1、CholeraYunsong Yu cholera Pathogen：vibrio choleraEight pandemics over most of the globeA infectious diseaseinternational quarantine infection disease etiology vibrio cholerae Gram-negativeIt is rapidly motile by means of a single polar flagellum.O139 serogroup with capsuleHanging drop test under mic
2、roscope Appearing school of fish in feces smearGenerate rapidly in the alkalinity environment antigen Bacterial cell（）antigenhas high specificity,and is the basis for the classification and typing of vibrio cholera Flagellum（）antigencommon in vibrio cholera Classification of vibrio cholera by WHO O1
3、 vibrio cholera Non-O1 vibrio cholera Untypical-O1 vibrio cholera O1 vibrio cholerae According to the phenotype，two biotypes were typed：classical biotype El-Tor biotype According to the O antigen，V.cholerae O1 are further divided into the following subserotypes：ogawa(小川）strains express A and B antig
4、ens inaba（稻叶）strains express A and C antigens hikojema 颜岛）strains express A,B and C antigens non-O1 vibrio cholerae No ability to agglutinate the multipartial serum of O1 vibrio cholerae Containing more than 200 serogroups such as O2,O3,O138 and so on，with no pathogenicity generally O139 serogroup h
5、as following specificities：A new serogroup detected in Bengal in 1992 With the same toxin gene with O1 serotype，and leading to epidemic diarrhea untipical-O1 vibrio cholerae With the ability to agglutinate the multipartial serum of O1 V.choleraeWith no enterotoxin and pathogenicity Resistance of vib
6、rio cholerae Sensitive to heat,dry,acid and common antisepticsDie after drying for 2 hours or heating to 55 for 10 minutesDie immediately after boilingSurvive for 4 minutes in the normal gastric acid Survive more longer in physical environment El Tor biotype can survive for 1-3 weeks in river and we
7、ll water Survive time prolonged as adhere to algae or crustaceanEven survive for more than one year,if external environment was suitable Resistance of vibrio cholerae Three types of toxin type toxin endotoxin，the major component of bacterial vaccintype toxinepitoxin，is cholera enterotocin，Product of
8、 metabolism in the generation of vibrio choleraKey substance leading to cholera diarrhea type toxin has no association with pathogeny epidemiology epidemic history 1st6th pandemic（18171923）：clssical biotype7th pandemic（1961up to now）：El Tor biotypeIn 1992,cholera caused by O139 serotype began in Ind
9、ia and Bengal,and spread to surrounding countries（8th pandemic）cases of vibrio cholerae in 1961-2000 yearcases source of infection Bacteria carrierPatientsBacterial eliminating time：5 days，2 weeks at mostSevere patients，with a great deal of bacterium eliminating，107109 vibrio cholerae stains per mil
10、liliter of stool，are the important infection source route of transmission Water or food polluted by vibrio cholera Contact in daily life susceptibility Susceptible generallyMore with inapparent infection，less with apparent infection Acquired immunity after infection，but persistent time is short and
11、reinfection will occur.epidemiologic character Tropical zone：onset whole yearChina：epidemic in summer or autumn，crest-time is July to SeptemberGeographic characteristic:distribute along river or sea pathogenic mechanism pathogenic mechanism Determinants：The level of gastric acid secretion Quantity a
12、nd virulence of V.cholera V.cholerae must survive passage through the gastric barrier of the stomach and reach the small intestine Generate greatly in the alkalinity environment of the small intestin and release cholera enterotoxin Pass though the slime layer of the intestinal mucosa paghogenic mech
13、anism Choleragen cholera enterotoxin（also named choleragen）plays the key role in pathogenesisFigure The bacterium produces a toxin（left）that is the cause of the cholera.The toxin molecule is composed of several parts,one of which（coloured blue）penetrates the cell membrane（yellow）mechanism for excess
14、ive secretion of small intestine Cholera Toxin is a prototype A/B subunit toxin,consisting of one A subunit and 5 B subunits.The B subunit binds the holotoxin to a eukaryotic cell surface receptor GM1（A）Cholera toxin approaching target cell surface.（B）Binding of B subunits to oligosaccharide of GM1
15、ganglioside.（C）Conformational alteration of holotoxin presenting A subunit（black）to cell surface.The mature A subunit is proteolytically cleaved to produce a 21.8kDa A1 polypeptide,and a 5.4kDa A2 polypeptide in cell.NAD is cleaved by A1 and yields ADP-ribose to act on G protein.（E）Reduction of disu
