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Morning Report

Morning Report. September 3, 2010 Smita Joshi Dr. Stock. Don’t Forget to do your Epic Training this weekend !!!!. MKSAP. An asymptomatic 35-year-old man comes for a routine annual examination. Medical and family histories are unremarkable, and his only medication is a daily multivitamin.

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Morning Report

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  1. Morning Report September 3, 2010 Smita Joshi Dr. Stock

  2. Don’t Forget to do your Epic Training this weekend !!!!

  3. MKSAP An asymptomatic 35-year-old man comes for a routine annual examination. Medical and family histories are unremarkable, and his only medication is a daily multivitamin. On physical examination, temperature is normal, blood pressure is 120/70 mm Hg, pulse rate is 64/min, and respiration rate is 14/min. There are no abnormal findings.

  4. Laboratory studies: Hemoglobin 9.1 g/dL (91 g/L) Leukocyte count 2100/µL (2.1 × 109/L) Platelet count 135,000/µL (135 × 109/L) Lactate dehydrogenase 890 U/L Uric acid 11.6 mg/dL (0.68 mmol/L) A peripheral blood smear shows circulating blasts and promyelocytes. Bone marrow examination shows hypercellular marrow with 80% myeloblasts and promyelocytes. Cytogenetic studies reveal translocation of chromosomes 15 and 17 [t(15;17)].

  5. In addition to hydration and allopurinol, which of the following is the most appropriate management at this time? A. Broad-spectrum antibiotics B. Chemotherapy C. Chemotherapy plus all-trans-retinoic acid D. HLA typing

  6. This patient has AML, promyelocytic subtype (subtype M3), based on the number of myeloblasts and promyelocytes in the bone marrow and confirmed by the presence of t(15;17). The 15;17 translocation results in a unique fusion gene, PML/RARα, which has been implicated in leukemogenesis. Patients with acute promyelocytic leukemia often present with pancytopenia and symptoms referable to the anemia, neutropenia, and thrombocytopenia, or they may be asymptomatic, like this patient. Patients with acute promyelocytic leukemia have an excellent response to chemotherapy plus a differentiating agent that interferes with PML/RARα protein function, such as all-trans-retinoic acid or arsenic trioxide. Response rates approach 85% to 95% for patients on this regimen. Randomized clinical trials have shown the superiority of combining differentiating agents such as all-trans-retinoic acid and chemotherapy as induction therapy.

  7. Case • 21 yo M p/w extreme fatigue and weakness

  8. HPI • 4 days of fatigue, subjective fevers and chills • +lightheadedness, DOE, non-productive cough • No dysuria/diarrhea/BRBPR/melena/neck stiffness/rash/abd pain

  9. PMH: Multiple L shoulder surgeries ALL: NKDA FH: Mother - HL SH: EtOH: 4 cases of beer/week. Is intoxicated 4-5 nights/wk No tob, no IVDU Lives in Denver Bartender/manager Meds: OTC body building supplements Medical History

  10. Physical Exam VS: T 37.2, HR 105, RR 16, BP 116/70, 98% RA Gen: Fatigued, muscular Caucasian man in NAD HEENT: PERRL. Sclerae anicteric. Pale conjuctivae. OP clear. Moist mucous membranes. No thrush. Lymph: No palpable supraclavicular, cervical, or axillary LAD CV: Tachy, reg rhythm, nl S1&S2, no mrg, warm, 2+ pulses Lungs: CTAB Abd: +BS, Soft NTND, no HSM Neuro: AO x 3, non-focal Extremities: No c/c/e Skin: No rashes

  11. Differential?Initial studies?

  12. Labs 8.9 4.6 137 104 12 1.2 42 97 3.9 25 0.8 N 66%, L 15%, M 11%, E 3% 6.7 4.5 ANC 800 MCV 87 0.9 37 75 50

  13. New Differential? What Additional Work-Up?

  14. Differential for Pancytopenia • Aplastic Anemia • Congenital vs acquired • Marrow Replacement • AML, fibrosis • MDS • Megaloblastic anemia • Folate, B12 • Infection • Sepsis • Viral etiologies • Splenomegaly • Alcohol • Medications

