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BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 1 Introduction to Solving Clinical Cases Steps in a Clinical Encounter 1. 2. 3. 4. Patient History - Information gained by a healthcare professional by asking specific questions, with the aim of obtaining information useful in formulating a diagnosis and providing medical care. Symptoms Signs - A History may include: Identification and demographics: name, age, sex, height, weight The "chief complaint (CC)" — the major health problem or concern, and its time course. History of present illness (HOPI) - details about the complaints enumerated in the CC. History of past illness (HPI) (including major illnesses, any previous surgery/operations, any current ongoing illness, e.g., diabetes, sickle cell) Review of systems(ROS) - Systematic questioning about different organ systems Family diseases Childhood diseases and immunizations Social history- including living arrangements, occupation, drug use (including tobacco, alcohol, other recreational drug use), recent foreign travel and exposure to environmental pathogens through recreational activities or pets. Regular medications (including those prescribed by doctors, and others obtained over the counter or alternative medicine) Allergies Sex life, obstetric/gynecological history and so on as appropriate. BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 2 Physical Examination - Process by which a healthcare professional investigates the body of a patient for signs of disease. A physical examination usually starts with first observation of the patient and systematically covers the patient head to extremities. It may include: General appearance – mobility, awareness, color, hydration, etc Basic biometrics – height, weight, pain Vital Signs – temperature, blood pressure, pulse, respiratory rate Organ systems – cardiovascular, lungs, breast, abdomen, genitalia, musculoskeletal, nervous, including mental status, HEENT (head, eyes, ears, nose, throat), skin History + Physical Examination Presumptive Diagnosis (a working theory) and a Differential (in our case, infectious disease, a list of specific microorganisms associated with the presumptive diagnosis). Presumptive + differential will guide your investigation, development of a strategy that will allow you to eliminate (or not) the most likely candidates. Always start with the idea that this is a “horse” and not a “zebra”. BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 3 Respiratory Tract I. Overview nose to alveoli continuous operation is essential divided into 2 regions: o upper – o lower A. Generalizations Many cause local infections, some may spread systemically Professional invaders - normal healthy host, specific attachment mechanisms, specific evasion tactics Secondary invaders - impaired host Most common infections seen by doctors Upper - usually mild & self-limiting Lower - can be severe & life-threatening in children bacterial in adults B. Clinical Syndromes 1. Upper Respiratory Tract Infections itis = inflammation - surface infections Exposed to 8 microbes/min or 10,000/day Predisposing factors decreased humidity – viral infections – antibiotic therapy - BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 4 1. Rhinitis = cold 100% viral (see Table 18.4) rhinovirus and coronaviruses 115 different rhinoviruses Other viruses (parainfluenza, enterovirus, respiratory synctial virus (RSV), etc) transmission bind to and infect ciliated epithelial cells of nose incubation diagnosed by clinical signs & symptoms (burning sensation in nose/throat, followed by sneezing, runny nose, fatigue, malaise. Sore throat and cough generally due to post nasal drip. No or low fever) treatment control – 2. Pharyngitis (= sore throat) and tonsilitis infected mucosa or inflammation of lymphoid tissue 70% viral – symptoms often include rhinorrhea, conjunctivitis, malaise or fatigue, hoarseness, and low-grade fever rhinovirus, coronavirus, adenovirus, etc, see Table 18.5 Cytomegalovirus (CMV) -clinically silent in URT esp. in infant/child – can spread from blood to placenta and infect fetus; second only to Down’s as a cause of mental retardation Epstein-Barr Virus (EBV) -2 peaks 1-6 years and 14-20 years (infectious mononucleosis – fever, sore throat, petechiae on hard palate, lymphadenopathy and splenomegaly, with anorexia and lethargy. Symptoms due to release of cytokines. Polyclonal activation of B cells; WBC dif shows at least 10% atypical lymphocytes) EBV infections can re-activate, see Fig. 18.6. 