Infection_and_anemia_2023.pptx

Infectious Causes of Anemia Debra E Bramblett, PhD Burrell College of Osteopathic Medicine CVI-2023 Objectives Part I • Describe how different classifications of anemia ( Aplastic, Hemolytic, Autoimmune hemolytic, Microcytic, Macrocytic) can occur due to different microbial infections including C...

Infectious Causes of Anemia Debra E Bramblett, PhD Burrell College of Osteopathic Medicine CVI-2023 Objectives Part I • Describe how different classifications of anemia ( Aplastic, Hemolytic, Autoimmune hemolytic, Microcytic, Macrocytic) can occur due to different microbial infections including Clostridium perfringens, Haemophilus influenza type B, Bartonella ballciformis, Plasmodium, Babesia, Hookworm and Diphyllobothrium latum, and the Parvovirus B19. • Recognize that viral infection by CMV, EBV, HIV, HSV or Hepatitis virus can cause hemolytic and/or autoimmune hemolytic anemia. • Describe the common characteristics of the Parvoviridae including structure and composition of the virion, genomic architecture, and replication. • Describe how infection with parvovirus B19 can lead to several different clinical syndromes depending on the host. • Describe the pathogenesis and immunity of Parvovirus B19, including the cellular targets for this virus and the variation of the clinical syndrome depending on the patient’s age and preexisting conditions. • Describe the epidemiology of B. bacilliformis including the regional prevalence and transmission vector and describe how a B. bacilliformis infection can lead to acute anemia. Anemia associated with chronic disease • The chronic illnesses associated with this form of anemia can be grouped into three categories: • 1. Chronic microbial infections, such as osteomyelitis, bacterial endocarditis, and lung abscess. • 2. Chronic immune disorders, such as rheumatoid arthritis and regional enteritis • 3. Neoplasms, such as carcinomas of the lung and breast and Hodgkin lymphoma. Anemia of Acute or Chronic Inflammation/Infection •Bacterial infections suppress erythropoietin (EPO) production and the proliferation of erythroid progenitors. •Chronic infection results in reduced erythroid progenitor proliferation and impaired iron utilization. •Anemia due to chronic disease will have Red Blood Cells that are normocytic and normochromic, or they can be hypochromic and microcytic. •Anemia associated with acute infection is typically mild but becomes more pronounced with time. •Acute infection can produce a fall in hemoglobin levels of 2-3 g/dL within 1 or 2 days.  Due to lysis of RBCs at the end of their life span.  Cytokines and fever select against the RBCs •Patients with preexisting cardiac disease may experience angina, exercise intolerance and shortness of breath due to anemia. Some Definitions • Macrocytic anemia -the red blood cells are larger than their normal volume. • Megaloblastic anemia is a condition in which the bone marrow produces unusually large, structurally abnormal, immature red blood cells (megaloblasts). • Microcytic, hypochromic anemia - the type of anemia in which the circulating RBCs are smaller than the usual size of RBCs (microcytic) and have decreased red color (hypochromic). Due to decreased iron reserves of the body which may be due to multiple reasons • Hemolytic anemia is the abnormal break-down of RBCs • Aplastic anemia, is a rare disease in which the bone marrow and the hematopoietic stem cells that reside there, are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). • Pure Red Cell Anemia (PRCA) a type of anemia affecting the precursors to red blood cells but not to white blood cells. • Autoimmune hemolytic anemia is where the body’s immune system creates antibodies (IgG) directed at RBC surface proteins Describe how different classifications of anemia ( Aplastic, Hemolytic, Autoimmune hemolytic, Microcytic, Macrocytic) can occur due to different microbial infections including Clostridium perfringens, Haemophilus influenza type B, Bartonella ballcifomis, Plasmodium, Babesia, Hookworm and Diphyllobothrium latum, and the Parvovirus B19. Summary of Different Types of Anemia due to Infection  Aplastic Anemia can occur with hepatitis virus, CMV, EBV and HSV viral infections and a special form, Pure Red Cell Aplasia occurs due to B19 virus.  Hemolytic anemia can be due to direct parasitization or by indirect mechanisms  Invasion of RBC by Bebesia leads to cell lysis.  