16、lfide bond of A subunit by intracellular glutathione,freeing A1 and A2.（F）Cleavage of NAD by A1 yielding ADP-ribose and nicotinamide.（D）Entry of A subunit.mechanism for excessive secretion of small intestine ADPribosylation of G protein inhibits the activity of GTPaseSince AC is activated,ATP is cha
17、nged to cAMP persistently cAMP stimulates pit cells to produce H2O,chloridate and bicarbonate,and inhibits the absorption of chloridate by chorionic villi cell.（G）ADP-ribosylation of G protein,inhibiting action of GTPase and“locking”adenylate cyclase in“on”mode.Second messenger mechanism for excessi
18、ve secretion of small intestine pathophysiologyThe feces of cholera patients is isosmotic.The concentrations of potassium and bicarbonate in feces are 25 times higher than those in blood.See Table：Severe vomiting and diarrhea lead to dehydration,electrolyte disturbances,and acid-base imbalance.Conce
19、ntrations of potassium,sodium and bicarbonate in feces and serum（mmol/L）sodiumpotassiumchloridebiocarbonateFeces of patients135 1510045Normal serum136 1483.8 5.098 10624 32pathologic anatomy Dry skin,contraction of parenchymatous organsDry gastrointestinal placenta percreta，mild inflammation of inte
20、stinal mucosa，full of“rice water stool”in intestine Renal megaly，angiotelectasis of glomcrulus and interstitium，cloudy swelling,degeneration and necrosis of renal tubule epithelium clinical manifestationclinical manifestationIncubation period：1-3 daysOnset abruptlyClinical manifestation is associate
21、d with the type of V.choleraInfections with clssical biotype and O139 V.cholera are relatively severe Infections with El Tor biotype V.cholera are mildcourse of diseasesI.Diarrhea and vomit periodII.Dehydration and prostration period III.Recovery and response period diarrhea and vomit period Persist
22、 for several hours or 12 daysVomit following diarrhea Afebrile commonly（except O139）diarrhea and vomit period Diarrhea character：profuse and frequentyellow water stoolrice water stoolblood water stoolNo fecal foul smellScare abdominal pain diarrhea and vomit period Vomiting character：Without nauseaP
23、rojectile vomiting Vomit gastric contents initially,but shortly vomit watery liquid.dehydration and prostration period 1.dehydrationpoor skin turgorsunken eyeshoarse voicehypourocrinia dehydration and prostration period Scaphoid abdomen“washer-womans hands”Tabescent,cold and clammy skin with poor tu
24、rgor dehydration and prostration period 2.Circulatory failureDegression of blood pressure Conscious disturbance dehydration and prostration period 3.Metabolic acidosisdeep breath,conscious disturbance sometimes4.Muscle convulsionspasmus region pain and muscle rigidity5.hypopotassemiahypomyotonia,ten
25、don reflex disappearmeteorismarhythmia dehydration and prostration period complication Renal failureAcute pulmonary edema and congestive heat failure recovery and response period A few patients have responsive low-grade feverclinical character of O-139 vibrio cholerae Severe symptoms Abdominal pain
26、Complications:extra-intestinal infections such as bacteremia clinical types Manifestation Mild type Medium type Severe type frequency20 timesd e h y d r a t i o n（weight%）10%mindcleardiscomfort or dulla g i t a t i o n o r unconsciousnessskinSlightly dryDry，poor turgorKraurosis and turgor disappeara
27、ncelipSlightly drydry，cyanochroiaExtremely dry，cyanochroiaAnterior fontanel and eye Slightly sunkenApparently sunkenDeeply sunken,even cannot close eyesmuscle convulsionnosometimescommonlypulsenormalgentle，frequent To o g e n t l e a n d frequent to feel Blood pressureNormal 129.3 kPa1.040“cholera s
28、icca”sudden onset of cholera with no diarrhea and vomiting toxic shock immediately High mortalitydiagnosisconfirmed diagnosis Correspond with one or more than one of the following items：with symptoms of diarrhea and vomiting,positive results of stool culturein epidemic region，with typical symptoms，4
29、 times increase of serum agglutinating antibodywithout diarrhea and vomiting，positive results of stool culture，with diarrhea symptom 5 days pre-or post-stool test，close contact historyuncertainable diagnosis Correspond with one or more than one of the following items:with typical symptoms，but uncert
30、ain results of etiology test obvious contact history in epidemic period，with diarrhea and vomiting symptoms,without other reasons differential diagnosisInfections with other Vibrions Infections with E.coli producing toxin Saimonella enteritisViral enteritisAcute bacillary dysentery laboratory test b
31、lood routine Increase of RBC and Hb WBC 10109/L，neutrophilc leukocytosis and mononuclear leukocytosis biochemistry test Decrease of serum sodium,potassium,and chlorine Decrease of HCO3 stool test Stool routine：mucago and several RBC and WBC are seen Gram stain：gram-negative Vibrion，appearing school
