Fusion Session Workshop Infections of the Heart PDF

a. Epidemiology/transmission : Where does the organism come from? Is there a geography associated? How does it infect patient? (Vectors are important.) Who gets infected and who gets what kind of disease? (patient profile: things like age group, underlying condition, etc.) b. Descriptor/Characterist...

a. Epidemiology/transmission : Where does the organism come from? Is there a geography associated? How does it infect patient? (Vectors are important.) Who gets infected and who gets what kind of disease? (patient profile: things like age group, underlying condition, etc.) b. Descriptor/Characteristics: The basics of the bug (usually 6-8 word descriptor) c. Colonization/pathogenesis: How/where does the organism colonize and cause the damage? How does the body react? Is pathogenesis different in different compromising conditions? d. Diagnosis: How is diagnosis made? Where is the bug in the body? (specimens) Learn the big picture on lab tests; specific media or tests when mentioned in class or HO.) e. Prevention: How can the infection be prevented or risks reduced? (Example: vaccines, vaccine content, and usage [age administered or special conditions.] Also, types of isolation or chemoprophylaxis, including immunoglobulins, wound management, etc.) f. Treatment: How is it treated? Microbiology will most commonly leave drug of choice to pharmacologists but if it is discussed in class, it may be tested. Know other treatments besides drugs, such as debridement, fluid-electrolytes, etc. Also, if treatment has been discussed, we might use it as a clue in the case."  Nomenclature Streptococcaceae: formal family name. (Clue: -aceae). streptococci: common name which could refer to the family, species or any chain of cocci depending on the context. Streptococcus is a genus name. Streptococcus sp. means any species. Streptococcus spp. means all or most species of Strep. Streptococcus pneumoniae is a species. S. pneumoniae is the proper abbreviation for the species. Strep. pneumo. (or pneumococcus) are colloquial usage.  Heart Diseases and the Causative Agents  Endocarditis Commonly a bacterial infection. Less commonly a fungal infection. Rheumatic heart disease (immune damage following untreated Streptococcus pyogenes pharyngitis). Myocarditis – by Coxsackie B virus; also from circulating diphtheria toxin. Pericarditis – Acute benign is commonly viral; bacterial pericarditis more serious. Vascular inflammation from infection may lead to plaque formation and play a major role in atherosclerosis.  Infective Endocarditis (IE) Endocarditis is the inflammation of the heart endothelium (endocardium), often involving the valves. May be an infectious or autoimmune disease. Fever, possibly low-grade and intermittent, is found in 90% of patients with IE Heart murmurs are heard in ~85% patients. For additional symptoms see Dr. Yakubovskyy’s lecture: Inflammatory & Valvular Heart Disease. Duke Criteria for Diagnosis of Infective Endocarditis (Microbial Evidence) Blood culture positive for IE: Typical microorganisms consistent with IE from 2 separate blood cultures. Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus or;. Community-acquired S. aureus or enterococci, in the absence of a primary focus or; Microorganism consistent with IE from persistently positive blood cultures, defined as follows: At least 2 positive cultures of blood samples drawn 12 h apart or; All of 3 or a majority of ;4 separate cultures of blood (with first and last sample drawn at least 1h apart). Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med. 1994 Mar. 96(3):200-9 What is the Source of the Causative Agent? Most are normal flora, but may be pathogens or contaminants. Chewing, brushing teeth, dental work, extraction, root canal, poor dental hygiene (caries). Procedures: Bronchoscopy, GI endoscopy; Urinary tract manipulation. Surgery (pacemakers, stents, etc.). Indwelling catheters. Child birth. Injection drug users – contaminated drugs, skin flora (increased # of S. aureus), sharing needles. Demographics/Patient Profiles: Endocarditis Patient with native, undamaged heart tissue. Patient with native, damaged hearts. Patients with damaged heart and prosthetic devices like pacemakers or defibrillators. #2 or 3 with recent specific exposures like dental work. Immunocompromised patients. Injection drug users (IDU or IVDA): Skin flora (S. aureus , Staphylococcus epidermidis). Contaminants from drugs (Candida in heroin and Aspergillus). Water (Pseudomonas). Oral flora (licking needles). Homeless (Bartonella). Patients with indwelling catheters S. epidermidis.  