Invasion of the reticuloendothelial system by Leishmania causes production of oxidative metabolic products that lyse RBCs  a sub-type of anemia that occurs when the body has fewer red blood cells than normal  Hemolytic anemia might be caused by bacterial toxin production  Alpha toxin in Clostridium perfringens lyses RBCs  Capsular polysaccharide (PRP) of Haemophilus influenza type B binds red blood cell surface and anti-PRP antibodies lyse the cell.  Autoimmune hemolytic anemia may result from EBV, CMV, or HIV infections.  Microcytic hypochromic anemia or iron deficiency anemia is associated with blood loss Recognize that viral infection by CMV, EBV, HIV, HSV or Hepatitis virus can cause hemolytic and/or autoimmune hemolytic anemia. Viruses Protozoans Helminths Bacteria Pathogen Form of anemia Parvovirus B19* Cytomegalovirus CMV Aplastic Anemia, Pure red cell aplasia, Transient Aplastic Crisis Hemolytic Anemia or Autoimmune Epstein Barr Virus EBV Autoimmune hemolytic anemia Plasmodium spp* Hemolytic (Normochromic/Normocytic) Trypanosoma Hemolytic not due to direct parasitization Leishmania donovani Hemolytic not due to direct parasitization Babesia* Hemolytic anemia due to direct parasitization Ancylostoma duodenale or Necator americanus; ( Hook worms) Microcytic hypochromic anemia or Iron deficiency anemia D. latum Megaloblastic anemia due to B12 deficiency Bartonella bacilliformis Hemolytic anemia Clostridium perfringens Hemolytic anemia due to toxin Haemophilus influenzae B Hemolytic anemia due to PRP Hemolytic anemia From Robbins and Cotran Atlas • Smaller RBCs lacking central pallor • Some Larger bluish-staining reticulocytes from increased marrow release to compensate for RBC loss. • Reduction in size or number of RBCs results in anemia Macrocytic anemia Megaloblastic • Unusually large, round red blood cells • Low hemoglobin • Can present as Megaloblastic anemia due to B12 efficiency in which there is large oval red blood cells (macro-ovalocytes), HowellJolly bodies (residual fragments of the nucleus), hypersegmented neutrophils, and reticulocytopenia Quiz 1 Parvovirus Parvoviridae • First discovered and introduced in 1975 • Very small, icosahedral capsid • Single-stranded DNA genome (ssDNA) • Parvoviruses must infect mitotically active cells because they do not encode the means to stimulate cell growth or a DNA polymerase (Murray 454) • We don’t know a lot about B19 DNA replication but we do know that Cellular S phase factors are required • B19 and Bocavirus are the only parvoviruses known to cause human disease Describe the common characteristics of the Parvoviridae including structure and composition of the virion, genomic architecture, and replication. Objective: Describe the pathogenesis and immunity of Parvovirus B19, including the cellular targets for this virus and the variation of the clinical syndrome depending on the patient’s age and preexisting conditions Human Parvovirus- B19 • • • • • • • • • Family: Parvoviridae Genome Composition: ssDNA ( + or -) Capsid Shape: Icosahedral (60 capsomers) 20 nm Virion: Non-Enveloped Disease: Fifths disease ( erythema infectiosum) in children or Acute aseptic arthritis in adults Interaction with the host: Lytic infection Transmission: Respiratory route Epidemiology: Approximately 65% of the adult population has been infected with B19 by age 40 Host cell target: Erythroid precursor cells (hEPCs) [Also erythrocytes] Receptor: Erythrocyte P antigen (globoside) B19 replication David Knipe, Fields Virology vol II, Section Ii chapter 65 figure 65.2 • No viral DNA polymerase • Two transcripts one for NS the other for structural proteins. • NSI is an endo nuclease and a helicase involved in DNA replication • Hairpin loops assist in genomic DNA replication as well as stability • The ssDNA is converted to ds DNA which is transcribed and replicated. Describe the common characteristics of the Parvoviridae including structure and composition of the virion, genomic architecture, and replication. Histological Diagnosis Bone marrow core biopsy specimen showing Parvovirus B19 intranuclear inclusions (arrows) Objective: Describe the pathogenesis and immunity of Parvovirus B19, including the cellular targets for this virus and the variation of the clinical syndrome depending on the patient’s age and preexisting conditions B19 virus and Anemia  B19 Target cell is erythroid progenitor cells:  erythroid progenitors and erythroblasts  Blood group antigen P  Transient Aplastic Crisis TAC (anemia)  If the patient has a preexisting high red blood cell turn over for some reason then a type of severe Anemia, Transient Aplastic Crisis can occur. But it goes away  Significant problem for Sickle Cell Patients  Pure red cell anemia PRCA- rare but very serious  Significant problem for immunocompromised.  