to neutropenia or changes in other cell lines in the blood count, a full evaluation should be undertaken.
    • 42. 42
    • 43. 43 Neutropenia in absence of recurrent or protracted infection• Most causes are benign, especially if the ANC is > 800/microL.• Thus, a period of observation is indicated if the patient is asymptomatic and there are no other significant clinical features, particularly if there is a recent history of viral infection or a medication has been taken that is known to be associated with neutropenia.• Examination of the oral cavity is important, since the presence of gingivitis or tooth abscess suggests presence of symptomatic neutropenia.• If neutropenia resolves, patient should be followed for one year with complete blood count being obtained whenever fever occurs.
    • 44. 44 Moderate to severe neutropenia with recurrent infection• Bone marrow aspiration with evaluation of cellularity and morphology - Late myeloid arrest - Myeloid hypoplasia• Late arrest - idiopathic or autoimmune neutropenia, most often associated with antineutrophil antibodies - collagen vascular diseases - some drug-induced neutropenias - chronic infection• Myeloid hypoplasia - toxic drug-induced neutropenias - pure white cell aplasia - T-gamma lymphocytosis (large granular lymphocyte syndrome) - severe congenital neutropenia - myelodysplastic syndrome
    • 45. 45
    • 46. 46 + Anemia• If anemia, particularly normocytic or macrocytic anemia, or thrombocytopenia is found, hematological consultation should be requested immediately and examination of the peripheral smear along with a bone marrow aspiration should be performed unless the cause is clear.
    • 47. 47 Isolated neutropenia• Tests for collagen vascular disease and nutritional disorders first, prior to marrow examination. - Antinuclear antibodies and complement - Antineutrophil antibodies - Immunoglobulins and immune evaluation - Screen for HIV infection - Methylmalonic acid and homocysteine levels - Serum copper and ceruloplasmin levels
    • 48. 48 Cyclic neutropenia• Episodic infections: twice weekly measurement of the ANC for at least six weeks to confirm diagnosis• Decreased marrow cellularity one week before the nadir• Rare syndrome• Symptoms every 21 days• Family history• Bone marrow aspiration is NOT helpful in this disorder
    • 49. 49 Antibiotic therapy (1/2)• gastrointestinal tract - skin• Rapid onset of overwhelming sepsis.• Febrile patients with neutropenia related to marrow suppression - treated immediately, following culture of body fluids, with broad-spectrum parenteral antibiotics for coverage of both Gram-positive and Gram-negative bacteria.• ANC >1000/microL: outpatient• ANC of <500/microL and marrow aplasia : inpatient treatment with parenteral antibiotics.• Routine reverse isolation procedures are of no benefit and serve to decrease contact with medical personnel !• When a patient first presents with HIGH FEVER and has a VERY LOW ANC, one must assume that the patient is high risk and has inadequate marrow reserve.
    • 50. 50 Antibiotic therapy (2/2)• Monitoring of C-reactive protein level and sedimentation rate daily• Often, cultures are negative and treatment is empiric.• Rapid response can indicate that appropriate antibiotics have been selected, and poor response or increase in ESR after a response can indicate that a change in antibiotics is necessary.• Antibiotics continued for several days after fever has subsided and sedimentation rate normalized. If ANC has risen > 500/microL on several measures, antibiotics may be discontinued as long as no source of infection is apparent.• If fever persists or there is no clear response to treatment, other therapies should be considered.• If fever and neutropenia persist beyond 7 days in the immunosuppressed patient, antifungal treatment should be considered in post-chemotherapy patients; not in patients with benign neutropenia.• Granulocyte transfusions to patients with Gram-negative sepsis who have not shown a clinical response to antibiotics within 24 to 48 hours. Waned due in part to difficulties in procurement, to better antibiotics, and to the use of bone marrow growth factors.
