Agents Of Cvs Infections

Marlon M. Maramion, MD, DPSP

BACTERIAL DISEASES Septic Shock

PATHOGEN Gram Negative & some Gram Positive Streptococcus pyogenes

Pericarditis Rheumatic Fever Leptospirosis

Grp A beta-hemolyric Streptococci Leptospira interrogans

Tularemia

Francisella tularensis

Brucellosis

Brucella spp

Anthrax

Bacillus anthracis

Gangrene

Clostridium perfringens

Cat-scratch disease

Bartonella henselae

Plague

Yersenia pestis

Endocarditis

a. Subacute b. Acute

Streptococci Staphylococcus aureus

BACTERIAL DISEASES

PATHOGEN

Relapsing fever

Borrelia spp

Lyme disease

Borrelia burgdorferi

Ehrlichiosis

Ehlichia spp

Epidemic typhus

Rickettsia prowazekii

Endemic murine typhus

Rickettsia typhi

Rocky Mountain spotted fever

Rickettsia rickettsii

VIRAL DISEASES

PATHOGEN

AIDS

HIV

Dengue fever

Arbovirus (Dengue fever virus)

Cytomegalovirus

Cytomegalovirus (CMV)

Burkitt’s lymphoma

Epstein-Barr virus (EBV)

Infectious mononucleosis

EBV

Myocarditis

Coxsackievirus A & B

Yellow fever

Arbovirus(Yellow fever virus)

Viral hemorrhagic fevers (Marburg, Ebola, Lassa)

Filovirus, Arenavirus

Hantavirus pulmonary syndrome

Sin Nombre hantavirus

PROTOZOAN DISEASES

PATHOGEN

American trypanosomiasis (Chagas’) Toxoplasmosis

Trypanosoma cruzi

Malaria

Plasmodium spp

Leishmaniasis

Leishmania spp

Babesiosis

Babesia microti

HELMINTHIC DISEASES

Toxoplasma gondii

PATHOGEN

Schistosomiasis

Schistosoma spp

Swimmer’s Itch

Schistosome larvae of animals

Isolation of bacteria from peripheral blood Sources

1. physical introduction (trauma) 2. focus of infection Outcomes 1. transient & inconsequential 2. establishment of distant foci of infection - meningitis, osteomyelitis, syphilis, endocarditis 3. progression to sepsis

Systemic disease triggered by infection

characterized by hemodynamic abnormalities and organ failure Hypotension Mechanism - activation of host cells leading to release of mediators activation of complement and coagulation systems Outcomes 1. circulatory collapse ( septic shock) 2. disseminated intravascular coagulation (DIC) 3. multiple organ failure

Gram Positive Bacteria Staphylococcus aureus Coagulase- negative staphylococci* S. epidermidis S. haemolyticus S. lugdunensis Enterococcal spp Viridans streptococci S. mutans S. milleri S. sanguis Streptococcus pneumoniae•

* More common in nosocomial infections • More common in community- acquired infections

Gram Negative Bacteria Escherichia coli Klebsiella spp* Proteus spp Pseudomonas spp* Haemophilus influenzae• Anaerobes* Bacteroides spp Fungi Candida spp

* More common in nosocomial infections • More common in community- acquired infections

Etiology

Enterobacteriaceae & Pseudomonaceae 1. Escherichia coli (35%) 2. Klebsiella, Enterobacter, Proteus & Serratia (38%) 3. Pseudomonas (12%) Origin - GIT - GUT - Skin

Predisposing Factors

1. Surgery (abdominal, genitourinary) 2. Urinary tract manipulation (catheterization) 3. Underlying diseases that compromise defenses 4. Large blood loss from trauma or surgery 5. Ischemia of intestinal wall

Pathogenesis - Endotoxin (LPS) release - Macrophage activation - Release of cytokines (IL-1, TNFα, IL-8) - Activation of complement & coagulation

systems Manifestations

Fever, ↑sleep, anorexia, ↑Acute phase proteins, Neutrophilia, Hemodynamic effects (shock)

Septic Shock

Common features

Fever, shock, hypotension, increase heart rate, acid-base problems, thrombosis and bleeding  The physiologic effects are due to activation of macrophages resulting in the release of cytokines (TNF, ILs), activation of complement and coagulation cascade Death may occur from multiple organ failure