Other Common B19 presentations  Erythema infectiosum, Arthralgia, Arthritis  Rare but important B19 presentations Erythropoiesis • Hemocytoblast P is present on erythroid progenitors, erythroblasts, and megakaryocytes. It is also present on endothelial cells, which may be targets of viral infection involved in the pathogenesis of transplacental transmission, possibly vasculitis, and the rash of fifth disease and on fetal myocardial cells • Unipotent stem cell • Pronormoblast/ Proerythroblast • Early normoblast/erythroblast • Intermediate normoblast • Late normoblast – Nucleus is expelled • Reticulocyte • RBC or erythrocytes 3 B19 differs between host  In children, human parvovirus B19 causes an acute selflimited illness known as erythema infectiosum (fifth disease).  In immunocompromised individuals, chronic infections can occur and cause a severe, persistent (Chronic) anemia (PRCA).  All people with hemolytic anemias rely on high erythrocyte production rates to maintain adequate hemoglobin levels.  sickle cell disease, thalassemia intermedia, hereditary spherocytosis (HS), autoimmune hemolysis and severe pyruvate kinase deficiency.  If the capacity of the bone marrow to manufacture new red cells is compromised, the hematocrit can dramatically fall to levels that are potentially deadly.  Parvovirus B19 suppresses bone marrow erythropoietic activity, leading to transient aplastic crisis TAC (which goes and away) orofPRCA inB19, immunocompromised. Objective: eventually Describe the pathogenesis immunity Parvovirus including the cellular targets for this virus and the variation of the clinical syndrome depending on the patient’s age and preexisting conditions B19 in Different Hosts Acute Host Disease Normal child Fifth Disease (erythema Normal Adult Polyarthropathy Chronic hemolytic anemia (Sickle Cell anemia, Hereditary spherocytosis HS or Thalassemia) Chroni Immunocompromised c patient Fetus Fetus infectiosum) Transient Aplastic Crisis (TAC) PRCA Pure red cell aplasia Congenital anemia Hydrops fetalis Objective: Describe the pathogenesis and immunity of Parvovirus B19, including the cellular targets for this virus and the variation of the clinical syndrome depending on the patient’s age and preexisting conditions Hydrops fetalis due to B19 infection • Generally Rare as most adult women have antibodies to B19. • Abnormal amounts of fluid build up in two or more body areas of a fetus. • The fetus is most at risk during second trimester Transient aplastic crisis TAC • TAC is the abrupt cessation of erythropoiesis characterized by reticulocytopenia, absent erythroid precursors in the bone marrow and precipitous worsening of anemia • B19 virus associated TAC is found in patients with underlying hemolytic disorders or in patients with high RBC turnover (ex. Sickle Cell Anemia or Hereditary Spherocytosis). • Other viruses associated with aplastic crisis: hepatitis, Epstein-Barr, cytomegalovirus, parvovirus B19 and HIV Diagnosis and work up for B19 infection with TAC  CBC with reticulocyte count      Low reticulocyte count ( 0-1%) Drop in hemoglobin levels by 2g/dL IgM antibodies by day 3 of illness IgG antibodies at time of recovery of erythrogenesis PCR will demonstrate high level viremia during TAC  Immunodeficient patients- have low or absent antibody levels, but can have chronic B19 infection. • In contrast to TAC, PRCA is characterized by very low or absent antibody levels. PCR is the diagnostic test of choice here. Also, bone marrow examination generally reveals the presence of viral inclusions and scattered giant pronormoblast • Therefore, PCR is the test of choice to detect viremia in these patients Quiz 2 Objectives part II • Identify the protozoans Plasmodium and Babesia by its morphology in a blood smear and/or by the clinical presentation and epidemiological features. • Define microcytic hypochromic