Central Michigan University
Introduction to Solving Clinical CasesSteps in a Clinical Encounter1.2.3.4.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 immunizationsSocial 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 historyand so on as appropriate.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, etcBasic biometrics – height, weight, painVital Signs – temperature, blood pressure, pulse, respiratory rateOrgan systems – cardiovascular, lungs, breast, abdomen, genitalia, musculoskeletal, nervous, including mental status, HEENT (head, eyes, ears, nose, throat), skinHistory + 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”.Normal Vital Signs Ranges for ChildrenTable 1: Normal Heart Rates (Resting)AgeNormal Range (Resting) bpmPremature120-1700-3 months100-1503-6 months90-1206-12 months80-1201-3 years70-1103-6 years65-1106-12 years60-95Over age 1255-85Table 2: Normal Respirations (Resting)AgeNormal Range (Resting) rpmPremature40-70 0-3 months35-553-6 months30-456-12 months25-401-3 years20-303-6 years20-256-12 years14-22Over age 1212-18Table 3: Normal Temperatures by Age and MethodAgeOralRectalAxillary(Armpit)Ear0-2 years-97.9-100.494.5-99.197.5-100.43-10 years95.9 to 99.597.9-100.496.6-98.097.0-100.0Over age 1197.6-99.698.6-100.695.3-98.496.6-99.7Table 4: Normal Blood PressuresAgeNormal RangeTop NumberNormal RangeBottom NumberPremature55-7535-450-3 months65-8545-553-6 months70-9050-656-12 months80-10055-651-3 years90-10555-703-6 years95-11060-756-12 years100-12060-75Over age 12110-13565-85Hematology References Ranges for ChildrenTable 1: Complete Blood CountRBCHgbHctMCVMCHMCHCRDWPLTSMPVAgeX 106/uLg/dL%fLpgg/dL%X 103/uLfLNewborn4.1-6.715-2444-70102-11533-3932-3613-18150-4506-9.51-23 mos3.8-5.410.5-1432-4272-8824-3032-3611.5-16150-4506-9.52-9 yrs4.0-5.311.5-14.533-4376-9025-3132-3611.5-15150-4506-9.510-17 yrsMaleFemale4.2-5.64.1-5.312.5-16.112-1536-4735-4578-9578-9526-3226-3232-3632-3611.5-1411.5-14150-450150-4506-9.56-9.5Table 2: Differential White Cell CountWBC*Total NeutrophilsSegsBandsLymphsMonosEosBasosAgeX103/uLX103/uLX103/uLX103/uLX103/uLX103/uLX103/uLX103/uLNewborn9.1-346-23.56-20<3.52.5-10.5<3.5<2<0.41-23 mos6-141.1-6.61-6<11.8-9<1<0.7<0.12-9 yrs4-121.4-6.61.2-6<11-5.5<1<0.7<0.110-17 yrsMaleFemale4-10.54-10.51.5-6.61.5-6.61.3-61.3-6<1<11-3.51-3.5<1<1<0.7<0.7<0.1<0.1Differential Shown as Absolute Numbers. *Total Neutrophils = SEGS + BANDSNormal Reference Values, AdultsHematologyWBC4.0-10.5 x 103/uLRBC – Female3.8-5.5 x 106/uLRBC - Male4.3-6.2 x 106/uLHemoglobin - Female12.0-15.0 g/dLHemoglobin - Male13.,2-16.2 g/dLHematocrit - Female37-46 %Hematocrit - Male40-52%Platelets140-415 x 103/uLNeutrophils (Polymorphs, PMNs)40-74 %Immature Polys (Bands)0-10%Lymphocytes14-46 %Monocytes4-13 %Eosinophils0-7 %Basophils0-3 %Neutrophils, Absolute1.8-7.8 x 103/uLMonocytes, Absolute0.1-1.0 x 103/uLEosinophils, Absolute0.0-0.4 x 103/uLBasophils, Absolute0.0-0.2 x 103/uLBlood ChemistryGlucose, Serum65-99 mg/dLBUN6-24 mg/dLCreatinine, Serum0.57-1.00 mg/dLBUN/Creatinine Ratio9-23Sodium, Serum135-145 mmol/LPotassium, Serum3.5-5.2 mmol/LChloride, Serum97-108 mmol/LCarbon Dioxide, Total20-32 mmol/LCalcium, Serum8.7-10.2 mmol/LProtein, Total, Serum6.0-8.5 g/dLAlbumin, Serum3.5-5.5 g/dLGlobulin, Total1.5-4.5 g/dLBilirubin, Total0.0-1.2 mg/dLAlkaline Phosphatase25-150 IUAST (SGOT)0-40 IU/LALT (SGPT)0-40 IU/LBlood GasesBicarbonate22-26 mEq/LBlood pH7.34-7.44Partial Pressure of Carbon Dioxide (pCO2)35-45 mmHgPartial Pressure of Oxygen (pO2)75-100 mmHgUrinalysisUrine BilrubinnegativeUrine Blood negativeUrine KetonenegativeUrine LeukocytesnegativeUrine RBC0-2/HPFUrine WBC0-2/HPFUrine RBC casts0/HPFUrine NitritenegativeUrine Proteinnegative-traceSpecific Gravity1.002-1.030Urine pH5-7Urobilogen0.2-1.0 hEr U/dLCerebral Spinal