The Infectious Process Bugs must get entry into the body. Bugs start planktonic in the blood stream so must resist serum killing. Escape phagocytosis and killing by PMNs (extracellular polysaccharides or cell envelope  proteins). Then they must adhere: This involves proximity to the endothelium (force physics) + pathogen adhesins and, most frequently, binding to host damage coated with a nonbacterial thrombosis. Fibronectin-binding is greater in bacteria causing endocarditis than in those not. Fibronectin is found on prosthetic devices, non-bacterial thrombotic vegetations; and on the subendothelial matrix exposed by damage to the endothelium. Fibronectin is not present on the normal cardiac endothelial surface. One agent (S. aureus ) binds fibrinogen (found on native heart.) S. aureus also binds to fibronectin. Note there are virulence differences in different strains of S. aureus. Vegetation Biofilm - 3D growths of bacteria, extracellular bacterial products, platelets, fibrin mesh, (but few immune cells), etc. Bacteria in the interior are less accessible to phagocytic cells. Interior cells have altered metabolism and so are tougher to treat with antibiotics. (slowed growth but possibly also lower oxygen). The presence of bacteria stimulates continued building. Cardiac Vegetation Image credit: See page for author (https://commons.wikimedia.org/wiki/File:Haemophilus_parainfluenzae_Endocarditis_PHIL_851_lores.jpg) , Public domain, via Wikimedia Commons Bacterial cells on the outside of the vegetation seed the blood to produce nearly continuous septicemia which seed other sites such as bones or joints. (Fever) Vegetation pieces break off and may cause infarcts in various body locales or strokes  Image credit: Sunjit17 via MicrobeWiki (https://microbewiki.kenyon.edu/index.php/File:Biofilm.png) Transcript  Biofilm Development Stages 1. Dispersion. 2. Planktonic bacteria. 3. Attachment. 4. Cell-cell adhesion. 5. Proliferation. 6. Maturation.  Summary of Endocarditis Causative Agents Bacteria Staphylococcus aureus  Coagulase negative staphylococci Viridans streptococci (oral) Enterococci HACEK group Gram negative; fastidious, CO2 Rarely coliforms Fungi Candida, Aspergillus Culture negative Bartonella HACEK (slow growers)  Bacterial Endocarditis Causative Agents Staphylococcus Aureus Major organisms infecting intact endothelium. fibrinogen binding. toxins damage the heart rapidly so murmur may not be present initially but show up rapidly. Also infects already damaged hearts (fibronectin-binding) causing more damage. Responsible for 70% of IE cases involving injection drug users. Onset is generally acute but may not be in injection drug users. Gram-positive cocci in clusters. Catalase-positive. Coagulase-positive. Beta-hemolytic. Yellow colonies. Haloduric: mannitol salt agar (ferments mannitol in the present of high salt).  Image credit: Sherris & Ryan's Medical Microbiology 8th edition by Kenneth J. Ryan. Epidemiology Normal flora of nasal membranes. Skin colonization; higher numbers on skin of IV drug abusers, diabetics (requiring insulin), hospital workers, individuals on hemodialysis and people getting allergy shots. Sturdy, survives on surfaces for a while. Spread by sloppy health care workers. Surgical wounds infections → bacteremia. Virulence Clumping factor = fibrinogen binding protein ("bound" coagulase) – facilitates attachment to fibrinogen found on normal endothelial surfaces. Coagulase converts fibrinogen to fibrin: coats cells with fibrin making them resistant to phagocytosis; also localizes infection; helps build vegetation. Alpha toxin – inserts self to form pores in human cell membranes → cell leakage: RBC, WBC, platelets, other tissue cells like heart valves. S. aureus