HEMOPOIETIC SYSTEM INFECTIONS BACTERIAL INFECTIONS OF THE BLOODSTREAM Reading Assignment: Chapters 50 & 63 Definitions I. Bacteremia: Viable bacteria in the blood as demonstrated by a positive blood culture A. Broad spectrum of organisms may cause bacteremia B. Causative agents depends on the age of patient and the route of infection M. Jackson Page 1 of 11 II. Septicemia: Bacteremia with symptoms suggesting bacteria are multiplying in bloodstream III. Septic shock: A. Septicemia may lead to hypotension, diminished organ perfusion, high mortality B. Complex series of enzymatic reactions triggered by microorganisms or microbial products C. Primary microbial product is endotoxin in the bloodstream. D. Endotoxin activates a series of physiological cascades in a pathological manner 1. Systemic coagulation pathways Disseminated Intravascular Coagulation (DIC) 2. Complement 3. Inappropriate stimulation of cytokines 4. Adult Respiratory Distress Syndrome (ARDS) IV. Bacterial Endocarditis involves 3 processes: A. Endothelial damage B. Bacterial colonization C. Amplification Viridans Streptococci I. Virulence factors relevant to stream Infections A. Adhesins B. Fibronectin-binding protein A. Viridans streptococci etiologic agent in 40% of infective endocarditis cases B. Viridans streptococci are normal residents of oral cavity 1. Transient bacteremia following dental procedure or periodontal disease 2. Colonization of damaged heart valves that have fibrin-platelet vegetations a. Congenital defect in heart valve b. Damage due to rheumatic fever c. Prosthetic valve d. Atherosclerotic heart disease C. Inflammatory response to vegetation damages heart tissue
Page 2 of 11 A. Diagnosis from clinical findings and blood culture B. Viridans streptococci (S. sanguis, S. mutans, S. milleri, S. mitis) not Lancefield group 1. Lack specific cell wall antigens, serological tests not used 2. Identification is made using biochemical tests Staphylococcus aureus I. Virulence factors relevant to stream Infections A. Adherence factors B. Antiphagocytic components C. α-toxin that damages a variety of cell types A. S. aureus responsible for 25-30% of native valve infections B. Common cause native valve infections among intravenous drug users C. Bacteria are introduced into bloodstream from skin colonization sites D. S. aureus is most virulent of endocarditis isolates, highest mortality A. culture B. Gram positive cocci in clusters C. Catalase and coagulase positive Group D Streptococcus & Enterococcus I. Virulence factors relevant to stream Infections A. Multiple, high-level resistance to wide variety of antibiotics considered virulence factor B. Vancomycin resistant enterococci (VRE) is a great concern A. Normal habitat for Group D streptococci and enterococci is intestine and vagina B. Introduction into bloodstream from surgical procedures, opportunistic pathogens C. Frequent cause of nosocomial infections A. culture B. Gram positive cocci, catalase negative C. Laboratory identification 1. Serologic identification for Group D antigen 2. Enterococci grow in 6.5% NaCl & hydrolyze esculin in 40% bile (bile esculin agar)
Page 3 of 11 D. Pathogenic species 1. Enterococcus faecalis and E. faecium most common human pathogens 2. Non-Enterococcal Group D pathogens are Strep. bovis, Strep. equinus SPECIAL CASE BACTERIAL HEMOPOIETIC SYSTEM INFECTIONS Bacteria Classification Syndrome Pseudomonas aeruginosa Gram negative rod Intravenous drug use Staphylococcus epidermidis Gram positive cocci Prosthetic heart valves, indolent infections FUNGAL INFECTIONS OF THE BLOODSTREAM Candida I. Virulence factors relevant to stream Infections A. Adhesins B. Antiphagocytic components A. C. albicans causes prosthetic valve infections B. Systemic infections seen in the immunosuppressed C. Candida parapsilosis causes 25% of yeast endocarditis (IV drug users) A. culture may reveal systemic infection B. Candida can be cultivated in the lab C. KOH or Gram stains reveal budding round or oval yeast cells with hyphae
Page 4 of 11 Aspergillus I. Virulence factors relevant to stream Infections Infectious spores that are ubiquitous in the environment Prosthetic valve infections in the immunosuppressed; poor prognosis A. cultures are negative B. Biopsy of infected tissue is necessary C. Aspergillus can be cultured in the lab; branched, septate hyphae PARASITIC INFECTIONS OF THE BLOODSTREAM Plasmodium spp. I. Virulence factors relevant to stream Infections A. Four Plasmodium species: P. falciparum, P. malariae, P. vivax, P. ovale B. Life cycle 1. Sporozoites injected into human host from mosquito 2. Schizonts is intracellular stage in liver parenchymal cells 3. Merozoites released from ruptured liver cells into bloodstream a. P. vivax releases 10,000 merozoites b. P. falciparum releases 40,000 merozoites 4. Hypnozoites ( sleeping animal ) are dormant liver stage a. Hypnozoites responsible for long-term relapses b. Hypnozoites stage occurs only with P. vivax and P. ovale 5. Asexual cycle in red blood cells a. Trophozoite, Schizont in erythrocytes b. Merozoites released from erythrocytes 6. Sexual cycle in mosquito gut
Page 5 of 11 C. Erythrocyte receptors 1. Duffy antigen is receptor for P. vivax on reticulocytes 2. P. falciparum binds to glycophorin A on all red blood cell types D. Adhesins 1. P. falciparum produces protein adhesin displayed on infected erythrocyte membrane 2. Adhesin binds to receptor (ICAM-1) on vascular wall 3. Consequences of adhesin/receptor interaction a. Keeps infected erythrocytes out of peripheral circulation hampering detection b. Contributes to pathogenesis by occluding small blood vessels E. Antigenic variation confounds antibody response 1. Genetic hypervarability of antigenic surface proteins in schizont stage 2. Genetic recombination during sexual stage contributes to surface antigens variability
Page 6 of 11 A. Epidemiology: 1. Malaria from Italian mala aria ( bad air ) from belief that swamp air caused disease 2. Leading cause of deaths due to an infectious disease 2. Malaria endemic in tropical areas a. Principally Africa, Far East, South America b. Occurs in areas where Anopheles mosquito thrives 3. Annually: 10,000,000 new cases; 200,000,000 Africans infected; 1,000,000 mortalities 4. ~1000 US cases in 1998 a. Brought in by travelers b. Onset may be delayed up to 6 months in individuals taking anti-malarial suppressants B. Fever 1. Induced by asexual blood stage, release of merozoites into bloodstream a. Released malarial metabolites & hemozoin (from hemoglobin) antigenic, pyrogenic b. Cytokines such as IL-1 and TNF contribute to fever 2. Bouts of fever, initially sporadic then cyclical: 48 (tertian) or 72 (quartan) hr. intervals a. Parasite growth eventually becomes synchronized b. Tertian or quartan fever cycles characteristic of individual Plasmodium spp. Cyclical temperature fluctuations in malaria patient. P. falciparum, P. vivax, and P. ovale follow tertian (3-day) cycle. P. malariae follows quartan (4-day) cycle.