FluidCSF Glucose50-80 ng/dLCSF Protein15-45 mg/dLCSF RBC0/uLCSF WBC0-3/uLRespiratory TractOverviewnose to alveoli continuous operation is essential divided into 2 regions:upper –lower - GeneralizationsMany cause local infections, some may spread systemicallyProfessional invaders - normal healthy host, specific attachment mechanisms, specific evasion tacticsSecondary invaders - impaired hostMost common infections seen by doctorsHigh morbidity ? absenteeismUpper - usually mild & self-limitingLower - can be severe & life-threateningin children bacterial in adultsClinical SyndromesUpper Respiratory Tract Infectionsitis = inflammation - surface infectionsExposed to 8 microbes/min or 10,000/dayPredisposing factorsdecreased humidity – viral infections – antibiotic therapy - 1. Rhinitis = cold100% 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 noseincubation -damage to epithelial cells ? 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 tonsilitisinfected mucosa or inflammation of lymphoid tissue70% viral – symptoms often include rhinorrhea, conjunctivitis, malaise or fatigue, hoarseness, and low-grade feverrhinovirus, coronavirus, adenovirus, etc, see Table 18.5Cytomegalovirus (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 retardationEpstein-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 conjunctivitisS. pyogenes age – onset – symptoms – complications - N. gonorrhoeae – C. diphtheria –.3. Otitis media and sinusitis = ear and sinusear infections are second most common infection of childhood (after colds) and most common cause of visits to pediatricians50% viralrespiratory syncytial virus (RSV), influenza, parainfluenza, rhinovirus, adenovirus50% bacteria - secondary invadersS. pneumoniae, Haemophilus influenzae, Moraxella4. EpiglottitisH. influenzae type B (vaccination = Hib)Severe inflammation with edema life-threatening respiratory obstructionAge – Symptoms - Lower Respiratory Tract InfectionsLower RT is a sterile site, there are no normal microbiota1. Laryngitis and tracheitisViruses (symptoms – hoarseness, burning retrosternal pain)Parainfluenza virus – croup (dry cough and inspiratory stridor)RSV, Influenza virus, AdenovirusBacteriaGAS, H. influenzae, S. aureusC. diphtheria - life threatening, rare in U.S. due to vaccination (DaPT)2. Whooping coughOrg - Bordetella pertussis (GNR, ox +, obligate aerobe)Humans are sole reservoirHighly contagiousTransmission - person - person airborne dropletsColonization - attach to ciliated mucosa in trachea using fimbriae & hemagglutinin also spreads to bronchiSeveral toxic factors -affect inflammation or damage ciliated epithelium1. pertussis toxin - A-B structure exotoxin; A unit is an ADP-ribosylase, disrupts signal transduction in affected epithelial cell - prod massive amts mucoid secretions2. Adenylate cyclase toxin - enters neutrophils & causes them to incr. cAMP - inhibits chemotaxis, phagocytosis, & killing3. Tracheal cytotoxin - kills tracheal epithelial cells4. EndotoxinIncubation - 1-3 weeksPathology - ciliated epithelium of trachea becomes covered w/ massive purulent exudatePresentationearly - runny nose, sneezing, fever, mild dry coughweek later - mucus & bact fill lower trachea, cough becomes paroxysmal - violent coughing fits, 5-20X w/ no breath in btwn - as air rushes back in - whoopalso vomiting, epistaxis, periorbital edema, conjunctival hemorrhageComplications - CNS anoxia, secondary pneumoniaImmunization - DaPTRate of infection in unvaccinated exposed - 90-95%; Mortality - up to 14%3. Acute bronchitis - Inflammation of the tracheal/bronchial tree assoc w/ infectionOrgsProfessional pathogens; Viruses (rhino-, corona-, adeno-, influenzae,) and Mycoplasma pneumoniaeSecondary invaders - S. pneumoniae, H. influenzae Presentation - cough - treatment