stimulates the production of tissue thromboplastin helping build vegetation. Teichoic acids bind to fibronectin of damaged host cells and clots. Protein A: surface, binds Fc portion of IgG, inhibits phagocytosis. FYI: Plus other hemolysins, hyaluronidase, nuclease, lipase, protease, and a plasminogen activator. Very damaging organism. Medically Important Staphylococci (Review)  Typical Important Species Coagulase Common diseases hemolysis Features NF nose/skin abscesses/mastitis/ ß-hemolytic furuncles Protein suppurative lesions Ainhibits surgical, impetigo Coagulase ß phagocytosis endocarditis S.aureus (normal or IVDA) positive hemolysis TSS- toxins Toxic Shock enterotoxins- Syndrome heat stable Osteomyelitis exfoliatins Gastroenteritis cytolysins Susc to novobiocin; catheter- prosthetic device infections; Coagulase NF skin; S. epidermidis none endocarditis in negative plastic IVDA or people on adherence – IVs extracell matrix Coagulase Urinary tract Resistant to S.saprophyticus none infections in young negative novobiocin; women Coagulase Negative Staphylococci (In Heart Commonly S. epidermidis) Gram-positive cocci in clusters. Catalase-positive.  Coagulase-negative. Not hemolytic. Cutaneous flora (skin, anterior nares, ear canals). Major agent in patients with prosthetic devices and IV lines. Up in immunocompromised patients (esp. neutropenic) & pre-mature babies. Lacks many virulence factors; needs entry. Makes polysaccharide slime → biofilms on catheters. Needs fibronectin to bind to heart. Viridans Streptococci Gram-positive cocci in chains Primarily alpha-hemolytic strep (catalase-negative) Not inhibited by optochin nor lysed by bile. Normal flora of the oral mucosa or a few in the gi tract (S. gallolyticus, formerly S. bovis) S. gallolyticus S. mutans (always mentioned with caries) S. sanguis Low virulence; require pre-existing heart damage. Enter with trauma or dental caries (poor dental hygiene); root canal/dental work without prophylactic antibiotics. Extracellular matrix of dextran adheres to platelet-fibrin aggregates on aortic valve. Bind to fibronectin (S. sanguis). Enterococci Gram-positive cocci with variable hemolysis, chains. Formerly part of group D streptococci (cat neg). PYR test positive (FYI: pyrrolidonyl arylamidase). Grow in presence of high salt or detergents such as bile. Part of the normal GI flora. Possibly worlds toughest bacteria. Generally require two drugs to treat (B-lactam and an aminoglycoside) Cause endocarditis in patients who have pre-existing heart disease and who have had GU or GI tract manipulations without prophylactic antibiotics. Symptoms: Subacute onset in someone who already has murmur; increasing fatigue & murmur worsens. Generally require two drugs to treat (B-lactam and an aminoglycoside); VRE- Vancomycin Resistant Enterococci. Treatment/Prevention of Bacterial Endocarditis Prophylactic antibiotics to prevent bacterial endocarditis in people with pre-existing diseases are used in very limited situations now. Specific treatment is beyond the scope of course. Read up and follow your local public health department, hospital and CDC recommendations for reducing drug resistance (e.g., rotations of hospital formulary drugs, restriction of use of certain drugs.). Hygiene! Hygiene!  Fungal Endocarditis Causative Agents Candida Spp. Image credit: Sherris & Ryan's Medical Microbiology 8th edition by Kenneth J. Ryan. Transcript   A. Candida albicans. A. When incubated at 37 degrees Celsius and in the presence of serum, C albicans rapidly form elongated hyphae called germ tubes. B. On specialized media, C albicans form thick-walled chlamydoconidia, which differentiates it from other Candida species. Candida: Normal Flora to Pathogen Polymorphic yeast converting to pseudohyphae ± hyphae (C. albicans) in tissue and disease. Normal moist skin and mucosa flora; contaminate some IV drugs (heroin). GI tract overgrowth w/ antibacterial. Invade catheters (or bowel defects) → septicemia (fungemia) → Endocarditis (most common in patients with catheters). Culture Negative Endocarditis Most are normal flora, but may be pathogens or contaminants. Chewing, brushing teeth, dental work, extraction, root canal, poor dental hygiene (caries). Procedures: Bronchoscopy, GI endoscopy; Urinary tract manipulation. Surgery (pacemakers, stents, etc.). Indwelling catheters. Child birth. Injection drug users – contaminated drugs, skin flora (increased # of S. aureus), sharing needles.  