24th Congress of the IAP Arab Division Khartoum, December 6-8, 2012

Transcription

1 KRISTIN HENRY IMPERIAL COLLEGE LONDON at CHARING CROSS HOSPITAL 24th Congress of the IAP Arab Division Khartoum, December 6-8, 2012 Bone Marrow Symposium: December 6th KH Talk II: Infections of BM- BM trephine biopsies

2 ACUTE INFLAMMATION Oedema cf gelatinous transformation Haemorrhage Necrosis Alterations in cellularity- eg. granulocytic hyperplasia, eosinophils; leukaemoid reaction; erythroid hyperplasia, hypoplasia; megaloblastic change; MgK hyperplasia In severe infections - hypocellularity; aplasia; dyshaematopoiesis/myelodysplasia

3 fibrinous exudate Acute inflammation Oedema Necrosis

4 Acute inflammation haemorrhage and necrosis Leukaemoid change - left shift Left shift Granulocytic - right shift

5 CHRONIC INFLAMMATION Granulomas Histiocytosis Lymphocytosis lymphoid aggregates lymphoid follicles with germinal centres lymphohistiocytosis Plamacytosis Alterations in cellularity Dyshaematopoiesis, myelodysplasia Fibrosis

6 Chronic bacterial infection Reticulin fibre reticulin fibre Reticulin fibre fibres Histiocytes CD 68 PCs polyclonal

7 Granulomas Lymphocytosis Plasmacytosis

8 LYMPHOID LESIONS Small size of aggregates (>1mm) ; REACTIVE PLASMACYTOSIS Intersittial; scattered singly or in small clusters 1-5 p er trabec. space; B- and T- cells* Number 10-20% rarely 50% Random distribution; often perivascular; well defined borders; away from trabeculae Sometimes follicles with GCs No atypia Few reticulin fibres except in HIV Present around capillaries or macrophsages; rarely around fat spaces Rarely form large clusters; do not form nodules Polyclonal; no atypia In chronic OM- sheets of PCs + fibrosis *Predominance of T-lymphocytes in HIV

9 GRANULOMAS BACTERIA: Tuberculosis M.tuberculosis MAI Leprosy Brucellosis Typhoid fever Legionnair s diseas Tularaemia VIRUSES: Herpes viruses CMV EBV HIV RICKETTSIA Q fever Rocky mountain spotted fever FUNGI: Histoplasmosis Cryptococcosis PROTOZOA: Leishmaniasis Toxoplasmosis

10 Mycobacterium tuberculosis

11 COMMON OPPORTUNISTIC INFECTIONS (OI) Bacterial: Mycobacterium avium intracellulare (MAI); M.Tuberculosis Fungal: Histoplasma capsulatum; Cryptococcus neoformans Protazoal: Leishmania donovanii;toxoplasma gondii; pneomocystis carinii Viral: Parvovirus B19; CMV

12 Mycobacterium avium intracellulare (MAI)

13 Histoplasma capsulatum Grocott mucicarmine

14 Crytococcus neoformans Methamine silver PAS PAS/Alcian blue

15 Leishmania donovani CD68

16 VIRUSES MOST COMMONLY INFECTING BM Herpes viruses: eg. EBV, CMV, HSV, HHV6 Hepatitis viruses HIV (+ HHV8 in MCD) Parvovirus B19 Adenoviruses Coxsackie viruses Influenza A Para-influenza

17 Specific effects of viral infections Hypercellularity* Hypocellularty*; aplasia Dyshaematopoiesis, dysplastic features* Inflammatory changes oedema acute infections haemorrhages- eg. hepatitis B, VAHS necrosis eg. CMV, EBV; PV B19 gelatinous transformation- eg. in severe infections; AIDS lymphoid aggregates common in young patients; HIV increase in PCs common; may be numerous in HIV lymphohistiocytic aggregates- especially HIV - T cells predominate granulomas -eg. CMV, EBV VAHS *one or more lineages affected; sometimes eosinophils

18 BMTB FINDINGS IN HIV +VE PATIENTS Cellularity: hypercellular 66%; hypocellular 10%; Dyshaematopoiesis: haematopoiesis - higgledy piggledy pattern Myelodysplasia: 69% in one or more lineage most evident in Mgk series Inflammatory & stromal reactions: lymphocytes; eosinophils; PCs; granulomas; reticulin fibre; BV changes Opportunistic infections: bacterial, fungal, protozoal, viral Lymphoma: HL, high grade B- Cell Lymphomas Henry K, Costello C. 1994

19 BMTBs IN HIV +VE PATIENTS

20 reticulin fibre

21 Lymhpocytosis CD3 CD20 CD8

22 Lymphoid aggregates κ λ CD4 λ CD8

23 PLASMACYTOSIS HIV infection

24 CD8 CD8

25 Dyserythropoiesis Glycophorin C Glycophorin C Perl s stain for iron

26 ALIP ranulocytic hyperplasia;left shift MPX

27 Dysmegakaryopoiesis

28 bare MgK nuclei CD61 AS/Ki67 PAS/Ki67p

29 CD61 CD79a CD31 Ki67

30 MYELODYSPLASIA IN HIV+ PATIENTS Can be present in early HIV infection without evidence of OI or malignancy and before therapy is started