  15. RPI: Measure of reticulocyte response Corrects for: Degree of anemia (normalized to HCT of 45%) Reticulocyte maturation time (RMT increases with worsening anemia) RPI = % Reticulocytes x (HCT/45) x (1/RMT) Normal RPI 1.0, RPI > 2.0 indicate adequate BM response in anemia Reticulocyte Production Index (RPI)

  16. Labs Iron 195 Ferritin 853 TIBC 346 Folate 12.5 B12 784 LDH 224 Haptoglobin 55 % Retic 1.6 Abs Retic 39.8 RPI 0.3

  17. Additional studies • HIV: neg • EBV titers, monospot: neg • CMV titers: neg • Parvovirus titers: Neg • Hepatitis A,B,C: neg • Urine tox: neg • Heavy metal screen: wnl

  18. Peripheral Smear

  19. RBCs normocytic Reticulocytes markedly reduced Remaining cellular elements, while reduced in #, morphologically normal Abnormal cells not present Peripheral Smear

  20. Cross-Cover Called: Patient has a Fever of 38.3 What do you do now?

  21. Symptoms: Fatigue, fevers VS: T 38.3, HR 110, RR 16, BP 105/60, 99% RA Gen: NAD HEENT: OP clear, no oral lesions, no facial TTP CV: Tachy, reg rhythm, nl S1&S2, no mrg Lungs: CTAB Abd: Soft NTND Rectal: No perirectal erythema/TTP/abscess Skin: No rashes, IV sites c/d/i w/o TTP Symptoms and Exam

  22. Blood cultures neg x 2 U/A, urine cx neg CXR neg Imipenem  dc’d when no longer neutropenic

  23. Neutropenic Fever Algorithm Hughes WT, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002 Mar 15;34(6): 730-51. Epub 2002 Feb13.

  24. Bone Marrow Biopsy

  25. Bone Marrow Biopsy BM – 10% cellularity, hypoplastic BM showing decreases in all hematopoietic lineages with numerous apoptotic/degenerating cells

  26. Bone Marrow Cellularity BM Cellularity ~100% at birth, declines with time Age-associated reduction in hematopoietic activity BM Cellularity (%) is approx: 100 – Age (yrs)

  27. Diagnosis:APLASTIC ANEMIA

  28. Aplastic Anemia BM bx in aplastic anemia. Nearly no hematopoietic cells, marrow space consists of fat and stroma BM bx in normal pt.

  29. Aplastic Anemia Definition • Diminished or absent hematopoietic precursors in BM • “Anemia” misnomer, dz w/ pancytopenia Incidence • 2-4 ppl per million per yr • In acquired cases, presents b/w 15-25 yrs and >65 yrs Pathophysiology • Usually immune mediated in acquired cases; autoreactive lymphs mediated destruction of hematopoietic cells

  30. Causes of Aplastic Anemia • Idiopathic • Congenital • Fanconi Anemia • Dyskeratosis congenita • Schwachman-Diamond syndrome • Medications • Chloramphenicol • Gold • NSAIDs • Sulfonamides • Antiepileptics • Nifedipine • Viruses • EBV • HIV • Parvovirus B12 • Immune Disorders • SLE • Thymoma • Eosinophilic fasciitis • GVHD • Toxins • Benzene • Chemotherapy • Pesticides • Solvents/degreasing agents • Other • Pregnancy • PNH • Seronegative hepatitis • Radiation

  31. Clinical Manifestations • Related to peripheral-blood cytopenias • Fatigue • DOE • Recurrent infxns, fevers • Pallor and petechiae • Liver, spleen and LNs not enlarged

  32. Diagnosis • CBC: pancytopenia, reduced Abs retic • Peripheral smear: RBCs usually normocytic, reticulocytes reduced • Remaining cellular elements, while reduced in #, are morphologically nl

  33. Bone Marrow Exam • Profoundly hypocellular with decrease in all elements • Marrow space mainly fat cells and marrow stroma • No infiltration of malignant cells • No fibrosis • Residual cells morphologically nl