Hypotension

1. LPS & other bacterial products activation of coagulation & complement (bradykinin & C5a- potent vasodilators) 2. IL-2 (increased vascular permeability)- from lymphocytes activated by IL-1 & TNF-α 3. PAF, Histamine, NO (vasodilators)- from activated macrophages & PMNs

DISSEMINATED INTRAVASCULAR COAGULATION (DIC) A disastrous complication of sepsis Common features Clotting in numerous blood vessels Bleeding due to depletion of coagulation

factors Can occur with septicemia or with any pathogen

but usually due to Gram-negative bacterial sepsis

Disseminated Intravascular Coagulation

1. increased expression of cell-adhesion molecules (CAM) in endothelial cells by IL-1 & TNF-α 2. endothelial cell damage by cytokines, proteases & oxygen radicals from activated phagocytes 3. PAF (most potent platelet agggregator)- from activated phagocytes 4. diminished synthesis of tissue factor pathway inhibitor (TFPI)- binding of enndotoxin to endothelial cells

Neisseria meningitidis Gram (-) diplococci Kidney bean-shaped Capsulated Piliated

Virulence Factors - Endotoxin- 10x potent than other endotoxins - IgA protease

- high fever, chills, nausea & vomiting, malaise - petechial hemorrhagic skin lesions - DIC - ischemic necrosis of skin & internal organs - Waterhouse- Friderichsen syndrome - hypotension & shock 85% mortality rate

Etiology

Coagulase-negative staphylococci S. S. S. S.

epidermidis Haemolyticus saprophyticus lugdunensis

Staphylococcus aureus Streptococcus pneumoniae Viridans streptococci S. mutans S. milleri S. sanguis

Pathogenesis

- EXOTOXINS bind to MHC-II molecules of macrophages - presentation to T lymphocytes - lymphokine activation of numerous T cells and macrophages - release of cytokines from activated macrophages and lymphocytes (same with Gseptic shock) TSST-1 – directly toxic to endothelial cells Peptidoglycan & capsule polysaccharide (S. pneumoniae)- activate macrophages, coagulation and complement systems

Staphylococcus aureus- most common Coagulase negative Staphylococci S. epidermidis S. saphrophyticus S. haemolyticus S. lugdunensis

Staphylococcus aureus Origin - cutaneous abscess/furuncle - minor skin trauma Outcome - establishment of infection at distant site (osteomyelitis, brain abscess) - Septic Shock- from Toxic Shock Syndrome Toxin1 (TSST1)

Staphylococcus epidermidis & Staphylococcus saprophyticus Origin - contaminated catheters, cannulae, shunts, IV drug abuse paraphernalia Outcome - transient bacteremia - prosthetic valve endocarditis

Sepsis- clinical Culture & isolation- confirmation & determination of specific etiology Factors influencing successful recovery of bacteria from blood: 1. Attention to proper technique in blood collection - avoid misdiagnosis as a result of skin flora contamination a. venipuncture site should be thoroughly sterilized b. drawing of blood from two different sites

Factors influencing successful recovery of bacteria from blood: 2. Multiple samples should be taken - 3 blood samples taken over a 24-hr period99% recovery of bacteria - 1 blood sample- 80% 3. Blood should be drawn prior to start of antimicrobial therapy -For those who have received antibiotics: 4 to 5 cultures in a span of two days

4. Volume of blood is directly related to yield (10ml)

Bacteremia 1. Antimicrobial therapy - based on results of susceptibility tests - start with broad-spectrum antibiotics before culture results are available, choice is based on: a. focus of infection b. age & condition of patient c. source of infection (hospital vs community acquired) 2. Surgical excision, debribement, draining of identified foci of infection

SEPSIS 1. Antimicrobial therapy 2. Supportive measures - fluid replacement - inotropic agents 3. Administration of inflammatory mediators antagonists (still under study) 4. Surgical excision of necrotic tissues

Streptococcus pyogenes - Respiratory tract & Skin pathogen o Gram (+) cocci in pairs or long chains o β hemolytic more virulent (strains with capsule) o Facultative anaerobe o Produces Streptolysin O and DNAse B