is symptomatic - antibiotics? usually recommended4. Influenza = the FluOrg - 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 dropletsColonization - attaches via HA to sialic acid receptors on ciliated epithelium of trachea/bronchi, RME Incubation - 1-3 daysPathology - impair mucociliary clearance, tracheobronchitis, bronchospasms; cytokines released from damaged cells & WBC may symptomsPresentation - fever 102-104, chills, severe headache w/ retro-orbital pain, muscular aches (esp backache), dry cough, weakness (prostration).Most cases resolve 1-2 wksComplications - 1? influenza pneumonia (1% of cases but 30% fatality, pregnant women ↑ risk), 2? 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 = epidemic5. Bronchiolitischildren less than 2swollen by inflammation, passage of air is restrictednecrosis of epithelial cells lining the bronchiolesOrgs75% RSVRespiratory Syncytial Virus - paramyxovirus (RNA), envelopedMost common cause of fatal bronchiolitis & pneumonia in infants (1/100 hospital) - humans only reservoirTransmission - resp. droplets to handsColonization - nasopharynx - surface spikes are fusion proteins that fuse host cells to cause "syncytia", then virus invades LRT by surface spread in secretionsIncubation 4-5 daysImmunopathology - maternal Ab in infant react w/ virus Ag, liberate histamine & other inflammatory mediatorsPresentation - cough, rapid respiration, cyanosis25% other viruses6. Pneumonia4,000,000 people/yr. Most common cause of infection related death in the US. 6th leading cause of deathwide range of microbes Transmission - inhalation or aspiration Colonization - attach to resp epitheliumPathology - respiratory distress from the interference of gas exchange in lungs, systemic effectsOrgschildren - viral or bacteria secondary to virusesadults - bacterial, kind depends on risk factors, age, other diseases - in hospitals GNBacterial - acute onset, high feverTypical - classic bacteria of acute, community-acquired - S. pneumoniae (25-60%), H. influenzae (5-15%), others - S. aureus, Klebsiella, E. coli, PseudomonasAtypical - M. pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, Coxiella burnetiiChest examrales (abnormal crackles)evidence of consolidationchest x-rayViralTransmission - inhaled or from bloodColonization - attach specificallyOrgsRSV - childrenParainfluenza virus types 1 & 2 – children; hemagglutinin & neuraminidase & fusion proteinsAdenovirus - 41 types; 5% of acute resp. illnessInfluenzavirus7. Chronic Infections of the lungsTuberculosis - reviewFungiAspergillus 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 diseaseHistoplasma capsulatum - histoplasmosisCoccidiodes immitis - San Joaquin Valley FeverBlastomyces dermititidis - blastomycosisPneumocystis jiroveci (formerally P. carinii) - pneumocystis pneumonia8. Cystic fibrosisvery viscous bronchiol secretions leads to fluid stasis in the lungs & infections w/ P. aeruginosa (S. aureus, H. influenzae, B. cepacia)Urinary Tract Infections and Sexually Transmitted InfectionsI. Overview UrinaryGeneral infoFunction - transport products from inside of body to outsideFree of microbes (sterile) except where the outflow meets the skinUrinary Tract Infections (UTI)Almost always bacterialUsually acquired as ascending infectionsMost originate from fecal microbiota - self-inoculationDifferential 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- acquiredHospital-acquired1. E. coli (80-90%)1. E. coli (40%)2. S. saprophyticus (5-15%)2. Klebsiella, Enterobacter, Serratia, Pseudomonas aeruginosa (25%)3. Proteus mirabilis3.GPC4. Klebsiella, Enterobacter, Serratia, Pseudomonas aeruginosa4. Proteus mirabilisviruses - rare?Predisposing FactorsAnything that:Disrupts urine flowPrevents complete emptying of bladderPromotes microbial