anemia and explain how it can develop in the course of an infection of A. duodenale and N. americanus • Define Megaloblastic anemia and explain how it can develop in the course of a D. latum infection and be able to recognize symptoms and epidemiological characteristics of a D. latum infection. • Describe the epidemiology of B. bacilliformis including the regional prevalence and transmission vector and describe how a B. Bacilliformis infection can lead to acute anemia. • Recognize anemia caused by Hemophilis influenzae and Protozoans I will be introducing protozoans on October 5th but you need to recognize the role of Plasmodium and Babesia in anemia for this lecture. Anemia associated with Blood Parasites  The protozoan Plasmodium  Plasmodium vivax  Plasmodium ovale  Plasmodium malariae  Plasmodium falciparum (Black water fever)  Target cell is erythrocytes RBCs  P. vivax binds Duffy blood group antigen  P. falciparum binds to sialic acid residues on glycophorin A  Vector is the mosquito- Anopheles Babesia microti  Tick (Ixodes scapularis) transmitted protozoan  Pyriform bodies (pairs) or cruciform bodies  Tends to form ring-forms in tetrads merozoites  Hemolytic anemia: RBC lysis and decreased production What causes malaria anemia? Nicholas J. White, What causes malaria anemia?, Blood, 2022, Copyright © 2023 American Society of Hematology Plasmodium do cause anemia by rupture of infected RBCs but the level of RBC loss is far to great for it to be just lysis by the plasmodium. It turns out there is intravascular lysis and phagocytic removal of infected erythrocytes and there are also additional processes including with parasite interference with the production of erythropoietin. There is a decreased responsiveness to erythropoietin and increased erythrophagocytic activity all due to the release of inflammatory cytokines. Furthermore, there is removal of uninfected RBCs due to alterations in the structure of nonparasitized RBCs and in splenic function, that results in Helminths known for causing anemia Hookworm Infection and Anemia Ancylostoma duodenale Necator americanus The hook worm species differ in the shape of their biting plates Define microcytic hypochromic anemia and explain how it can develop in the course of an infection of A. duodenale and N. americanus Hook worm life cycle What Helminth Helminth type: Nematode Type? Rhabditiform larva non infectious Filariform larva infectious Adults are small 7 to 13 mm in length Define microcytic hypochromic anemia and explain how it can develop in the course of an infection of A. duodenale and N. americanus. Disease caused by Hookworm  Often asymptomatic  Microcytic/ hypochromic anemia  Iron deficiency anemia ( small and pale)  Other symptoms might include  vague gastrointestinal complaints  “ground-itch” rash  Respiratory symptoms (eosinophilic pneumonitis) due to 1.Ring shaped erythrocytes 2.microcytes 3. Faintly visible target cells 4. A lymphocyte 5. A normal sized cell after transfusion. Epidemiology  Hookworms (nematodes) infect humans found worldwide  New world hookworm: Necator americanus  Southeastern United States (warm and wet)  Old world hookworm: Ancylostoma duodenale  Ancylostoma braziliense, Ancyclostoma caninum  infects cats and dogs and accidentally humans causes “ground itch”found in southeastern United States, Latin America, South America, and Africa In addition to anemia, patients present with pallor, weakness, lassitude, dyspnea, and edema due to hypoproteinemia especially in malnourished children. Moderate infections and anemia can impair physical, cognitive and intellectual growth in children, diminished productivity of workers and threaten the outcomes of pregnancy for both mother and child.  