Virulence Factor

Biologic effect

capsule

antiphagocytic

Lipoteichoic acid

Binds to epithelial cells

M protein

Adhesin; mediates internalization by host cells; degrades complement C3b

F protein

Mediates adherence to epithelial cells and internalization Mediate pyrogenecity; enhancement of delayed HPS and susceptibility to endotoxin; cytotoxicity; mitogenicity for T cells; suppression of B cells; production of scarlatiniform rash

Pyrogenic proteins

Virulence factor

Biologic effect

Streptolysin S

DNAse

Lyses leukocytes; platelets and erythrocytes; stimulates release of lysosomal enzymes; non immunogenic Lyses leukocytes; platelets and erythrocytes; stimulates release of lysossomal enzymes, immunogenic Lyses blood clots; facilitates spread of bacteria in tissues (used in the treatment of acute MI) Depolymerizes cell-free DNA in purulent material

C5a peptidase

Degrades complement C5a

Streptolysin O

Streptokinase

- Acute, immune mediated disease (Type 2) - Multisystem involvement - Common in children 5-15 years old - Manifestations develop 2-3 weeks after

Streptococcal Pharyngitis - Genetic susceptibility (only a minority of infected patients develop RF)

Antibodies against M protein of Strep

Clinical manifestations 1. fever 2. migratory polyarthritis 3. Carditis - murmur & cardiomegaly - tachycardia, arrhythmia - progressive worsening with every recurrence 4. Subcutaneous nodules 5. Sydenham chorea 6. Erythema marginatum

Diagnosis JONES CRITERIA Major criteria  migratory polyarthritis; Diagnosis:  carditis; a. 2 major  Sydenham chorea; b. 1 major & 2 minor  Subcutaneous nodules; and  erythema marginatum. Minor criteria  fever  Polyarthralgia in the absence of polyarthritis as a major criterion;  prolonged PR interval on the electrocardiogram  Acute phase reactants (leukocytosis, raised erythrocyte sedimentation rate, and elevated C-reactive protein),  evidence of a preceding streptococcal infection (elevated or rising antistreptolysin titre, isolation of streptococci from throat swab culture, and positive streptozyme test)

PROGNOSIS - Generally good (only 1% die from fulminant RF) - After initial attack, vulnerability to reactivation of the disease with subsequent pharyngeal infections is increased - Most important consequence: Rheumatic Heart Disease - chronic valvular deformities (mitral stenosismost common)

TREATMENT 1. Treatment of streptococcal infection that led to the disease - Penicillin 2. Anti-inflammatory drugs a. NSAIDs b. Corticosteroids 3. Supportive (CHF)

PRIMARY & SECONDARY PREVENTIONS Primary Prophylaxis - Treatment of Pharyngitis to prevent initial attack of RF -DOC: Penicillin, Erythromycin Secondary Prophylaxis - Prevention of subsequent streptococcal infection in patients who already had RF - Prevention for the long term consequence of recurrent RF - Penicillin (oral/IM) up to 18th birthday or after 5 years from most recent attack

Leptospira interrogans Tightly coiled, thin, flexible spirochetes, 620 micra in length and 0.1 micron in diameter, one or both ends are hooked Ultrastructure  Leptospira consists of a helicoidal protoplasmic

cylinder, 2 axial filaments, and an outer envelope

Microaerophilic Oxidase (+) Catalase (+)

Leptospira interrogans Antigenic structure Outer envelope contains large amounts of lipopolysaccharide (LPS) of antigenic structure that is variable from one strain to another Among the pathogenic strains there are about 19 serogroups

Mechanism of virulence is uncertain; these are

the findings  Complement activation  Production of hemolysins and endotoxins  Probably cell-mediated immune response

Zoonotic disease  Host reservoirs include wild mammals and domestic animals, with high prevalence in rodents Major mode of transmission between

animals and humans  Direct contact with urine infected with virulent

Leptospira from an animal with leptospiruria (URINE) Leptospira enter the body through break in

the skin and mucous membranes

Dissemination: enters bloodstream

(spirochetemia) & spreads to variety of organs & tissues 1. Hepatic involvement - elevated liver enzymes - hyperbilirubinemia, jaundice 2. Vascular involvement - diffuse vascular injury hypovolemic shock - petechial hemorrhage, conjunctival suffusion - DIC 3. Renal involvement