  34. Treatment • Withdrawal of offending agents • Supportive care (transfusions, antibiotics) • Definitive therapy • Hematopoietic cell transplant (HCT) • Immunosuppressive therapy • Anti-thymocyte globulin and cyclosporine • Cyclophosphamide

  35. Classification • Moderate Aplastic Anemia • Marrow cellularity <30% • Absence of severe pancytopenia • Depression of at least 2 of 3 blood elements • Severe Aplastic Anemia • Marrow cellularity <25% • 2 out of 3 of following: • Abs Retic Count <40K • ANC <500 • Plts <20K • Very Severe Aplastic Anemia • Criteria for severe AA and ANC <200

  36. HCT most effective tx, but usefulness declines with age 2/2 fatal complications In pts up to age 40-45 in otherwise good health and a fully-matched sibling donor, HCT first choice Retrospective study assessed 395 pts with SAA who received HCT or immunosuppressive therapy Mean age 22 and 25 in two groups. Survival at 15 yrs significantly higher in HCT group - 69% vs 38% If not fully-matched sibling donor or >45 yrs, immunosuppressive therapy Treatment

  37. Hospital Course • In Denver OSH, received 4 units pRBCs • Transferred care to U of C • Received ATG and cyclosporine • On day of discharge, pt’s counts were on upward trajectory • Aplastic anemia may have been 2/2 OTC supplements, but unable to prove

  38. References • Brodsky RA, Jones RJ. Aplastic anaemia. Lancet. 2005. May 7-13;365(9471):1647-58 • Doney K et al. Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy. Seattle Bone Marrow Transplant Team. Ann Intern Med 1997 Jan 15;126(2):107-15 • Hughes WT, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002 Mar 15;34(6): 730-51. Epub 2002 Feb13. • Special thanks to Divya Singh

  39. MKSAP revisted A 37-year-old man with HIV infection has a 1-week history of increasing fatigue and dyspnea on exertion. He is receiving highly active antiretroviral therapy and trimethoprim-sulfamethoxazole. On physical examination, temperature is normal, blood pressure is 120/70 mm Hg, pulse rate is 72/min, and respiration rate is 24/min. The patient appears pale but does not have jaundice or a rash. Examination is unremarkable. There is no lymphadenopathy, organomegaly, or edema. A stool sample is negative for occult blood.

  40. Laboratory studies: Hemoglobin 7.2 g/dL (72 g/L) Leukocyte count 4600/µL (4.6 × 109/L) Platelet count 346,000/µL (346 × 109/L) Reticulocyte count 0.3% of erythrocytes Erythropoietin 500 mU/mL (500 U/L) Haptoglobin 72 mg/dL (720 mg/L) Ferritin 55 ng/mL (55 mg/L) Iron 135 µg/dL (24.2 µmol/L) Transferrin saturation 65% Lactate dehydrogenase 124 U/L Direct antiglobulin (Coombs) test Negative A peripheral blood smear shows normocytic, normoblastic erythrocytes without inclusion bodies. Bone marrow examination reveals a mildly hypocellular marrow with giant pronormoblasts. Parvovirus B19 DNA is present in the serum and bone marrow. There are no IgG antibodies to parvovirus.

  41. Which of the following is the most appropriate treatment? A. Erythrocyte transfusion, antithymocyte globulin, and cyclosporine B. Erythrocyte transfusion, cytarabine, and an anthracycline C. Erythrocyte transfusion and intravenous immune globulin D. Recombinant erythropoietin

  42. This patient with HIV infection has pure red cell aplasia secondary to parvovirus B19 infection. Immunocompromised patients often lack the characteristic rash and arthralgia observed in immunocompetent patients. The diagnosis is suggested by the presence of giant pronormoblasts in the bone marrow and confirmed by the presence of viral DNA in the serum and bone marrow. Patients with HIV infection may not be able to mount an appropriate antibody response to parvovirus B19 and subsequently develop pure red cell aplasia due to the destruction of erythroid precursors. Once the diagnosis is made, treatment includes erythrocyte transfusions and pooled intravenous immune globulin to infuse antibodies against parvovirus.

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