30% bacterial – usually no rhinorrhea, no cough, no conjunctivitis S. pyogenes o age – o onset – o symptoms – o complications N. gonorrhoeae – C. diphtheria –. BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 5 3. Otitis media and sinusitis = ear and sinus ear infections are second most common infection of childhood (after colds) and most common cause of visits to pediatricians 50% viral respiratory syncytial virus (RSV), influenza, parainfluenza, rhinovirus, adenovirus 50% bacteria - secondary invaders S. pneumoniae, Haemophilus influenzae, Moraxella 4. Epiglottitis H. influenzae type B (vaccination = Hib) Severe inflammation with edema life-threatening respiratory obstruction Age – Symptoms - BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 6 2. Lower Respiratory Tract Infections Lower RT is a sterile site, there are no normal microbiota 1. Laryngitis and tracheitis Viruses (symptoms – hoarseness, burning retrosternal pain) Parainfluenza virus – croup (dry cough and inspiratory stridor) RSV, Influenza virus, Adenovirus Bacteria GAS, H. influenzae, S. aureus C. diphtheria - life threatening, rare in U.S. due to vaccination (DaPT) 2. Whooping cough Org - Bordetella pertussis (GNR, ox +, obligate aerobe) Humans are sole reservoir Highly contagious Transmission - person - person airborne droplets Colonization - attach to ciliated mucosa in trachea using fimbriae & hemagglutinin also spreads to bronchi Several toxic factors -affect inflammation or damage ciliated epithelium 1. pertussis toxin - A-B structure exotoxin; A unit is an ADP-ribosylase, disrupts signal transduction in affected epithelial cell - prod massive amts mucoid secretions 2. Adenylate cyclase toxin - enters neutrophils & causes them to incr. cAMP - inhibits chemotaxis, phagocytosis, & killing 3. Tracheal cytotoxin - kills tracheal epithelial cells 4. Endotoxin Incubation - 1-3 weeks Pathology - ciliated epithelium of trachea becomes covered w/ massive purulent exudate Presentation early - runny nose, sneezing, fever, mild dry cough week later - mucus & bact fill lower trachea, cough becomes paroxysmal - violent coughing fits, 5-20X w/ no breath in btwn - as air rushes back in - whoop also vomiting, epistaxis, periorbital edema, conjunctival hemorrhage Complications - CNS anoxia, secondary pneumonia Immunization - DaPT Rate of infection in unvaccinated exposed - 90-95%; Mortality - up to 14% 3. Acute bronchitis - Inflammation of the tracheal/bronchial tree assoc w/ infection Orgs Professional pathogens; Viruses (rhino-, corona-, adeno-, influenzae,) and Mycoplasma pneumoniae Secondary invaders - S. pneumoniae, H. influenzae Presentation - cough - treatment is symptomatic - antibiotics? usually recommended BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 7 4. Influenza = the Flu Org - Influenzavirus types A, B, C; A - segmented RNA, 3 major HA types, 2 major NA types; antigenic epitopes change from yr-yr (antigenic drift & shift) Transmission - person - person small airborne droplets Colonization - attaches via HA to sialic acid receptors on ciliated epithelium of trachea/bronchi, RME Incubation - 1-3 days Pathology - impair mucociliary clearance, tracheobronchitis, bronchospasms; cytokines released from damaged cells & WBC may symptoms Presentation - fever 102-104, chills, severe headache w/ retro-orbital pain, muscular aches (esp backache), dry cough, weakness (prostration). Most cases resolve 1-2 wks Complications - 1º influenza pneumonia (1% of cases but 30% fatality, pregnant women ↑ risk), 2º bacterial pneumonia (H. influenzae, S. pneumonia, S. aureus, S. pyogenes) Epidemics are indicated by the number of unexpected deaths due to influenza, when # exceeds 10,000-50,000 = epidemic 5. Bronchiolitis children less than 2 swollen by inflammation, passage of air is restricted necrosis of epithelial cells lining the bronchioles Orgs 75% RSV Respiratory Syncytial Virus - paramyxovirus (RNA), enveloped Most common cause of fatal bronchiolitis & pneumonia in infants (1/100 hospital) - humans only reservoir Transmission - resp. droplets to hands Colonization - nasopharynx - surface spikes are fusion proteins that fuse host cells to cause "syncytia", then virus invades LRT by surface spread in secretions Incubation 4-5 days Immunopathology - maternal Ab in infant react w/ virus Ag, liberate histamine & other inflammatory mediators Presentation - cough, rapid respiration, cyanosis 25% other viruses 6. Pneumonia 4,000,000 people/yr. Most common cause of infection related death in the US. 6th leading cause of death wide range of microbes Transmission - inhalation or aspiration Colonization - attach to resp epithelium Pathology - respiratory distress from the interference of gas exchange in lungs, systemic effects Orgs children - viral or bacteria secondary to viruses adults - bacterial, kind depends on risk factors, age, other diseases - in hospitals GN BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 8 Bacterial - acute onset, high fever Typical - classic bacteria of acute, community-acquired - S. pneumoniae (25-60%), H. influenzae (5-15%), others - S. aureus, Klebsiella, E. coli, Pseudomonas Atypical - M. pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, Coxiella burnetii Chest exam rales (abnormal crackles) evidence of consolidation chest x-ray Viral Transmission - inhaled or from blood Colonization - attach specifically Orgs RSV - children Parainfluenza virus types 1 & 2 – children; hemagglutinin & neuraminidase & fusion proteins Adenovirus - 41 types; 5% of acute resp. illness Influenzavirus 7. Chronic Infections of the lungs Tuberculosis - review Fungi Aspergillus fumigatus – aspergillosis - Predisposing condition - asthma, pre-existing lung cavities, chronic pulmonary disorders - fungal ball aspergilloma doesn’t invade but in immunosuppressed - invade lungs to produce disseminated disease Histoplasma capsulatum - histoplasmosis Coccidiodes immitis - San Joaquin Valley Fever Blastomyces dermititidis - blastomycosis