Culture Negative Endocarditis Bartonella often endocarditis in homeless alcoholics. Rheumatic heart disease. HACEK group is slow to grow. Coxiella burnetii – subacute and generally on a damaged heart or prosthetic device but unrelenting; can be cultured on special media but PCR is method of choice.  If the patient is seropositive, can be diagnostic. Bartonella Gram-negative bacteria (formerly classified as Rickettsias but extracellular) (doesn’t show up on Gram stain: tiny). Both B. quintana and B. henselae can cause endocarditis generally in immunocompetent patients. Endocarditis in immunocompetent homeless with poor hygiene (body lice – B. quintana). Endocarditis in individuals with a history of exposure to cats (B. henselae). Aerobic, fastidious (blood agar + CO2), slow growing (1-6 weeks) (often culture negative) Increasing serotiter is important in diagnosis Rheumatic Heart Disease: Pancarditis Post Streptococcus Pyogenes Pharyngitis Immune-mediated heart damage as a result of untreated S. pyogenes sore throat. Primary infection: Sore throat from S. pyogenes (Lancefield Group A Streptococcus ). Untreated may lead to rheumatic heart disease. RHD more likely with certain M types. Delays up to 1 week are usually ok. Each subsequent strep throat infection causes more heart damage. Check guidelines for prevention. It is critical to EDUCATE PATIENTS! Rheumatic Heart Disease (RHD) Autoimmune phenomenon (non-suppurative sequel) involving molecular mimicry between Streptococcal antigens (M proteins) and human antigens. Antibodies and/or cell-mediated immunity triggered by the streptococcal antigens cross- react with heart muscular and valvular connective tissue. Diagnosis of RHD: Symptoms and serology Increasing or high anti-streptolysin O titer. The patient may not remember having a sore throat. Not associated with GAS impetigo. Do not use anti-M protein antibodies to diagnose. Streptococcus Pyogenes (Group A Streptococcus)  Gram-positive cocci in chains (occasionally pairs). Catalase-negative. Beta-hemolytic. Lancefield Group A. Remember in Rheumatic Fever or Rheumatic Heart Disease, GAS is not infecting heart; this is an auto-immune disease following GAS pharyngitis.  Pharmacologic Management of Endocarditis General Principles of Treatment The primary goal in the treatment of bacterial endocarditis is to eradicate infection including sterilizing the vegetations. There are multiple challenges in the management of this infection including: Endocarditis is a focal infection with high bacterial density. Slow rate of bacterial growth within biofilms. Low microorganism metabolic activity. Impaired host immune system is present in many patients. Increased drug binding to serum proteins. Problems with drug penetrating into vegetation. Pharmacokinetic and Pharmacodynamic issues. Because of the challenges presented in the treatment of bacterial endocarditis characteristics of appropriate antibiotic selection include: Bactericidal agent. Parenteral administration. Prolonged course of therapy. Minimum duration of 4 weeks. Common Antibiotics (Review) Drug/Class Mechanism Adverse Effects Spectrum Inhibit cell wall Strep Penicillin/ Hypersensitivity Ampicillin/ Nafcillin cross linking; reactions Enterococcus Enhance Staph (non MRSA) autolysins Inhibit cell wall Cephalosporin cross linking; Hypersensitivity Strep (1st, 3rd) Enhance reactions Staph (non MRSA) autolysins Infusion reaction Strep Inhibit cell wall Vancomycin Nephrotoxicity Enterococcus elongation Ototoxicity Staph (+MRSA) Strep Binds and Daptomycin depolarizes cell Muscle aches Enterococcus membranes Staph (+MRSA) Gram(-) alone Nephrotoxicity Irreversible Gram(+) in Aminoglycoside inhibition 30s Ototoxicity combination with ribosome cell wall active Neurotoxicity agent Discolors secretions Staph Inhibit RNA Rifampin Not used as polymerization Hepatotoxicity monotherapy Drug interactions Anemia