31 HIV ASSOCIATED MYELODYSPLASIA: mechanisms leading to dyshaematopoiesis STAGE OF DISEASE ACCORDING TO CDC CLASS DAMAGE BY HIV GENE PRODUCTS SYSTEMIC DISEASE: OPPORTUNISTIC INFECTIONS;eg, MAI, MTB, LEISHMANIASIS, PARVOVIRUS LYMPHOMA, CARCINOMA THERAPEUTIC AGENTS AUTOIMMUNE REACTIONS DIRECT INFECTION AND DESTRUCTION OF HAEMOPOIETIC PROGENITOR CELLS AND/OR STROMAL CELLS PRODUCTION OF CYTOKINES: eg. Increased secretion of TNFα & IFNγ by CD8+ γδ Tcells

32 MULTICENTRIC CASTLEMAN S DISEASE (MCD) Plasmacytosis, often >50%; lymphoid aggregates HHV8 associated MCD cases usually HIV +ve Scattered interstitial HHV8 +ve cells HHV8

33 PV 19 in HIV +ve patients

34 HUMAN PARVOVIRUS B19 Common worldwide infectious agent in humans - IgG antibodies to VP1 30 in 60% of adults (>85%- geriatric population) IgM in recent infection Small non enveloped DNA virus; genome- NSI left side, VP1&VP2 right side Tropic for erythroid progenitor cells, binds to blood group P antigen on RBCs; productive replication in mitotically active cells P antigen also expressed by MgKs, endothelial cells, fetal myocytes Cytopathology of affected red cells: eosinophilic intranuclear inclusions in tissue sections giant pro-erythroblasts Infects healthy individuals as well as those with immunity & RBC producttion Clinical aspects: Associated with a wide variety of diseases in pregancy, infants, children, adults Virus Associated Haemophagocytic Syndrome Heegaard ED, Brown KE. 2002; Lehmann HW, von Landenberg P, Modrow S. 2003

35 Parvovirus B19

36

37 PARVOVIRUS B 19 INFECTION Identified in 1974; implication in human diseases in 80s BM major site of viral replication Infection of healthy hosts occurs in : inutero; neonates; children; adults Immunodeficiant hosts haematological malignancies; lymphoma HIV- up to 25% of severe chronic anaemia post organ transplantation iatrogenic immunosupressive therapy Underlying hematological disorder In chronic infection VAHS

38 DISEASES CAUSED BY PV B 19 INFECTION - I PREGNANCY Hydrops fetalis; miscarriage, congenital anaemia CHILDREN Erythema infectiosum (fifth disease) Transient erythroblastopaenia (TEC) of childhood +/- immune mediated neutropaenia ADULTS Polyarthropathy Cytopaenias eg. Thrombocytopaenia

39 DISEASES CAUSED BY PV B 19 INFECTION - II UNDERLYING HAEMATOLOGICAL DISORDER Transient aplastic crisis (TAC) in patients with: Increased red cell turnover eg. sickle cell anaemia*; hered. spherocytosis or Decreased RBC production eg. Thalassaemia, Fe. def. anaemia Red cell aplasia; Thrombocytopaenia; occ. mimics MDS IMMUNOCOMPROMISED HOSTS Congenital or acquired- especially AIDS, post-transplant, malignancy Chronic anaemia; cytopaenias VAHS * If extensive bone necrosis syst. emboli and acute chest syndrome

40 Man aged 41 HIV +ve. Developed severe anaemia. BM erythroid hypoplasia.treated with erythropoietin and PV infection revealed Courtesy of David Hudnall

41 BMTB manifestations Erythroid series: Hypoplasia; residual precursors size; few nulear inclusions (may be missed) Regenerating erythroblasts in recovery phase In imm. deficiency, may be intact erythroid lineage, hyperplasia; many inclusions Dyspoietic features; isolated cytopaenia- granulocyte or Mgk Bone necrosis Detection IHC Mab B19 (clone R92FX) Serology PCR; In situ hybridization techniques of blood or tissues - most sensitive- ISH for B19 DNA

42 HAEMOPHAGOCYTIC SYNDROMES (HPS) In children, as familial erythrophagocytic lymphohistiocytosis (FEL) As a reaction to infectious agents (IAHS), notably viruses (VAHS)* In association with malignant disease eg. Periphreral T-cell lymphoma; NK lymphoma In immunocompromised individuals As a primary event HPS is a severe life threatening illness characterized by: acute onset of fever usually hepatosplenomegaly pancytopaenia phagocytosis by macrophages of haemopoietic cells, mature and immature, most easily seen as erythrophagocytosis * VAHS is reversible

43 IAHS Peripheral T cell lymphoma HIV +VE BM AIL T cell Lymphoma

44 INFECTION RELATED HAEMOPHAGOCYTIC SYNDROME Bacterial Fungal Staphylococci, streptococci, E.coli, H.influenzi Pseudomonas &, klebsiella species Mycobacteria Legionnaire s diseaase Brucellosis Typhoid fever Mycoplasma infection Psittacosis Histoplasmosis Candidiasis Protozoal Toxoplasmosis Leishmaniasis Malaria Viral (VAHS) Herpes viruses: EBV, CMV, HSV, HZV, HHV6 & 7 Hepatitis B & C Adenoviruses Coxsackie viruses Parvovirus B19* Dengue Influenza A Para-influenza (HIV) Rickettsial Rocky mountain spotted fever Q fever