accessFemalesFemales & malesMalesPregnancyRenal stonesEnlarged prostateIntercourseTumorsNeurological disordersCathetersVirulence Factors of Urinary Pathogens (examples):E. coli – uropathogenic strains (O and K serotypes) = UPECpathogenicity islandP fimbriae (attachment)capsular acid polysaccharide (resist phagocytosis)membrane active cytotoxinsS. saprophyticusadherence to uroepithelium (high proportion of bladder cells w/ adherent bacteria)microbistatic to GP and GNureaseP. mirabilisflagella (motility)ureaseB. Clinical SyndromesLower UTIurethritis (urethra)Symptoms - dysuria2. cystitis (bladder)Symptoms - rapid onset of dysuria; increased urgency/frequencyUrine - cloudy - pyuria (inflammation) or bacteriuria (bacteria); blood (hematuria)3. prostatitis (prostate)Symptoms - dysuria, increased frequency, low back pain, systemic indications (fever)Upper UIT1. pyelonephritis (renal parenchyma)Symptoms - cystitis + more severe systemic indications (fever)Complications - septicemia, loss of renal functionCollecting Urine SamplesVoiding (Midstream clean-catch)Urinary catheterSuprapubic bladder aspirationLaboratory Diagnosis of Urinary Tract InfectionsRead in text pages 257-259 carefully, especially pay attention to how to tell what is significant bacteriuriaII. Genital/ReproductiveGeneral infoOnly system that is significantly different in males & femalesLargely free of microbes, except for the vaginaSexually Transmitted Infection (STI) ( = Sexually Transmitted Disease (STD) = venereal disease (VD)Incidence is increasingAlmost no vaccinesRampant on college campusesOften asymptomaticSexually Transmitted Diseases - Top Ten in US By OccurrencePathogenDiseaseHuman Papillomavirus (HPV)genital warts; associated w/ cervical cancer*Chlamydia trachomatis D-K. C. trachomatis L1, L2, L3non-specific or non-gonococcal urethritislymphogranuloma venereum Candida albicansvaginal thrush, balanitisTrichomonas vaginalisvaginitis, urethritisHerpes simplex virus (HSV)genital herpes*Neisseria gonorrhoeagonnorheaHIVAIDS*Treponema pallidumsyphilis*Hepatitis B virushepatitis10. Haemophilus ducreyichancroidClinical Syndromes#1 Human Papilloma Virus (HPV)Transmission – sexuallyEntry – attach to target cell via capsid protein, enter via RMEIncubation – 1-6 monthsPathology – dyplasia = abnormal growthSymptoms – warts on penis, vulva, perianal regions (types 6 or 11) – BUT majority asymptomaticComplications – high-risk HPV types 16, 18, 31, 33, and 35 are strongly associated with cervical neoplasiaTreatment (Txt) – asymptomatic and subclinical not treated; warts treatedPrevention - vaccine#2. Non-gonococcal urethritis - Chlamydia trachomatis - Obligate intracellular bacterium –Transmission – sexualEntry – abrasionsAttachment - to receptors on host cell, parasite-induced endocytosisIncubation – 2-6 weeks or longerPathology – cells destruction & inflammationSymptoms – asymptomatic infection is common, esp. in women OR urethritisComplications –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 microbiotaTransmission – normal microbiota of female vagina - disruptions to bacterial vagina community can result in an overgrowth with yeast.Symptoms – UTI, intensely itchy/burning, cottage cheesy dischargeBalanitis (inflammation of glans penis) in 10% of male partnersTxt – antifungals like micronazole or nystatin (topical) or oral fluconazole#4. Vaginitis - Trichomonas vaginalis - protozoaTransmission – sexualEntry – vagina in women; urethra and prostate in menSymptoms – vaginitis – copious, yellow/green frothy discharge, rise in vaginal pHTxt - metranidazole#5. Genital herpes - Herpes simplex viruses types 1 and 2 (HSV1, HSV2)Transmission – sexualEntry - by membrane fusionIncubation – 3-7 daysPathology - 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, malaiseThe 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. 