Page 7 of 11 C. Anemia is primary complication due to erythrocyte lysis and phagocytosis D. Cerebral malaria may occur with P. falciparum 1. Occlusion of small blood vessels with plasmodium-filled erythrocytes causes necrosis 2. TNF-α up-regulates ICAM-1, adherence of infected erythrocytes to vessel walls 3. P. falciparum is the most virulent due to large parasite load in the infected individual E. Hypotension and shock may be related to cytokine production during merozoite release F. Blackwater fever (black urine) 1. Caused by massive intravascular hemolysis (hemoglobinuria) 2. Autoimmune reaction in patients with history of infection may contribute G. Antigen-antibody complex deposition may lead to renal tubular necrosis H. Relapses with P. vivax and P. ovale caused by liver hypnozoites I. Natural resistance to infection 1. Lack of Duffy red blood cell antigen receptor 2. Altered hemoglobin that cannot be utilized by parasite a. Heterozygous for sickle cell (hemoglobin S) b. β-thalassemia c. Glucose-6-phosphate dehydrogenase deficiency J. Immunity to infection 1. Antibody to bloodstream stages (merozoite, sporozoite) 2. Cell-mediated immunity & intracellular killing mechanisms for intracellular schizont 3. Eventually there is a natural cure from adequate antibody response a. P. falciparum may take up to 1 yr. to be cleared b. P. malariae is more persistent, longest documented case was 53 yr. c. Hypnozoite hepatic infections with P. vivax & P. ovale can relapse in 5 yr. periods
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Page 9 of 11 A. smears show intraerythrocytic stages 1. Thick films for rapid diagnosis of parasitemia 2. Thin films (one blood cell thick) for speciating Plasmodia B. Antibody detection by ELISA indicates infection C. Molecular techniques (gene probes, PCR) developed for P. falciparum IV. Prophylaxis A. CDC recommendations: Mefloquine, Chloroquine, Hydroxychloroquine, Doxycycline B. Mosquito control and bed nets for prevention of malaria C. Vaccine development 1. Acellular vaccine to surface antigens under development 2. Vaccine development difficult due to antigenic variation of parasite
Page 10 of 11 Babesia microti I. Virulence factors relevant to stream Infections A. Species of Babesia 1. Rodent species is Babesia microti more common in US 2. Cattle species is Babesia bovis more common in Europe B. Life cycle similar to Plasmodia spp. 1. Asexual cycle in human red blood cells a. Sporozoites transmitted from salivary glands of the tick b. Trophozoites formed in cytoplasm of infected red blood cells c. Asexual division in red cells produces 4 merozoites d. Ring forms seen in erythrocytes 2. Sexual stage in occurs in ticks A. Transmission via ticks 1. Transmission via ticks (Ixodes spp.) that infest cattle and rodents 2. Ixodes tick also transmits Lyme disease Borrelia, simultaneous infections possible B. Most human cases occur in the Northeastern coastal regions of the USA C. Babesiosis is typically mild or subclinical 1. 1-4 week incubation period 2. Symptoms a. Fever, but periodic febrile paroxysms of malaria not seen with Babesiosis b. Myalgia, hepatosplenomegaly, hemolytic anemia, renal dysfunction c. Spontaneous resolution in a few weeks D. Babesiosis has severe manifestations in asplenic individuals 1. All European cases of babesiosis have been in asplenic patients 2. Complications: Severe hemolytic anemia, jaundice, and renal failure A. Giemsa-stained blood film shows ring forms similar to P. falciparum B. Serology may be used; Babesia antigens cross-react with Plasmodium
Page 11 of 11 CASE STUDY FOR BLOODSTREAM INFECTIONS A 42-year-old man reported a 1-week history of high fevers and shaking chills followed by periods of relative good health. His personal history included an extended trip to Africa 4 months prior to onset of the fevers. A blood specimen was collected and a thick film revealed the source of the patient s infection. Questions: 1. What is the likely pathogen causing this patient s fevers? 2. Why was the onset of disease delayed for 4 months? 3. Infection may not have been initiated if an effective vaccine was available. Which life cycle stage of this parasite should be targeted for vaccine development? 4. Name the genetic mechanism preventing development of an effective vaccine against this pathogen.