Transmission is by direct penetration of skin by the filariform larvae  Bare feet and fecal contaminated areas. · Define microcytic hypochromic anemia and explain how it can develop in the course of an infection of A. duodenale and N. americanus. Pathogenesis of Hookworm infection • Adult worms adhere to mucosa and suck blood • Enzymes for tissue destruction • Anti coagulants increase bleed • Iron deficiency anemia caused by chronic blood loss • Microcytic/hypochromic erythrocytes (small and pale) Notice the very thin band of hemoglobin around the periphery(arrows). There are a few darkly stained cells in this field with normal amounts of hemoglobin from a recent transfusion of this patient D. latum life cycle plerocercoid. Cestode Helminth Type? Scolex Cyclops Proglottid Eggs embryona te in water operculum procercoid Coracidiu m Define Megaloblastic anemia and explain how it can develop in the course of a D. latum infection and be able to recognize symptoms and epidemiological characteristics of a D. latum infection. Megaloblastic Anemia and Diphyllobothrium latum • Parasite induces impaired B12 absorption • Intrinsic factor complex disassociation • Heavy vitamin B12 uptake by the parasite • Vitamin B12 and folate are required for thymine synthesis a building block for DNA • Megaloblastic anemia is characterized by large (macrocytic) & oval red blood cells and low reticulocyte count. Possibly nucleated RBCs in circulation • It is caused by Nuclear to cytoplasmic asynchrony • Impaired DNA synthesis • Normal hemoglobin accumulation • Symptoms: symptoms can include abdominal discomfort, diarrhea, vomiting, and weight loss & fatigue Megaloblastic anemia due to D. latum Large and oval Normal neutrophils are hypersegmented Normal red blood cells are smaller than the nucleus of a small lymphocyte A megaloblastic anemia resulting from decreased DNA synthesis with normal RNA/protein synthesis. As a result RBCs are large (megaloblastic) and the Define Megaloblastic anemia and explain how it can develop in the course of a D. latum infection and be able to recognize symptoms and epidemiological characteristics of a D. latum infection. Prolonged ( more than 3 to 4 years) or heavy D. latum infection may lead to Megaloblastic anemia caused by vitamin B12 deficiency. The vitamin B12 deficiency is a consequence of two factors: 1.Parasite mediated dissociation of the vitamin B12 intrinsic factor complex in the gut lumen ( making vitamin B12 inaccessible) 2.Heavy vitamin uptake and use by the parasite. Bone Marrow smear of Megaloblastic anemia Showing large nucleus B12 absorption: • • • • B12 is released from food in diet and bound by R R-B12 travels through GI and R is degraded by pancreatic enzymes B12 is bound by intrinsic factor (IF) B12 is then taken up by enterocytes carried into the blood stream Quiz 3 Bacteria Known for causing hemolytic anemia You will see these three bacteria again! Describe the epidemiology of B. bacilliformis including the regional prevalence and transmission vector and describe how a B. Bacilliformis infection can lead to acute anemia. Bartonella bacilliformis a bacterial species that causes severe anemia • • • • • • Gram-Negative Rods that penetrate RBCs Carrión disease- acute febrile illness Oroya fever- severe anemia Verruga peruana – blood-filled nodules Transmission by sandfly bite Restricted to Andes mountain region of Peru, Ecuador and Colombia Haemophilus influenzae B • Gram-negative v. short rods ( coccobacillus) • Serotypes “a” through “f” • Often colonizes the upper respiratory tract and an important cause of epiglottitis and meningitis. Anemia is common with young children • Antibody to the capsule play the primary role in immunity • Fails to grow on MacConkey agar and BAP. • V Factor (NAD) requirement • X factor requirement • Grows on “Chocolate” agar well Virulence Factors • Anti-phagocytic Polyribose Phosphate (PRP) Capsule • IgA1 protease • Haemophilus influenza type B capsular polysaccharide (PRP) binds red blood cell surface and anti-PRP antibodies lyse the cell. Clostridium perfringens • Large rectangular, Gram-positive anaerobic rods (boxcars) • Spores can be present but rarely observed in vivo or in vitro. • Ubiquitous in soil, water and sewage and normal microbial flora of GI tract of animals and humans. • Obligate Anaerobic: Often found along with facultative or aerobic organisms in infections • They produce exotoxins, enterotoxins and neurotoxins • Soft tissue diseases associated with C. perfringens: ▫ Cellulitis ▫ Fasciitis or suppurative myositis • releases enzymes acutely degrade the phospholipids of the ▫ Myonecrosis or gas that gangrene red cell membrane bilayer and the structural membrane proteins. Phospholipase C (alpha toxin) is the toxin thought most likely to be implicated in the hemolysis associated with clostridial infection. Intravascular hemolysis due to C. perfringens sepsis • RBC ghosts – black arrows • Spherocytes – Blue arrows • Reticulocytes – red arrow Quiz 4