1504953175I it is believed that herpes infected individuals may always be somewhat plications (in addition to reactivation) – aspetic meningitis or encephalitis in adults. Neonatal disseminated herpes or encephalitis.Txt – acyclovir (Zovirax), famciclovir, valacyclovir (Valtrex)#6. Gonorrhea - Neisseria gonorrhoea – 260,530 U.S. in 2009/ 14,471 cases MITransmission – direct, usually sexual, person-personIf 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 cellsIncubation – 2-7 daysPathology – see picture– what process causes the damage?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% asymptomaticComplications – 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.#8. Syphilis ((#3 bacterial STI in U.S.) - Treponema pallidum – 12,833 U.S. in 2009/ 231 cases MITransmission – close physical contact; usually sexual, saliva, blood - 1/3 of those exposed to the syphilis spirochete will become infected.Entry – small abrasionsIncubation – 10-90 days, 3 weeks is averageSymptoms - 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 plications – 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.Infections of the GI and Diarrheal IllnessClinical SyndromesGastritis - inflammation of the stomach - pain in the upper abdomen, sometimes bleedingGastroenteritis - inflammation of stomach & intestines - primarily diarrhea, sometimes nausea, vomiting, crampy abdominal painColitis - intestinal syndrome that primarily involves the colon or large intestines.Enterocolitis - inflammation of mucosa of both large & small intestine = dysentery - diarrhea often contains blood & mucus.Hepatitis - liver damage causes a clinical syndrome called hepatitis. Patients with hepatitis become jaundiced because bilirubin builds up in their bodies.PathogensCause disease by 3 mechanisms:action of toxinsadherence to & effacement of microvilli inflammationinvasion of intestinal epithelial cellsA. Toxins cause disease – microbes are not present in the bodyToxin typesAction on intestine/intestinal cellsEnterotoxinresults in net secretion w/out intestinal damageCytoskeleton-altering toxinalters cell shape, may injure cells but is not lethalCytotoxincauses cell damage and ultimately cell deathNeural toxinalters smooth muscle activity in intestines1. 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 [100?C 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 intoxicationemetic – 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.B. True infections – microbes enter and then colonize the GI - 3 mechanisms for damage1. Pathogens colonize epithelial surfaces of small intestine (do not enter) & then release toxins Vibrio cholera - choleraSource - Pathology1. Ingestion of large numbers (> 108); only 0.001% survive passage through stomach2. Flagella & mucinase allow Vibrio to reach epithelial cells3. Attachment by way of fimbriae to receptors on brush border & crypt cells of small intestine4. 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)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 MISource - Pathology – a descending infection of the intestine – small intestine then colonIngestion - only 10-100 organisms required, 55% survive passage through stomach - most effective of bacterial pathogens of GI2. Secrete enterotoxins during passage through small intestine profuse, watery diarrhea3. 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 epithelium5. Phagocytized by macrophages but escape from phagolysosome into cytoplasm6. Trigger macs to produce IL-1, also triggers apoptosis7. 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 stoolS. 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 + diarrheaYersinia enterocolitisEntamoeba histolytica amoebic dysenteryHuman diarrhoeal viruses (rotavirus, Norwalk virus) - gastroenteritisVirus 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.