Staph 50s inhibition of  Linezolid protein synthesis Thrombocytopenia Strep Neurotoxicity Enterococcus Arrhythmias Block topoisomerase II Neurologic Gram(-) including Fluoroquinolone and IV to impair Tendonitis/rupture pseudomonas transcription Hypoglycemia Choosing Antibiotic Therapy This is a serious illness, and you will often use TWO agents, a cell wall inhibitor and an inhibitor of bacterial protein synthesis. Choosing the cell wall inhibitor. If the infection is penicillin-sensitive: Viridans Streptococcus → penicillin G Enterococcus species → penicillin G or ampicillin Staphylococcus aureus → penicillin G or cefazolin Beta-lactamase secreting staphylococcus aureus → nafcillin MRSA or PCN allergy → vancomycin Choosing the inhibitor of bacterial protein synthesis: Viridans Streptococcus → gentamicin Enterococcus species → gentamicin or streptomycin Staphylococcus aureus → gentamicin Endocarditis Prophylaxis People with the highest risk for poor outcomes from bacterial endocarditis may be prescribed antibiotics prior to certain dental procedures to reduce their risk. These include procedures that involve manipulation of gingival tissue or the periapical region of teeth, or perforation of the oral mucosa. Antibiotic prophylaxis is reasonable before the above-mentioned dental procedures for people with heart valve disease who have any of the following:  Prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts. Prosthetic material used for heart valve repair. Previous IE. Unrepaired cyanotic congenital heart defect (birth defects with oxygen levels lower than normal) or repaired congenital heart defect, with residual shunts or valvular regurgitation at the site adjacent to the site of a prosthetic patch or prosthetic device. Cardiac transplant with valve regurgitation due to a structurally abnormal valve. Antibiotic prophylaxis before dental procedures is not recommended for any other types of congenital heart disease. In addition, antibiotic prophylaxis is not recommended for patients with valvular heart disease who are at high risk of endocarditis for non-dental procedures (e.g., TEE, esophagogastroduodenoscopy, colonoscopy, or cystoscopy) in the absence of active infection. Situation Agent Adults Children Oral Amoxicillin 2g 50 mg/kg 2 g IM or Ampicillin 50 mg/kg IM or IV IV Unable to take oral OR medication cefazolin or 1 g IM or 50 mg/kg IM or IV ceftriaxone IV 2g 50 mg/kg Cephalexin* OR Allergic to penicillin or 500 mg 15 mg/kg ampicillin- oral azithromycin or clarithromycin OR doxycline 45 kg. 100 mg Allergic to penicillin or ampicillin and unable to Cefazolin or 1 g IM or 50 mg/kg IM or Iv  take oral medication ceftriaxone IV Data credit: Wilson WR; Gewitz M; Lockhart PB; Bolger AF; DeSimone DC; Kazi DS; Couper DJ; Beaton A; Kilmartin C; Miro JM; Sable C; Jackson MA; Baddour LM; 2021. Prevention of viridans group streptococcal infective endocarditis: A scientific statement from the American Heart Association. American Heart Association.https://pubmed.ncbi.nlm.nih.gov/33853363/ (https://pubmed.ncbi.nlm.nih.gov/33853363/)  Myocarditis Inflammation/infection of myocardium. Many are asymptomatic. Symptoms depend on agent but often include chest pain and arrhythmia; if it becomes chronic may lead to dilated cardiomyopathy and congestive heart failure with dyspnea. More common in immunocompromised people. Causative agents: Viral; most commonly Coxsackie; (fecal oral spread); many other viruses can cause including adenoviruses, other enteroviruses, and Parvovirus B19. (coxsackie B and adenovirus bind to coxsackie and adenovirus receptor (CAR) found on myocytes.) Trypanosoma cruzi (in chronic cases) infected in South America. Image credit: Ross University Transcript  Viral myocarditis typically progresses through phases including viral invasion, immune response activation, tissue damage, and potential resolution or chronicity, with manifestations ranging from mild flu-like symptoms to severe heart failure or sudden death. Week 1: Acute phase (viral replication) Weeks 2-3: Subacute phase (immune response) 30-90 days: Chronic phase (dilated cardiomyopathy) Image credit: Ross University  Transcript  Acute viral myocarditis