Pneumocystis jiroveci (formerally P. carinii) - pneumocystis pneumonia 8. Cystic fibrosis very viscous bronchiol secretions leads to fluid stasis in the lungs & infections w/ P. aeruginosa (S. aureus, H. influenzae, B. cepacia) BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 9 Urinary Tract Infections and Sexually Transmitted Infections I. Overview Urinary A. General info Function - transport products from inside of body to outside Free of microbes (sterile) except where the outflow meets the skin Urinary Tract Infections (UTI) Almost always bacterial Usually acquired as ascending infections Most originate from fecal microbiota - self-inoculation Differential lists varies depending on whether infection is acquired in the community or in the hospital, and whether the infection is uncomplicated or complicated (e.g., persons with abnormal UT) Community- acquired 1. E. coli (80-90%) 2. S. saprophyticus (5-15%) 3. Proteus mirabilis 4. Klebsiella, Enterobacter, Serratia, Pseudomonas aeruginosa viruses - rare Hospital-acquired 1. E. coli (40%) 2. Klebsiella, Enterobacter, Serratia, Pseudomonas aeruginosa (25%) 3.GPC 4. Proteus mirabilis Predisposing Factors Anything that: Disrupts urine flow Prevents complete emptying of bladder Promotes microbial access Females Pregnancy Intercourse Females & males Renal stones Tumors Neurological disorders Catheters Males Enlarged prostate BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 10 Virulence Factors of Urinary Pathogens (examples): E. coli – uropathogenic strains (O and K serotypes) = UPEC pathogenicity island P fimbriae (attachment) capsular acid polysaccharide (resist phagocytosis) membrane active cytotoxins S. saprophyticus adherence to uroepithelium (high proportion of bladder cells w/ adherent bacteria) microbistatic to GP and GN urease P. mirabilis flagella (motility) urease B. Clinical Syndromes Lower UTI 1. urethritis (urethra) Symptoms - dysuria 2. cystitis (bladder) Symptoms - rapid onset of dysuria; increased urgency/frequency Urine - cloudy - pyuria (inflammation) or bacteriuria (bacteria); blood (hematuria) 3. prostatitis (prostate) Symptoms - dysuria, increased frequency, low back pain, systemic indications (fever) Upper UIT 1. pyelonephritis (renal parenchyma) Symptoms - cystitis + more severe systemic indications (fever) Complications - septicemia, loss of renal function Collecting Urine Samples Voiding (Midstream clean-catch) Urinary catheter Suprapubic bladder aspiration Laboratory Diagnosis of Urinary Tract Infections Read in text pages 257-259 carefully, especially pay attention to how to tell what is significant bacteriuria BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 11 II. Genital/Reproductive A. General info Only system that is significantly different in males & females Largely free of microbes, except for the vagina Sexually Transmitted Infection (STI) ( = Sexually Transmitted Disease (STD) = venereal disease (VD) Incidence is increasing Almost no vaccines Rampant on college campuses Often asymptomatic Sexually Transmitted Diseases - Top Ten in US By Occurrence Pathogen 1. Human Papillomavirus (HPV) 2. *Chlamydia trachomatis D-K. C. trachomatis L1, L2, L3 3. Candida albicans 4. Trichomonas vaginalis 5. Herpes simplex virus (HSV) 6. *Neisseria gonorrhoea 7. HIV 8. *Treponema pallidum 9. *Hepatitis B virus 10. Haemophilus ducreyi Disease genital warts; associated w/ cervical cancer non-specific or non-gonococcal urethritis lymphogranuloma venereum vaginal thrush, balanitis vaginitis, urethritis genital herpes gonnorhea AIDS syphilis hepatitis chancroid B. Clinical Syndromes #1 Human Papilloma Virus (HPV) Transmission – sexually Entry – attach to target cell via capsid protein, enter via RME Incubation – 1-6 months Pathology – dyplasia = abnormal growth Symptoms – warts on penis, vulva, perianal regions (types 6 or 11) – BUT majority asymptomatic Complications – high-risk HPV types 16, 18, 31, 33, and 35 are strongly associated with cervical neoplasia Treatment (Txt) – asymptomatic and subclinical not treated; warts treated Prevention - vaccine BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 12 #2. Non-gonococcal urethritis - Chlamydia trachomatis - Obligate intracellular bacterium – Transmission – sexual Entry – abrasions Attachment - to receptors on host cell, parasite-induced endocytosis Incubation – 2-6 weeks or longer Pathology – cells destruction & inflammation Symptoms – asymptomatic infection is common, esp. in women OR urethritis Complications –systemic dissemination, infertility – in women also PID, ectopic pregnancy – in infants pneumonia, trachoma. Treatment (Txt) – tetracycline, doxycycline, azithromycin #3. Yeast infection or Candida vulvovaginitis - Candida albicans – yeast, part of normal microbiota Transmission – normal microbiota of female vagina - disruptions to bacterial vagina community can result in an overgrowth with yeast. Symptoms – UTI, intensely itchy/burning, cottage cheesy discharge Balanitis (inflammation of glans penis) in 10% of male partners Txt – antifungals like micronazole or nystatin (topical) or oral fluconazole #4. Vaginitis - Trichomonas vaginalis - protozoa Transmission – sexual Entry – vagina in women; urethra and prostate in men Symptoms – vaginitis – copious, yellow/green frothy discharge, rise in vaginal pH Txt - metranidazole BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 13 #5. Genital herpes - Herpes simplex viruses types 1 and 2 (HSV1, HSV2) Transmission – sexual Entry - by membrane fusion Incubation – 3-7 days Pathology The herpes virus causes the membranes of host cells to fuse together to form “giant” cells. This picture was taken of PAP smear material and the arrow indicates a giant cell. Symptoms - First sign – primary genital lesion vesicles ulcer w/tender, swollen nodes, fever, headache, malaise The herpes virus travels up sensory nerve endings to the root ganglion neurons where it remains in a latent stage for the life of the host. The herpes virus can not be eliminated by the immune system or by anti-viral drugs. Herpes infections can re-activate. Virus travels back down the nerve fibers and causes new lesions at the surface of the skin or mucosal membranes. Re-activations are common and are triggered by trauma, stress, and sun. I it is believed that herpes infected individuals may always be somewhat infectious. Complications (in addition to reactivation) – aspetic meningitis or encephalitis in adults. Neonatal disseminated herpes or encephalitis. Txt – acyclovir (Zovirax), famciclovir, valacyclovir (Valtrex) BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 14 #6. Gonorrhea - Neisseria gonorrhoea – 260,530 U.S. in 2009/ 14,471 cases MI Transmission – direct, usually sexual, person-person If the woman has gonorrhea there is a 20% chance during each sexual encounter that she will transmit to her male partner. If the man has gonorrhea, there is a 50-90% chance he will transmit to his partner (female or male). Asymptomatically infected individuals, almost always women, form a major reservoir of infection. Entry – vaginal or mucosa of penis – or other mucous membranes (pharynx, conjunctiva) Attachment - via common pilus (which undergoes antigenic variation), Opa proteins. Invade non-ciliated epithelial cells Incubation – 2-7 days Pathology – see picture– what process causes the damage? BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 15 Symptoms - First sign in men – dysuria, purulent discharge (shown center and a Gram stain of shown right, see the GNC engulfed by the PMNs). First sign in woman – vaginal discharge if symptomatic, BUT 50% asymptomatic Complications – similar to Chlamydia – pelvic inflammatory disease (PID) and/or damage to the fallopian tubes resulting in infertility in 10-20%, disseminated infection (1-3%), opthalmia neonatorum (neonate blindness shown at right – this is what newborns get silver nitrate drops to prevent, mandated in MI). Txt – Cefixime, Ciprofloxacin PLUS treat for Chlamydia – very often people who have gonorrhea have Chlamydia and visa versa. #7. Acquired Immune Deficiency Syndrome (AIDS) - Human Immunodeficiency Virus (HIV) – globally, 2.7 million new infections in 2008 Transmission - Sexually transmitted (but not a disease of the reproductive tracts but of the immune cells, specifically CD4+ cells like macrophages and TH), also transmitted by blood. Incubation – 2 weeks to 3 months, sometimes 6 months. Read in text pages 275-283. BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 16 #8. Syphilis ((#3 bacterial STI in U.S.) - Treponema pallidum – 12,833 U.S. in 2009/ 231 cases MI Transmission – close physical contact; usually sexual, saliva, blood - 1/3 of those exposed to the syphilis spirochete will become infected. Entry – small abrasions Incubation – 10-90 days, 3 weeks is average Symptoms - First sign – chancre – develops after 2-4 weeks apparently not painful! Primary – the bacteria multiply in regional lymph nodes and cause swelling. Secondary – after 3-6 weeks, the bacteria multiply and produce lesions in many sites. Symptoms include myalgia, headache, fever, and rash (in 75-100% of cases). 2/3 are cured at this point but 1/3 develop go into a latent phase that can last 3-30 years, which can then progress to tertiary. Tertiary – bacteria again multiply and spread. Host cell-mediated response causes progressive destruction of neuro-, cardio-, skin, and/or joints. Complications – congenital syphilis (intrauterine death, congenital abnormalities) Txt – arsenic (historical), penicillin (modern) or doxycycline for pen-sensitive patients. If you haven’t seen the movie “Miss Evers’ Boys” you could watch this for extra credit (I know some rental places carry it, in the “true stories” section). It is about the Tuskegee experiments on syphilis conducted by the U.S. government. Relate presentation of syphilis in the movie with info from Medical Microbiology. BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 17 Infections of the GI and Diarrheal Illness Clinical Syndromes 1. Gastritis - inflammation of the stomach - pain in the upper abdomen, sometimes bleeding 2. Gastroenteritis - inflammation of stomach & intestines - primarily diarrhea, sometimes nausea, vomiting, crampy abdominal pain 3. Colitis - intestinal syndrome that primarily involves the colon or large intestines. 4. Enterocolitis - inflammation of mucosa of both large & small intestine = dysentery - diarrhea often contains blood & mucus. 