1. Subclinical (Asymptomatic) Disease - positivity to antibodies, no sign/symptom - thru serological survey of veterinarians 2. Anicteric Leptospirosis Initial stage (IP=7-12 days) - non specific flu-like symptoms Secondary stage (duration: few days up to 1 month) - serum positivity for antibody & immune complex - severe headache, N & V, myalgia - splenomegaly, hepatomegaly, meningitis

3. Icteric Leptospirosis (Weil’s Syndrome) - most severe form of the disease - disseminated endothelial damage & vasculitis - impaired renal & hepatic fxn, internal hemorrhages, meningitis, cardiovascular collapse & shock - hepatomegaly (25%)

Laboratory Diagnosis

1. Culture & Isolation - blood, CSF, urine - growth may take up to 6 weeks - materials from culture examined under dark field microscopy 2. Serologic testing - antibody peaks in 4 weeks

Treatment 2.Penicillin- DOC 3.Tetracycline- for Penicillin sensitive

- Disease primary to hervibores

Bacillus anthracis Gram positive bacillus Obligate aerobe Spore-forming Encapsulated Non motile

Bacillus anthracis Antigenic Structure 1. Capsule polypeptide - (D-glutamic acid) - poorly immunogenic - stimulates antibody formation but not protective 2. Polysaccharide somatic antigen 3. Complex protein toxin

Bacillus anthracis Virulence Factors 1. Polypeptide capsule 2. Exotoxin - responsible for the development of lethal effects - 3 components a. Protective antigen - binds to cell receptor Exert synergistic effect b. Edema factor - adenylate cyclase activity c. Lethal factor

Pathogenesis 1. Cutaneous Route - through small abrasions or cuts - local multiplication 2. Inhalation - local & hilar node multiplication - hemorrhagic necrosis 3. Ingestion - ingestion of infected meat - invasion & ulceration of GIT mucosa Possibility of bloodstream invasion & toxemia from 3 areas

Clinical Disease 1. Cutaneous Anthrax - IP: 2-5 days - small painless papules to vesicles which rupture then develop black eschar 2. Pulmonary Anthrax (wool sorter’s disease) - influenza-like which develops to severe fatal pneumonia 3. Gastrointestinal Anthrax - N & V, hemorrhagic diarrhea, shock, death Bacteremia, Meningitis, Toxemia

Diagnosis Specimen: pustule, sputum, blood Presumptive diagnosis: - gram stain & fluorescent-antibody stain Penicillin containing medium - String of pearls reaction

Treatment DOC: Penicillin, alternative: Tetracycline or Erythromycin - large IV dose - time of diagnosis is critical esp for Pulmonary & GIT anthrax

Clostridium perfringens Requires ischemia & necrosis - nutrient & anaerobic environment Gram positive bacillus Spore-forming Obligate anaerobe

Clostridium perfringens Virulence factors 1. Exotoxin (α-toxin) - hydrolyzes lecithin & sphingomyelin - cell & mitochondrial membrane disruption 2. Enterotoxin - associated with food poisoning

Pathogenesis

Exogenous contamination - deep penetrating wounds Endogenous contamination - part of GIT & female genitalia flora (5% of population) - secondary to abdominal surgery/trauma - associated with septic abortion

Manifestations

Myonecrosis -necrosis, foul smell - gas formation (bubbles) - extension along muscle bundles up to the blood Suppurative infections - GIT & GUT Enteritis necroticans - acute ulcerative process with gut denudation

Diagnosis

- Culture & Isolation Treatment - Antibiotic: Penicillin - Debridement - Hyperbaric oxygen exposure

- Black Death - Zoonotic infection (rodents)

Yersenia pestis Gram negative coccobacillus Non motile Facultative anaerobe Catalase positive Grows best at 28°C Facultative intracellular organism

Yersenia pestis Virulence factors 1. F-1 glycoprotein (capsule)- antiphagocytic 2. Pla (protease)- activates plasminogen - bacteremic spread - inactivates C3b & C5a 3. W/V antigen - antiphagocytic - promote intracellular growth