is characterized by direct viral invasion and acute inflammation leading to myocardial injury, while subacute myocarditis involves persistent inflammation and ongoing myocardial damage often accompanied by the development of autoimmune responses or viral persistence. Long list of viruses Coxsackie. B classically one of the most common. PCR data suggests that parvovirus B19 (PVB19) may now be leading cause. Sporadic with any age but life threatening in babies (febrile with sudden heart failure). Coxsackie, Echo- and Enteroviruses Small, naked, (+) ssRNA viruses (Picornaviridae). Fecal oral spread; replicate in GI first and then causes viremia. Pathogenesis: infect heart cells, triggers WBC to attack infected cells and also makes antibodies and WBC to attack uninfected cells (autoimmune). Commonly occurs in elderly or infants. Other Causative Viruses Parvovirus B19. Single-stranded DNA virus. Naked. Adenoviruses. Double-stranded DNA viruses. Naked. Trypanosoma Cruzi Image credit: Stefan Walkowski (https://commons.wikimedia.org/wiki/File:Trypanosoma_brucei_gambiense_-_trypomastigote.jpg) , CC BY- SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0) , via Wikimedia Commons American Trypanosomiasis – a.k.a. Chagas disease. Vector: reduviid bug (belong to the Triatomid family (Common names: cone, kissing or assassin bug). The infectious stage is trypomastigote; (reduviid bug defecates as it bites human; the trypomastigote is transferred in feces and either rubbed into eye or scratched into bite site to start infection.)  Image credit: The CDC (https://www.cdc.gov/dpdx/trypanosomiasisamerican/index.html) Transcript  1. Triatomine bug takes a blood meal. 2. Metacyclic trypomastigotes penetrate various cells at bite wound site. Inside cells they transform into amastigotes. 3. Amastigotes multiply by binary fission in cells of infected tissues. 4. Intracellular amastigotes transform into trypomastigotes, then burst out of the cell and enter bloodstream. 5. Triatomine bug takes a blood meal. 6. Epimastigotes in midgut. 7. Multiply in midgut. 8. Metacyclic trypomastigotes in hindgut. Chagas Disease Image credit: Beucler N, Torrico F, Hibbert D (2020) A tribute to Cecilio Romaña: Romaña’s sign in Chagas disease. PLoS Negl Trop Dis 14(11): e0008836. https://doi.org/10.1371/journal.pntd.0008836 (https://journals.plos.org/plosntds/article? id=10.1371/journal.pntd.0008836) CC BY-4.0 (https://creativecommons.org/licenses/by-sa/4.0/) Trypanosoma cruzi. South and Central America poverty housing where the reduviid bugs nest in houses and feed at night, defecating as they feed. Organism is rubbed/scratched into bite or eye. In children, asymptomatic or acute febrile disease with chagoma or unilateral eyelid edema (a.k.a. Romaña sign) at the original entry site. Lasts 1-3 months and dissemination with the associated immune damage may cause significant tissue damage. Any human nucleated cell may become infected with the organism replicating inside the cells (as amastigotes) producing cysts. When released, some of the antigens coat tissue cells triggering cell/tissue damage, particularly to heart, skeletal and smooth muscle and neural ganglia cells. Up to 30% of those infected Symptoms include myocarditis and in some megaesophagus and megacolon. Transmitted also by transplantation and transfusion. Reactivates with immunosuppression. Diptheria and Diphtheria Toxin Corynebacterium diphtheriae is a Gram-positive, non-spore-forming coryneform rod. Diphtheria toxin is produced only in strains of Corynebacterium diphtheriae which are  stably infected by a specific corynebacterium virus (a.k.a., Corynephage beta). These lysogenized cells are referred to as Tox+ strains. And they produce the toxin. Circulating diphtheria toxin binds, enters, and kills cells of the myocardium producing myocarditis in about the 2nd week of the disease resulting in heart failure. Diphtheria toxin ADP-ribosylates eukaryotic EF-2, shutting down protein synthesis, and killing cells.  