5. Hepatitis - liver damage causes a clinical syndrome called hepatitis. Patients with hepatitis become jaundiced because bilirubin builds up in their bodies. Pathogens Cause disease by 3 mechanisms: a. action of toxins b. adherence to & effacement of microvilli inflammation c. invasion of intestinal epithelial cells A. Toxins cause disease – microbes are not present in the body Toxin types Action on intestine/intestinal cells Enterotoxin results in net secretion w/out intestinal damage Cytoskeleton-altering toxin alters cell shape, may injure cells but is not lethal Cytotoxin causes cell damage and ultimately cell death Neural toxin alters smooth muscle activity in intestines 1. Bacterial Food Poisoning - Intoxications NOT infections – a. Clostridium botulinum - botulism - canned foods, spores survive 5 hrs boiling & germinate under anaerobic conditions in can neural toxin gut – binds to epithelial cell and is transported across bloodstream presynaptic regions (disease of CNS, symptoms begin 12-48h) b. Staphylococcus aureus - most common – 2 different heat [100ºC for 30 min] & enz stable enterotoxins stimulate vegus nerve (so also a neural toxin) of stomach lining emetic response (vomiting),w or w/o diarrhea 30 min to 8 hrs after ingestion. These toxins also function as superantigens and stimulate T cells to over secrete IL2. 1ug of toxin is enough to induce symptoms, can be achieved when # of Staph in food reaches 1,000/gram. Resolves within 24h. c. Bacillus cereus - 2 distinct presentations caused by two different toxins – only one is a true intoxication emetic – cereulide (an enterotoxin) targets vagus nerve (also a neural toxin) nausea & vomiting 1-5 hrs after ingestion of toxin - lasts ~1-6 hrs. can be difficult to distinguish from S. aureus food poisoning. BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 18 B. True infections – microbes enter and then colonize the GI - 3 mechanisms for damage 1. Pathogens colonize epithelial surfaces of small intestine (do not enter) & then release toxins Vibrio cholera - cholera Source Pathology 1. Ingestion of large numbers (> 108); only 0.001% survive passage through stomach 2. Flagella & mucinase allow Vibrio to reach epithelial cells 3. Attachment by way of fimbriae to receptors on brush border & crypt cells of small intestine 4. Damage due to production of toxin called cxt that is an ADP ribosyl transferase. Toxin binds to receptors for the glycolipid GM1 ganglioside by the B subunit & A enters epithelial cells disrupts adenylate cyclase (cxt - enterotoxin, cytotoxin, & neural toxin) 5. Secretion of large quantities of Cl- into intestine, causing H2O & and Na+ to follow hypersecretion of fluids & electrolytes Incubation – Symptoms - Txt - Other pathogens that cause disease by similar mechanism: Enterotoxigenic E. coli strains (ETEC) - traveler’s diarrhea – 2 enterotoxins – LT-1 similar to cholera toxin. ST – activates guanylate cyclase activity increase in cGMP increased fluid secretion. B. cereus – ingested diarrheal toxin produced in the small intestine (cytotoxin targets villi villus necrosis) diarrhea 8-16.5 hrs after ingestion (note, this is the other presentation for B. cereus, not the food poisoning) BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 19 BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 20 2. Pathogens attach to and enter epithelial cells, multiply intracellularly & destroy (efface) microvilli of epithelial cells (may release toxins), and induce diarrhea. Shigella spp. (dysenteriae, boydii, flexneri, sonnei) – shigellosis - 14,581 U.S. / 212 MI Source Pathology – a descending infection of the intestine – small intestine then colon 1. Ingestion - only 10-100 organisms required, 55% survive passage through stomach - most effective of bacterial pathogens of GI 2. Secrete enterotoxins during passage through small intestine profuse, watery diarrhea 3. Adhere specifically to epithelial cells of colon by way of outer membrane proteins (OMP) 4. Induce parasite-directed endocytosis by enterocytes and by M cells of GALT (Gut Associated Lymphoid Tissue) that transport Shigella across intestinal epithelium 5. Phagocytized by macrophages but escape from phagolysosome into cytoplasm 6. Trigger macs to produce IL-1, also triggers apoptosis 7. IL-1 induces inflammation & stimulates edema & extravasation of neutrophils (PMNs) across epithelial barrier. 8. Movement of PMNs across destroys the epithelial barrier & Shigella can now move across in massive number. 9. Further induce prod. of cytokines & intense inflammation w/ destruction of epithelium ulcerations blood in stool S. flexneri and S. sonnei secrete enterotoxins (shET1 and shET2) S. dystenteriae secretes a cytotoxin (shiga toxin, stx) Incubation – Symptoms Txt – Complications - Other pathogens that cause disease by similar mechanism: Enterohemorrhagic E. coli (EHEC) including E. coli O157:H7 4(toxins stx1 and stx2) Campylobacter enteritis + diarrhea Yersinia enterocolitis Entamoeba histolytica amoebic dysentery Human diarrhoeal viruses (rotavirus, Norwalk virus) - gastroenteritis Virus replicates in intestinal epithelial cells, damages transport mechanisms in the gut, leads to loss of water, salt, glucose diarrhea. Infected cells are destroyed but no inflammation, no blood. Shed at rate of 1,000 million virus particles/g feces. BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 