    • 51. 51 Myeloid growth factors• G-CSF therapy not indicated for all causes of neutropenia.• Helpful in neutropenia associated with early myeloid arrest• Reserved for patients with demonstrated infectious morbidity related to the neutropenia• Use of G-CSF in patients with chemotherapy-induced neutropenia - use as primary or secondary prophylaxis - neutropenia without fever - neutropenic fever
    • 52. 52 Neutropenia summary1. Absolute neutrophil count <1500/microL2. Peripheral blood white blood cell count does not accurately reflect the body’s capacity to deliver neutrophils to tissues and protect against bacterial infection.3. Infection, drugs, and immune disorders are the most common acquired causes4. Management includes the prevention of infection, regular dental care, use of antibiotic mouthwashes, aggressive antibacterial therapy for fever, and the judicious use of myeloid growth factors in selected patients
    • 53. 53PART 2: LEUKOCYTOSISPicture: Sagrada Familia by Antoni Gaudi, Barcelona
    • 54. 54 Leukocytosis and leukemoid reaction*• Total white blood cell (WBC) count more than two standard deviations above the mean, or a value >11,000/microL in adults.• *Leukocytosis >50,000/microL, when due to causes other than leukemia
    • 55. 55 Neutrophilic leukocytosis = neutrophilia• Total WBC > 11,000/microL along with an absolute neutrophil count (ANC) > 2 standard deviations above the mean (greater than 7700/microL (> 7.7 x 109/L).• Infection, stress, smoking, pregnancy, following exercise, (chronic myeloproliferative disorders, such as polycythemia vera (PV) and chronic myeloid leukemia)
    • 56. 56 Lymphocytic leukocytosis = lymphocytosis• Total WBC >11,000/microL primarily due to an absolute lymphocyte count > 4800/microL (> 4.8 x 109/L).• Infections such as infectious mononucleosis and pertussis (or in lymphoproliferative disorders such as the acute and chronic lymphocytic leukemias)
    • 57. 57 Monocytic leukocytosis = monocytosis• Total WBC > 11,000/microL primarily due to an absolute monocyte count > 800/microL (> 0.8 x 109/L).• (Acute and chronic monocytic variants of leukemia) and acute bacterial infection or tuberculosis.
    • 58. 58 Eosinophilic and basophilic leukocytosis = eosinophilia and basophilia• Total WBC > 11,000/microL due primarily to an absolute eosinophil or basophil count > 450/microL (> 0.45 X 109/L ) or 200/microL (> 0.2 x 109/L)• (Variant forms of chronic leukemia, solid tumors), infection with helminthic parasites, allergic reactions, and following treatment with Interleukin-2.
    • 59. 59 Basophilia- Myeloproliferative neoplasms- Basophilic leukemia, mastocytosis, hypereosinophilic syndrome, atypical acute and chronic leukemias, myelodysplastic syndrome- Allergic or inflammatory reactions, including hypersensitivity reactions, ulcerative colitis, rheumatoid arthritis- Endocrinopathy, including hypothyroidism (myxedema), administration of estrogens- Infections, including viral infections, tuberculosis, helminth infections
    • 60. 60 Left shift in the WBC differential• Band form count >700/microL, often called "BANDEMIA"• In infection, cells as immature as metamyelocytes are often seen on the peripheral smear,• It is unusual to see more immature cells (myelocytes, promyelocytes, and blasts). When these latter cells are present, they indicate a "severe left shift", most likely due to the presence of an acute or chronic myeloproliferative disorder - chronic myeloid leukemia - idiopathic myelofibrosis - acute leukemia
    • 61. 61
    • 62. 62
    • 63. 63 Major causes of leukocytosis• Any active inflammatory condition or infection• Cigarette smoking, most common cause of mild neutrophilia• Pregnancy and uncomplicated spontaneous or cesarean delivery• Previously diagnosed hematologic disease• Certain medications (glucocorticoids, catecholamines)• Presence of, and treatment for, chronic anxiety state, panic disorder, rage, or emotional stress• Recent vigorous exercise, thermal burn, electric shock, surgery, or trauma• Laboratory artifact (platelet clumping, cryoglobulinemia)
    • 64. 64 Leukopenia and leukocytosis Take home messages1. Laboratory error2. Marrow storage pool3. Collagen vascular disease4. Bone marrow if + anemia and/or + thromboctopenia5. Bone marrow if severe left shift
    • 65. 65This "pink meanie" jellyfish feeds on other jellyfish species, such as moon jellies.In 2011, with the help of DNA sequencing, researchers discovered that this large,pink-hued jelly was, in fact, a new species in an entirely new family.Photo: Mary Elizabeth Miller, Dauphin Island Sea Lab
    • 66. 66THE END