Pericarditis Inflammation/infection of pericardium often with pericardial fluids. Acute benign most often viral (Enteroviruses or Coxsackie plus many others). Bacterial is much less common but more serious. Often an extension of pneumonia or tb. Symptoms: Sharp pain (often precordial) - can be mistaken for a heart attack. (Fever will be more prominent in infection.) Usually involves the myocardium too. Inflammation/infection of pericardium often with pericardial fluids. Acute benign most often viral (Enteroviruses or Coxsackie plus many others). Bacterial is much less common but more serious. Often an extension of pneumonia or tb. Symptoms: Sharp pain (often precordial) - can be mistaken for a heart attack. (Fever will be more prominent in infection.) Usually involves the myocardium too.  Borrelia Lyme Disease (Spirochetes Causing Multisystem Dz) Recommended reading: Murray 7th edition: 355-360 (http://www.cdc.gov/lyme/) Borrelia Spirochetes: highly motile spiral-shaped bacteria with endoflagella (flagella beneath the outer membrane).  Larger and fewer spirals than Treponemes. ~35 species. Maintained in nature by cycling through wild animals and the ticks that feed upon them. 2 species have an exclusive reservoir in humans: B. recurrentis & B. duttonii Antigenic variation occurs in many species. Image credit: Alan R Walker (https://commons.wikimedia.org/wiki/File:Borrelia-theileri-cow.jpg) , CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) , via Wikimedia Common Borrelia Burgdorferi Sensu Lato (US) Large spirochete: intracellular or extracellular. Able to sequester in tissues (probably inside human cells) or coat self with human membrane. There is evidence for gene rearrangement and antigenic variation as is seen in other Borrelia; recombination between bacterial genes and linear plasmids produces new surface proteins. If gene from the silent site is recombined into where there is a promoter, it then is expressed. Transmitted by bite of Ixodes tick Ixodes scapular is in north central and eastern US Ixodes pacificus in western US  OspA is a major surface protein Borrelia. This is the outer surface protein produced on B. burgdorferi when in the tick. ospA gene is downregulated and OspC (another Borrelia Osp) is turned on by feeding on human blood and becomes a major surface antigen before B.b. can be transmitted to humans. Ixodes Scapularis (Deer Tick) Image credit: Sherris & Ryan's Medical Microbiology 8th edition by Kenneth J. Ryan. Transcript  Deer tick size 2mm compared to US penny coin. May also transmit Anaplasma phagocytophila or Babesia microti or be associated with tick paralysis. Maintained in deer and mouse hosts. Larvae and nymphs overwinter on white-footed mice. Adults overwinter on white-tailed deer. Nymphs and adults transmit B. burgdorferi. Incidence in the area is due to the geographical distribution of both reservoirs and vectors, fluctuations in their population numbers, and incidence of B. burgdorferi in animals. View the CDC map and drag the slider to see how infection distribution has changed  over time: Lyme Disease Cases Over Time by State of Residence – United States. Lyme Disease Progression Image credit: Sherris & Ryan's Medical Microbiology 8th edition by Kenneth J. Ryan. Transcript  1. Female drops from host and lays uninfected eggs. 2. Uninfected larvae hatch. 3. Larvae feed on infected animal host and acquire Borrelia burgodorferi. 4. Infected larvae become dormant. 5. Infected larvae molt, becoming nymphs. 6. Infected nymphs feed, transmitting Borrelia burgodorferi. 7. Infected nymphs molt becoming adults. 8. Adults feed on animal (deer) host and mate. 9. Female dormant; male dies.   1st Stage  Lasts 3d-4 weeks: single EM (erythema migrans at bite site); regional lymphadenopathy. Minor constitutional symptoms. No scaling as in ringworms. Most commonly asymptomatic. Often no knowledge of tick bite. Erythema Migrans Rashes Image credit: The CDC (https://www.cdc.gov/lyme/signs_symptoms/rashes.html)  Click to view other Lyme Disease Rashes and Look-Alikes on the CDC website. (https://www.cdc.gov/lyme/signs_symptoms/rashes.html) 2nd Stage  Few days of bite to weeks-months: Severe constitutional: severe malaise, fatigue, fever, chills. Skin: multiple EMs (sign of hematogenous dissemination) plus possible other lesions. Neurological: meningitis (HA-may be excruciating with neck pain), facial palsy, painful radiculopathy (dz of the nerve roots), etc. Migratory musculoskeletal pains: joint, bone, tendon, bursa, muscle, etc. Cardiac: cardiac conduction defects (which resolve generally with treatment; in a smaller percentage: myopericarditis. 