21 BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 22 3. Pathogen attaches to, enters, & multiplies in deep tissues that are normally sterile - submucosal or subepithelial tissues – sometimes will spread systemically. Salmonella enteritidis, S. typhimurium salmonellosis 44,468 U.S. / 911 MI Salmonella typhi, paratyphi – invasive species typhoid fever Sources S. enteritidis S. typhi Pathology 1. Ingestion of large numbers (105-1010); 0.001% survive passage through stomach 2. Attach specifically to fibronectin of epithelial cells of small intestine 3. Transported by M cells of GALT 4. Invade gut wall ulcerations & hemorrhage. Also spread to intestinal lymphatics & are phagocytized by macs but escape from phagolysosome into cytoplasm 5. Produces toxin that increase cAMP & fluid secretion loose, watery diarrhea & nausea (enterotoxin and cytoskeletal altering toxin) 6. Causes influx of PMN (nontyphoid species) that confines infection to GI 7. OR influx of macrophages (typhoid species) and systemic spread S typhi organisms spread through the reticuloendothelial system, mainly to the liver, spleen, and bone marrow. Within 14 days, the bacteria appear in the bloodstream, facilitating secondary metastatic foci (eg, spleen, heart). In some patients, gallbladder infection leads to long-term carriage of S typhi or S paratyphi in bile and secretion to the stool Salmonellosis Incubation – Symptoms – Txt Complications – Other pathogens that cause disease by similar mechanism: Hepatitis A virus - 1,849 cases U.S. / 70 MI Reoviruses Enteroviruses (includes poliovirus) BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 23 BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 24 Nervous System = peripheral nerves + central nervous system (CNS) I. Generalities: A. Structure of B. Protection of C. How do microbes get to the central nervous system (CNS)? **1. from the bloodstream - cross the Blood-Brain-Barrier (ex. bacterial meningitis, polio) *2. from the peripheral nerves (ex. herpes, VZV, rabies) 3. invasion from: bone sinuses middle ear 4. trauma II. Clinical Syndromes A. meningitis - of meninges Characterized by high fever, headache, stiff neck (classic triad) Pathology due to acute inflammation: Vascular permeability ↑WBC, ↑fluids Fluids swelling Swelling ↑pressure headache Inflammation affects muscles stiff neck Inflammation fever Causes: clogging of blood vessels (DIC) necrosis of tissue ↓ CSF flow impaired CNS function In bacterial meningitis, death occurs from shock & other serious complications within hours as a result of release of peptidoglycan + endotoxins (GN) or teichoic acid (GP) B. encephalitis - of the brain Characterized by acute febrile illness + changes in mental state, consciousness, behavior C. myelitis - of spinal cord Symptoms vary depending on where damage to cord occurs BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 25 III. Infections of the Meninges A. Bacterial meningitis Acute - nearly always fatal Strong correlation of microbe with age of patient – influences the top R/O: Neonates – E. coli, Group B streptococci 1 month to 5 yrs - Haemophilus influenzae type B (Hib) 5 to 40 - Neisseria meningitidis 30 and over - Streptococcus pneumoniae Pathogenesis 1. colonization and invasion of nasopharynx 2. nasopharynx bloodstream BBB to subarachnoid 3. replicate and induce inflammation in subarachnoid space increased permeability of BBB, cerebral edema, increased intracranial pressure, decreased cerebral blood flow. Pathology Subarachnoid space purulent exudates, vein distension, focal necrosis Diagnosis CSF examination – elevated opening pressure, very ↑neutrophils, very ↑ protein, ↓glucose Prognosis Serious to grave Mortality rates Hib N. meningitides S. pneumoniae without txt = near 100% without txt = near 100% without txt = near 100% All can be present in humans in an asymptomatic carrier state with txt = 5% with txt = 7-10% with txt = 20-30% BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 26 1. Haemophilus influenzae type B (Hib) (1 month – 5) GNR Normal upper RT microbiota Inactivate IgA using IgA protease Colonize the nasopharynx using common pili Penetrate submucosa (invasive) bloodstream (capsule to avoid phagocytosis) Incubation - 5-6 days Symptoms develop over 1-2 days Endotoxin: 1. inflammation 2. DIC Complications – hearing loss, delayed language development, mental retardation Prevention – Vaccination 2. Neisseria meningitidis (5-40) GNdC Person-person in respiratory droplets; 20% carriers (as high as 60-80%) Inactivate IgA using IgA protease Colonize the nasopharynx using pili sore throat Endocytized bloodstream (capsule to avoid phagocytosis) Incubation 1-3 days Symptoms develop over 6-24 hours Endotoxin: 1. affects blood vessel permeability cross BBB (attach to dura mater w/ pili) 2. drop in blood pressure shock 3. clotting of blood hemorrhage (rash = petichiae and purpura), also DIC Complications – amputations, permanent hearing loss Prevention - Vaccination 3. Streptococcus pneumoniae (30+) GPC Normal upper RT microbiota sinuses or middle ear brain or pneumonia in lungs bloodstream brain Capsule Teichoic acid inflammation Prevention - Vaccination BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 27 B. Viral meningitis = aseptic meningitis Most common Self-limiting, non-fatal Many different viruses: 1. Enteroviruses - 40% (primarily Coxsackievirus and Echovirus) 2. Arboviruses 3. HIV 4. HSV-2 Several considerations affect differential: Summer, fall + geographic clustering Arboviruses Late fall, winter + history of exposure to mice LCMV Late winter, early spring + male mumps virus With genital lesions HSV-2 With atypical lymphocytes EBV With chickenpox or shingles VZV Diagnosis CSF examination – ↑ lymphocytes, moderately ↑ protein, normal glucose Prognosis - In adults, excellent C. Fungal meningitis Chronic presentation – symptoms develop over days to weeks 1. Coccidioides immitis 2. Cryptococcus neoformans - AIDS IV. Infection of the Brain (Encephalon) – involvement of brain parenchyma A. Viral encephalitis Same viruses as for aseptic meningitis but relative frequency varies 1. Arboviruses (Arthropod-borne) Ex. Equine encephalitis, (West Nile virus) Bird Mosquito Bird Horse (human) Epidemics, geographic clustering Mosquito BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 28 2. HSV-1 no insect sporadic, not epidemic 3. Enteroviruses, mumps 4. Rabies - Rhabodovirus Bite Multiplies at site Travels to local nerves Peripheral nerves spinal cord brain Long incubation Prodromal phase - flulike symptoms, tingling, burning, depression Excitation phase - muscle function, speech, vision, anxiety, hydrophobia Paralytic phase - muscles weaken, consciousness fades, death Mortality - 100% with best treatment Post exposure prophylaxis (PEP) - has never failed in US B. Protozoan encephalitis 1. Primary amebic encephalitis - Naegleria fowleri Mortality = 100% 2. African Sleeping Sickness - Trypanosoma Misc. 1. Tetanus Clostridium tetani – exotoxin tetanospasmin (mimics strychnine poisoning) 2. Botulism Clostridium botulinum Genes for toxin are carried on a bacteriophage Exotoxin botulinum prevents release of acetylcholine Produces a limp, flaccid, paralysis Eyes blurry, double vision Throat slurring speech, difficulty swallowing Difficulty breathing Cardiac problems BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 29 Infections of Skin and Wounds Abscesses Abscess - a localized collection of pus Abscess formation localizes an infection and prevents spread Microorganisms in abscesses are difficult to treat with antimicrobial agents because: 1.microbes aren’t multiplying - many antimicrobial agents only work against actively growing cells. 2.chemical nature of pus interferes with action of some antibiotics 3.antibiotics have difficulty reaching the site because of lack of vessel penetration Abscesses are a potential source of infection for other sites, can seed microbes into the blood or lymph I. Bacterial Infections of Skin, Soft Tissue, Muscle All acute (24-48h) A. By skin layer involved 1. infections of hair follicles – usually S. aureus a. folliculitis - involves only the hair follicle - small red bump of inflammation b. furuncles = boil – intense inflammation spreads to surrounding tissue – abscess w/localized redness, swelling, tenderness, pain, pus - 1.5 mil/yr - S. aureus food poisoning c. carbuncles - larger - several sites of draining pus - usually on neck or upper back - systemic symptoms (fever) 2. Stratum corneum Impetigo - a highly contagious pyoderma cau exclusively in children - spread by contact -streptococci (GAS)- almost 3. Epidermis Ecthyma – untreated impetigo 4. Dermis a. Erysipelas = St. Anthony’s fire – usually GAS - blockage of dermal lymphatics – welldefined edges. Pain and fever. 5% develop bacteremia with high mortality. b. Lymphangitis – inflammation of the lining of lymphatic vessels 5. Subcutaneous fat layer Cellulitis – usually S. aureus or S. pyogenes. Initial superficial skin trauma. inflammation, enlarged lymph, malaise, chills, fever. Diffuse BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 30 B. By specific strains of S. aureus or S. pyogenes 1. Scalded skin syndrome Caused by certain exotoxin producing strains of S. aureus infected by lysogenic phages Exotoxin is exfoliatin - carried in bloodstream to the epidermis where it causes a split in deep layers - 40% of outer layers of skin are lost - loss of body fluid, high fever, bacteremia. Rapid txt is necessary to prevent death. Txt with antibiotics - remove dead skin and tissue Most common in children under 2, esp. newborns. Also assoc. with w/late stages of STSS (60% mortality) 2. Necrotizing fasciitis - "flesh-eating strep" – GAS infected by phage - infection is secondary to minor ski trauma Involves the subdermal tissues produces 2 toxins: 1. Pyrogenic toxin A - a superantigen, stimulates excessive IL-2 production 2. Exotoxin B - destroys tissues by breaking down protein, rate of 1 inch/hr. Similar clinical picture induced by Methacillin Resistant Staphylococcus aureus (MRSA) II Viral diseases resulting in skin rashes = exanthems Several childhood diseases are characterized by distinctive skin rashes caused by viruses that are carried to the skin by the blood from sites of infection in the upper respiratory tract. All spread by inhalation of respiratory droplets. 