Pathogenesis & Manifestations - Inoculation (flea bite) - Proliferation in the lymph - Enlargement of lymph nodes (buboes), Fever - Further proliferation- SEPTICEMIC PLAGUE

- vascular injury (dark blue areas in the skin) - septic shock - Entry to the lungs- PNEUMONIC PLAGUE - 100% death rate (3 days) - can be spread thru respiratory

Diagnosis

Culture & Isolation Treatment Antibiotic therapy: Streptomycin Chloramphenicol Tetracycline

Infection of endocardium Associated with cardiac abnormalities  congenital valvular diseases

Pathogenesis - attachment of blood borne bacteria to heart valves - multiplication - covered with platelets & fibrin (shield from phagocytes & complement) - sorce of bacteremia - may become an embolus

Pathology- Vegetations

Common among nondrug-abusers  Viridans streptococci: S. anginosus, S. sanguis, S.

mutans  Enterococci  Staphylococcus aureus

Common among drug-abusers  Coagulase-negative staphylococci  Pseudomonas spp

Others: Enterobacteriaceae, Yeast spp,

Haemophilus spp

Risk factors  An artificial (prosthetic) heart valve  A family history of endocarditis  Heart valves damaged (scarred) by conditions such as

rheumatic fever  Congenital heart or heart valve defects  Mitral valve prolapse with a murmur  Hypertrophic cardiomyopathy  Patients who already have some kind of heart problem have a greater risk  Children with congenital, rheumatic, or degenerative heart diseases have a 60-80 per cent risk  Adults age 15 - 50 with a preexisting heart disease have a 35-60 per cent risk

Manifestations fever, malaise, fatigue, weight loss, skin petechiae, embolic infarction of vital organs, and valve dysfunction with congestive failure Diagnosis 1. blood culture 2. Echocardiogram Treatment - Antibiotic specific for etiology

VIRAL DISEASES

PATHOGEN

AIDS

HIV

Dengue fever

Arbovirus (Dengue fever virus)

Cytomegalovirus

Cytomegalovirus (CMV)

Burkitt’s lymphoma

Epstein-Barr virus (EBV)

Infectious mononucleosis

EBV

Myocarditis

Coxsackievirus A & B

Yellow fever

Arbovirus(Yellow fever virus)

Viral hemorrhagic fevers (Marburg, Ebola, Lassa)

Filovirus, Arenavirus

Hantavirus pulmonary syndrome

Sin Nombre hantavirus

Ubiquitous DNA virus Trophic for B lymphocytes (C3 receptor)  B cell infection:

- does not cause death - results in polyclonal proliferation and EBV antigen expression (some cells become permanently infected) - latent infection Transmission

- respiratory secretions, saliva - oral contact - minority of cases: blood transfusion &

EBV in saliva

Infection of oropharyngeal epithelial cells

Infection of B cells

Formation of heterophile antibodies (IgM)

Enlargement of liver, spleen, and lymph nodes

Pharyngitis

B cell proliferation

Viral shedding in saliva

Expression of EBV early proteins T-cell activation

Atypical lymphocytes

Atypical lymphocyte: “Downy cell”

Clinical Disease 1. Infectious Mononucleosis - pharyngitis, lymphadenopathy, fever, rash - heterophile antibody formation - slow recovery with relapses 2. Burkitt’s Lymphoma 3. Nasopharyngeal Carcinoma - common in Asia

- Lymphoid malignancy of the jaw - High prevalence in Africa - Associated with translocation of c-MYC gene on chromosome 8 (EBV implicated in the mutation) - viral antigens/DNA in tumor tissue - transformation of cultured B lymphocytes by EBV in vitro - high EBV antibody titers in patients with Burkitt Lymphoma - induction of lymphoma by EBV in primates

Diagnosis 1. Lymphocytosis with atypical lymphocytes 2. Decreased CD4/CD8 ratio (increased CD8) 3. Serology a. (monospot test) detection of heterophile antibody b. Epstein-Barr virus specific antibody tests 1. viral capsid antigen (VCA) IgM- recent infection IgA- nasopharyngeal CA 2. Early antigens (EA) Antibody- Burkitt Lymphoma & Nasopharyngeal Ca