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 MISalmonella typhi, paratyphi – invasive species typhoid fever SourcesS. enteritidis - S. typhi - Pathology1. Ingestion of large numbers (105-1010); 0.001% survive passage through stomach2. Attach specifically to fibronectin of epithelial cells of small intestine3. Transported by M cells of GALT4. Invade gut wall ? ulcerations & hemorrhage. Also spread to intestinal lymphatics & are phagocytized by macs but escape from phagolysosome into cytoplasm5. 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 GI7. OR influx of macrophages (typhoid species) and systemic spreadS 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 stoolSalmonellosisIncubation – Symptoms –Txt - Complications – Other pathogens that cause disease by similar mechanism: Hepatitis A virus - 1,849 cases U.S. / 70 MIReovirusesEnteroviruses (includes poliovirus)Nervous System = peripheral nerves + central nervous system (CNS)I. Generalities:A. Structure ofB. Protection ofC. 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:bonesinusesmiddle ear4. traumaII. Clinical SyndromesA. meningitis - of meningesCharacterized by high fever, headache, stiff neck (classic triad)Pathology due to acute inflammation:Vascular permeability ↑WBC, ↑fluidsFluids swellingSwelling ↑pressure headacheInflammation affects muscles stiff neckInflammation feverCauses:clogging of blood vessels (DIC) necrosis of tissue↓ CSF flowimpaired CNS functionIn 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 brainCharacterized by acute febrile illness + changes in mental state, consciousness, behaviorC. myelitis - of spinal cordSymptoms vary depending on where damage to cord occursIII. Infections of the MeningesA. Bacterial meningitisAcute - nearly always fatalStrong correlation of microbe with age of patient – influences the top R/O:Neonates – E. coli, Group B streptococci1 month to 5 yrs - Haemophilus influenzae type B (Hib)5 to 40 - Neisseria meningitidis30 and over - Streptococcus pneumoniaePathogenesiscolonization and invasion of nasopharynx nasopharynx bloodstream BBB to subarachnoidreplicate and induce inflammation in subarachnoid space increased permeability of BBB, cerebral edema, increased intracranial pressure, decreased cerebral blood flow.PathologySubarachnoid space purulent exudates, vein distension, focal necrosisDiagnosisCSF examination – elevated opening pressure, very ↑neutrophils, very ↑ protein, ↓glucosePrognosisSerious to graveMortality ratesHibwithout txt = near 100%with txt = 5%N. meningitideswithout txt = near 100%with txt = 7-10%S. pneumoniaewithout txt = near 100%with txt = 20-30%All can be present in humans in an asymptomatic carrier stateHaemophilus influenzae type B (Hib) (1 month – 5)GNRNormal upper RT microbiotaInactivate IgA using IgA proteaseColonize the nasopharynx using common piliPenetrate submucosa (invasive) bloodstream (capsule to avoid phagocytosis)Incubation - 5-6 daysSymptoms develop over 1-2 daysEndotoxin:1. inflammation2. DICComplications – hearing loss, delayed language development, mental retardationPrevention – Vaccination2. Neisseria meningitidis (5-40) GNdCPerson-person in respiratory droplets; 20% carriers (as high as 60-80%)Inactivate IgA using IgA proteaseColonize the nasopharynx using pili sore throatEndocytized bloodstream (capsule to avoid phagocytosis)Incubation 1-3 daysSymptoms develop over 6-24 hoursEndotoxin:1. affects blood vessel permeability cross BBB (attach to dura mater w/ pili)2. drop in blood pressure shock3. clotting of blood hemorrhage (rash = petichiae and purpura), also DICComplications – amputations, permanent hearing lossPrevention - Vaccination3. Streptococcus pneumoniae (30+) GPCNormal upper RT microbiotasinuses or middle ear brainorpneumonia in lungs bloodstream brainCapsuleTeichoic acid inflammationPrevention - VaccinationB. Viral meningitis = aseptic meningitisMost commonSelf-limiting, non-fatalMany different viruses:1. Enteroviruses - 40% (primarily Coxsackievirus and Echovirus)2. Arboviruses3. HIV4. HSV-2Several considerations affect differential:Summer, fall + geographic clustering ArbovirusesLate fall, winter + history of exposure to mice LCMVLate winter, early spring + male mumps virusWith genital lesions HSV-2With atypical lymphocytes EBVWith chickenpox or shingles VZVDiagnosisCSF examination – ↑ lymphocytes, moderately ↑ protein, normal glucosePrognosis - In adults, excellentC. Fungal meningitisChronic presentation – symptoms develop over days to weeks1. Coccidioides immitis 2. Cryptococcus neoformans - AIDSIV. Infection of the Brain (Encephalon) – involvement of brain parenchymaA. Viral encephalitisSame viruses as for aseptic meningitis but relative frequency varies1. Arboviruses (Arthropod-borne)Ex. Equine encephalitis, (West Nile virus) BirdMosquitoMosquitoBirdHorse(human)Epidemics, geographic clustering2. HSV-1no insectsporadic, not epidemic3. Enteroviruses, mumps Rabies - Rhabodovirus BiteMultiplies at siteTravels to local nervesPeripheral nerves spinal cord brainLong incubationProdromal phase - flulike symptoms, tingling, burning, depressionExcitation phase - muscle function, speech, vision, anxiety, hydrophobiaParalytic phase - muscles weaken, consciousness fades, deathMortality - 100% with best treatmentPost exposure prophylaxis (PEP) - has never failed in USB. Protozoan encephalitis1. Primary amebic encephalitis - Naegleria fowleri Mortality = 100%2. African Sleeping Sickness - Trypanosoma Misc.Tetanus Clostridium tetani – exotoxin tetanospasmin (mimics strychnine poisoning)Botulism Clostridium botulinum Genes for toxin are carried on a bacteriophageExotoxin botulinum prevents release of acetylcholineProduces a limp, flaccid, paralysisEyes blurry, double visionThroat slurring speech, difficulty swallowingDifficulty breathingCardiac problemsInfections of Skin and WoundsAbscessesAbscess - a localized collection of pusAbscess formation localizes an infection and prevents spreadMicroorganisms in abscesses are difficult to treat with antimicrobial agents because:microbes aren’t multiplying - many antimicrobial agents only work against actively growing cells.chemical nature of pus interferes with action of some antibioticsantibiotics have difficulty reaching the site because of lack of vessel penetrationAbscesses are a potential source of infection for other sites, can seed microbes into the blood or lymphI. Bacterial Infections of Skin, Soft Tissue, MuscleAll acute (24-48h)A. By skin layer involved1. infections of hair follicles – usually S. aureusa. 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 poisoningc. carbuncles - larger - several sites of draining pus - usually on neck or upper back - systemic symptoms (fever)2. Stratum corneumImpetigo - a highly contagious pyoderma caused by group A ?-streptococci (GAS)- almost exclusively in children - spread by contact3. EpidermisEcthyma – untreated impetigo4. Dermisa. Erysipelas = St. Anthony’s fire – usually GAS - blockage of dermal lymphatics – well-defined edges. Pain and fever. 