1 - Rubeola virus – measles High fever and rash that starts head & neck, then arms, upper trunk, back, finally legs Koplik's spots are diagnostic Extremely contagious – 90% Rash is caused by the reaction of Tc cells with virus-infected cells in the small vessels of the skin. More than 15% of children infected with measles die of measles complications pneumonia, encephalitis - major ww killer In U.S. in children less than 15 months because of vaccination program (2 – Scarlet fever – phage infected S. pyogenes – produces an erythrogenic toxin that is distributed systemically scarlet fever rash) BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 31 3 - Rubella virus - German measles = 3 day measles - one of the mildest of the viral diseases that cause rashes Low grade fever, eye pain - rash first on face then spreads downward Seriousness - maternal infection in 1st trimester serious fetal damage 4 – Scarlatina - ?? 5 - Fifth Disease = Erythema infectiosum - Parvovirus B19 6 - Sixth Disease = Roseola infantum - Human Herpesvirus 6 (HHV-6) Others un-numbered Varicella-Zoster - chickenpox and shingles Chickenpox - highly contagious Spread by coughing, sneezing, direct contact, aerosolization Highest incidence in March and April Generally mild in 5-9 year olds, 1in 10 experience complications Fatal in infants, adolescents, adults, immunocompromised of any age (10-30% mortality) due to __________________________________________ Deaths every year in unvaccinated individuals Dorsal root ganglion near spine - Shingles, reactivation, over 45. Kawasaki Disease III. Fungal Skin Diseases - Read in your text BIO 580 Medical Microbiology Unit 3 – Clinical Manifestations 32 IV. Infections of Wounds A. Infections of Trauma Induced Wounds Many type wounds result in anaerobic conditions in the tissues: 1. Dirty 2. Crushed 3. Puncture wounds (including little puncture wounds from nails, tacks, thorns, splinters) 4. Projectile (bullets, fireworks) - battlefields, especially cavalry - tetanus EX. Gas gangrene - Clostridium perfringens and C. septicum - many trauma wounds Onset 12-48 hrs after injury - tissues become anoxic spores germinate bacteria grow & ferment carbohydrates of muscles prod gases (carbon dioxide & hydrogen), gas bubbles destroy tissue. Foul odor, high fever, shock, massive tissue destruction, blackening of the skin, rapidly spreading Txt - Debridement, amputation, hyperbaric chamber - pressurized oxygen-rich atmosphere - oxygen saturates the infected tissue, prevents growth of clostridia. EX. Pasteurella multocida - GNR, ox +, grows on MAC. - animal bite wounds B. Infections of Surgical Wounds 5-12% of all surgical patients develop post-operative infections. Role of sutures - usually 10,000 S. aureus needed to establish infection but sutures down to 100. Also IV catheters, artificial valves & joints. The pathogens: S. aureus - highest single agent, about 20% all surgical wounds BUT Infections caused by coagulase (-) staphylococci, Enterobacteriaceae, and Pseudomonas together cause 60% of surgical wound infections. They are less invasive than S. aureus but more antibiotic resistant. C. Infections of Burn Damaged Skin Burned areas with damaged skin are ideal sites for infection by bacteria from the environment or normal flora. Almost any opportunistic pathogen can infect wounds but the most serious is Pseudomonas aeruginosa - very antibiotic resistant - major cause of death in burn patients. GNR, oxidase +, characteristic blue-green pigment called pyocyanin- can color tissues green as well. Staphylococcus aureus virulence factors Factor 1. Leukocidin 2. Coagulase Effect Kills WBC by producing holes in their cytoplasmic membranes (also kill RBC). May impede the progress of WBC into the infected area by causing plasma to clot in the surrounding capillaries. Also disguises staph antigens with self material (antigenic mimicry). Separates the layers of epidermis, aids in invasion. 3. Exfoliative toxin (exotoxin) 4. Toxic Shock Syndrome Superantigen - stimulates TH to over produce IL-2. Causes rash, toxin (exotoxin) diarrhea, falling blood pressure resulting in shock 5. Protein A secreted Binds to Fc portion of antibody so antibody can’t bind to Fc receptors on phagocytes (anti-opsonic). 6. Capsule Inhibits phagocytosis of nonopsonized bacteria. 7. Lipase Breaks down lipids, aids in colonization of oily hair follicles. 8. Protease Degrades collagenase, aids in spread. 9. Hyaluronidase Breaks down hyaluronic acid in connective tissue, aids in spread. 10. Penicillinase Destroys the beta-lactam ring of penicillin. Streptococcus pyogenes virulence factors Factor 1. Hemolysins = streptolysins 2. Streptokinase 3. DNase 4. Hyaluronidase 5. Erythrogenic toxin 6. Proteases 7. Hyaluronic acid capsule 8. M-protein Effect Kill WBC by producing holes in their cytoplasmic membranes (also kill RBC). Converts plasminogen to plasmin, promotes lysis of fibrin clots, aids in spread. Breaks down the viscous DNA in pus to facilitate spread. Breaks down hyaluronic acid (the cement that holds cells together) in connective tissue, allows rapid spread (also eventually breaks down their own capsule). Produced by lysogenic strains (virus infected), responsible for rash. Break down proteins. Same as hyaluronate of connective tissue. Inhibits phagocytosis of nonopsonized bacteria, also disguises strep antigens. Interferes with phagocytosis and blocks complement action. The major virulence factor.