3rd Stage  Months-years after the initial bite with persistent infection: fatigue; prolonged arthritis attacks and progressive CNS disease (cognitive problems); scleroderma, etc. Highly variable: individual and international patterns. Congenital infection is possible but not proven. Ixodes co-infections → human co-infections (estimates vary with study 2-39%). Anaplasma (rickettsial agent causing human granulocytic ehrlichiosis) or; Babesia (protozoan) malarial-like disease. Diagnosis of Lyme Disease Erythema migrans. Visit to risk area (or your dog may have gone). Lack of known tick bites irrelevant (tick trickery). Erythema migrans. Visit to risk area (or your dog may have gone). Lack of known tick bites irrelevant (tick trickery). Immunoblot to dx Bb antibodies.* PCR (joint or CNS).  Culture-special medium (skin) NOT urine antigen test * Not early; both have false neg and positives. Management of Lyme Disease Prevent: tuck pant legs into socks, use a repellent with DEET (on skin or clothing) or permethrin (on clothing); inspect for ticks 24h. Human vaccine disappeared ($). Check prophylaxis for tick bites. Early Lyme: oral doxycycline unless CNS sx then systemic drugs. CNS or late Lyme (arthritis): systemic. Reinfection can occur if Rx is successful before immunity sets in.  Relapsing Fever (Orphan Febrile Disease) Relapsing Fever is a disease characterized by relapsing or recurring episodes of fever, often accompanied by headache, muscle and joint aches and nausea. Relapse is due to antigenic variation. There are two forms of relapsing fever: Tick-borne relapsing fever (TBRF). Louse-borne relapsing fever (LBRF). Tick Borne RF is caused by several species of Borrelia (spiral-shaped bacteria) that are transmitted to humans through the bite of infected soft ticks. Most cases occur in the summer months and are associated in particular with sleeping in rustic cabins in mountainous areas of the Western United States. There are approximately 25 cases of TBRF reported in the United States each year. Most Western states require reporting. This includes Texas to Montana and west. LBRF is caused by another spiral-shaped bacteria, Borrelia recurrentis that is transmitted from human to human by the body louse. LBRF still causes sporadic illness and outbreaks in Africa. Illness can be severe, with mortality of 30 to 70% in outbreaks. Tick Borne Relapsing Fever General timeline for TBRF relapse intervals.  Experience 1-4 episodes of fever before illness resolves. Antigenic variation is the reason for repeat occurrences. Image credit: The CDC (https://www.cdc.gov/relapsing-fever/symptoms/index.html) Transcript  General timeline for TBRF relapse intervals. 1. ~7 days after bite is the incubation period. 2. ~3 days after the incubation period is symptomatic periods/Relapsing episodes. 3. ~7 days after symptomatic periods/relapsing episodes is Afebrite (no fever) periods. 4. ~3 days after Afebrite periods is symptomatic periods/relapsing episodes. 5. ~7 days after symptomatic periods/relapsing episodes is Afebrite (no fever) periods. 6. ~3 days after Afebrite periods is symptomatic periods/relapsing episodes. Symptoms In general, patients are moderately ill with dehydration but there are no classical findings. As the fever is resolving there is a crisis: Phase one: Chill (10-30 minutes) with fevers up to 106.7 degrees. Phase 2 Flush: drenching sweats as fever drops; blood pressure may also drop dramatically. Problems in pregnancy. Problems in Pregnancy Rx with antibiotics.  Jarisch-Herxheimer reaction in most patients ~ 2 hours (also Lyme Rx). Treat lice if louse borne!  Quiz Quiz | Infections of the Heart (https://rossmed.instructure.com/courses/3499/quizzes/21875)  Contact Dr. Sean D. Reid, Ph.D., Microbiology and Immunology Email: [email protected] (mailto:%[email protected]) Dr. Todd Gundrum, PharmD, Pharmacology Email: [email protected] (mailto:[email protected]%20 %20 )