5% develop bacteremia with high mortality.b. Lymphangitis – inflammation of the lining of lymphatic vessels5. Subcutaneous fat layerCellulitis – usually S. aureus or S. pyogenes. Initial superficial skin trauma. Diffuse inflammation, enlarged lymph, malaise, chills, fever.B. By specific strains of S. aureus or S. pyogenes1. Scalded skin syndromeCaused by certain exotoxin producing strains of S. aureus infected by lysogenic phagesExotoxin 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 tissueMost 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 skin trauma Involves the subdermal tissuesproduces 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 = exanthemsSeveral 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 – measlesHigh fever and rash that starts head & neck, then arms, upper trunk, back, finally legsKoplik's spots are diagnosticExtremely 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)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 downwardSeriousness - maternal infection in 1st trimester serious fetal damage4 – Scarlatina - ??5 - Fifth Disease = Erythema infectiosum - Parvovirus B196 - Sixth Disease = Roseola infantum - Human Herpesvirus 6 (HHV-6)Others un-numberedVaricella-Zoster - chickenpox and shingles Chickenpox - highly contagiousSpread by coughing, sneezing, direct contact, aerosolizationHighest incidence in March and AprilGenerally mild in 5-9 year olds, 1in 10 experience complicationsFatal in infants, adolescents, adults, immunocompromised of any age (10-30% mortality) due to __________________________________________Deaths every year in unvaccinated individualsDorsal root ganglion near spine - Shingles, reactivation, over 45.Kawasaki DiseaseIII. Fungal Skin Diseases - Read in your textIV. Infections of WoundsA. Infections of Trauma Induced WoundsMany type wounds result in anaerobic conditions in the tissues:DirtyCrushed Puncture wounds (including little puncture wounds from nails, tacks, thorns, splinters)Projectile (bullets, fireworks) - battlefields, especially cavalry - tetanusEX. 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 spreadingTxt - 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 woundsB. Infections of Surgical Wounds5-12% 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 woundsBUTInfections 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 SkinBurned 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 factorsFactorEffect1. LeukocidinKills WBC by producing holes in their cytoplasmic membranes (also kill RBC).2. CoagulaseMay 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).Exfoliative toxin (exotoxin)Separates the layers of epidermis, aids in invasion.4. Toxic Shock Syndrome toxin (exotoxin)Superantigen - stimulates TH to over produce IL-2. Causes rash, diarrhea, falling blood pressure resulting in shockProtein A secretedBinds to Fc portion of antibody so antibody can’t bind to Fc receptors on phagocytes (anti-opsonic). 6. CapsuleInhibits phagocytosis of nonopsonized bacteria.7. LipaseBreaks down lipids, aids in colonization of oily hair follicles.8. ProteaseDegrades collagenase, aids in spread.9. HyaluronidaseBreaks down hyaluronic acid in connective tissue, aids in spread.10. PenicillinaseDestroys the beta-lactam ring of penicillin.Streptococcus pyogenes virulence factorsFactorEffect1. Hemolysins = streptolysinsKill WBC by producing holes in their cytoplasmic membranes (also kill RBC).2. StreptokinaseConverts plasminogen to plasmin, promotes lysis of fibrin clots, aids in spread.3. DNaseBreaks down the viscous DNA in pus to facilitate spread.4. HyaluronidaseBreaks down hyaluronic acid (the cement that holds cells together) in connective tissue, allows rapid spread (also eventually breaks down their own capsule).5. Erythrogenic toxinProduced by lysogenic strains (virus infected), responsible for rash.6. ProteasesBreak down proteins.7. Hyaluronic acid capsuleSame as hyaluronate of connective tissue. Inhibits phagocytosis of nonopsonized bacteria, also disguises strep antigens.8. M-proteinInterferes with phagocytosis and blocks complement action. The major virulence factor. ................
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