Treatment

- SUPPORTIVE

- Ubiquitous DNA virus - Associated with wide spectrum of illness - Target cells:

Neutrophils, monocytes, B cells, epithelial cells(salivary glands & kidneys) (possible latent infection) Pathology: - cell enlargement - inclusion bodies

MOT 2.Respiratory route (oral secretions) 3.Sexual transmission 4.Perinatal transmission 5.Congenital transmission

Clinical Disease 1. Infectious mononucleosis - EBV mononucleosis- like S/Sx - no heterophile antibody 2. Congenital % Perinatal Infection - asymptomatic or severe disease - hepatosplenomegaly, jaundice, chorioretinitis, petechiae, respiratory distress, microcephaly - hearing loss, Low IQ (congenital)

Diagnosis

1. Microscopic examination - urinary sediment/ kidney biopsy (+) owl-eye inclusion 2. Culture & isolation 3. Serology (IgM & IgG) Treatment

DOC- Ganciclovir and Foscarnet

Dengue Virus (Flavivirus) Enveloped, spherical viruses, 40-60nm diameter. Capsid proteins: nucleocapsid ('C') and matrix ('M'). Envelope: 1 glycoprotein ('E') Single-stranded, (+)sense RNA, ~10.5kb.

Four closely related, but antigenically distinct

serotypes (DEN-1, DEN-2, DEN-3, DEN-4)  maintained in a cycle that involves humans and

the Aedes mosquito Infection provides lifetime immunity to only that

serotype:  persons living in endemic areas can have more

than one dengue infection during their lifetime

Flu-like viral disease spread by the bite of

infected mosquitoes  Aedes aegypti  Day-biting; short-distance flight  Breed in discarded tires, flower pots, old oil

drums, and water storage containers close to human dwellings Occurs in most tropical and subtropical areas of

the world

Pathogenesis

Target cells: macrophages - Inoculation - Multiplication : bite site regional lymph nodes reticuloendothelial system - Viremia - Release of cytokines from the infected macrophages > vascular injury > complement activation > abnormal hemostasis

3 Distinct Syndromes 2.Classic Dengue Fever 3.Dengue Hemorrhagic Fever 4.Dengue Shock Syndrome

The time between the bite of a mosquito carrying dengue virus and the start of symptoms averages 4 to 6 days, with a range of 3 to 14 days

Self limiting

Fever phase (3-5 days) - headache, N & V - severe myalgia & bone pain (break bone fever) Rash phase (maculopapular) - trunk limbs & face - lymphadenopathy, granulocytopenia, thrombocytopenia - minor bleeding: petechiae, epistaxis, menorrhagia (+) tourniquet test

- Begins with fever & other S/Sx of Classic

Dengue

increased vascular permeability and abnormal homeostasis (diffuse capillary leak) - Hemorrhagic diathesis -associated with hemoconcentration, thrombocytopenia & DIC - May progress into Shock - Marked

- Marked increase in vascular permeability - Decreased plasma volume - Shock

- acidosis, hyperkalemia & death * 90% of DHF & DSS occur in children with history of multiple dengue infections

A. Enhancement of viral entry into macrophages by antibodies: 1. maternal antibody 2. antibody from previous infections - enhanced phagocytosis & increased viral replication of the virus in the macrophages B. Cross reacting helper T cells

Host Defense

- Antiviral antibody (IgM & IgG) - Virus- specific Cytotoxic T cells - helper T cells

Primary Infection  IgM antibodies appear approximately 5 days after onset of symptoms and rise for the next 1-3 weeks; detectable for up to 6 months  IgG are detectable at approximately 14 days after onset of symptoms and are maintained for life Secondary Infection  Approximately 5% patients do not produce detectable levels of specific IgM  IgM titre can be slower to rise in secondary infection  IgG appears approximately 2 days after symptoms appear; significantly higher in secondary infection

Epidemiology

- incidence is associated with vector dispersion - affects primarily children - major cause of death in children in epidemics (3-10% case fatality rate) Diagnosis 1. Clinical features: tourniquet test thrombocytopenia 2. Laboratory test: serology