32、of fish arrangement stool test Dynamic test：Vibrion is observed shuttling by hanging drop on glass under microscope Immobilization test：To aggulate the antiserum of O1 or O139 serogroup Bacterial culture：To ascertain the type of pathogenic bacteria serology test It is significant for diagnosis that
33、paired serum titres of antiagglutinin antibody more than 4 times increase than normal.Used to the following purposes：Diagnosis of epidemiologyDiagnosis of the uncertainable cases with negative stool culture results treatment treatmental principle Strict isolationPrompt fluid infusion Antibacterial a
34、nd symtomatic treatment serious isolation Submit the epidemic statusIsolation according to the criteria of A infectious diseaseAfter disappearance of symptoms，stool are cultured every other day.When results of continuous twice stool cultures are negative,isolation can be released.veinal fluid infusi
35、on Principle of fluid Principle of fluid infusion infusion Earlier,prompt,adequateDrip of NS-GS,drip of fast-slow，correct acidosis and supply calcium，Correct acidosis and supply calcium，supply potassium as soon as urine appears.which fluid?fluid categories：541 fluid（most suitable）diarrhea treatment
36、solution 21 solution Ringers natrium lacticum solution Feces of patients are isosmotic，in which the concentrations of potassium and bicarbonates are 2-5 times of those in blood.Severe vomiting and diarrhea can lead to dehydration,electrolyte disturbances and acid-base imbalance Concentrations of nat
37、rium,potassium,chlorinum and bicarbonatesin feces and 541 solution（mmol/L）489913134541 solution4510015135 Patients feces composition bicarbonatesinchlorinumpotassiumnatrium which fluid?Fluid dosage：according to the degree of dehydration,dosage in the initial 24 hours：adults（ml）children（ml/kg）dosage（
38、ml/kg）Mild type300040001201506080Medium type4000800015020080100Severe type800012000200250100120 which fluid?velocity?Correct in shock phase：4080ml/minMaintain in blood pressure phase：2030ml/minCorrect in dehydration phase：510ml/minMaintain in transfusion phase：35ml/min take orally compoundings of OR
39、S：Glycose 20gNaCL 3.5gNaHCO3 2.5gKCL 1.5gDissolved in drinking water with the volume of 1000ml take orally Principle：No damage to the absorption of glycose in intestinal tract Leading to the absorption of water Leading to the absorption of electrolytes Especially suitable for：Old and weak patients P
40、atients with cardiorespiratory dysfunctional Patients necessary for supplying potassium promptly antibacterial treatment Antibacterial agents：doxycyclinequinolonesSMZ（O139 insensitive）（purposeto reduce the quantity of diarrhea，to shortern the diarrhea and vomit stage and excreting bacteria stage）ass
41、istant treatment Drugs to inhibit the secretion of intestinal mucosa：chlorderazinberberineantifaniAdrenocortical hormone symptomatic treatment Correct acidosisCorrect hypopotassemiaCorrect shockTreat pulmonary edema prevention contaminator control Establish and perfect the out-patient clinic of the
42、diarrhea diseaseIsolate patientsbreak off transmission route Improve the environment sanitation Strengthen the disinfection of drinking water and the administration of food immunity improvement Innoculate bacterial vaccin in epidemic influencing complication?Answer：the main factors which effect the
43、liability of cholera are：1.Gastric acid,such as hypoacidity or absence 2.Hygienic habit,such as eating raw marine products,drinking raw water,no washing hands before meal and after toilet,and so on3.Age.In the endemicity of cholera，children are liable to infect and onset because of low or no immunit
44、y.Adolescents are more liable to infect in the cholera emerging district,because they are all sensitive,and have broad action range and more opportunities to contact V.cholera.4.Population fluxion.Fluid population are liable to affect cholera.main pathogenic mechanismAnswer：the main pathogenic mecha
45、nisms are：1.Onset of cholera is determined by the following two aspects:a.Level of gastric acid b.Amount and virulence of V.cholera.2.When the secretion of gastric acid decreases or the amounts of V.cholera increase，V.cholera will pass though the barrier of gastric acid and into the small intestine.
46、3.With the help of flagellar movement and protease，V.cholera pass though the slime layer of intestinal mucosa and adhere to the brush border of epithelial cell.4.V.cholera generate greatly in the alkalinity environment in the small intestine and produce cholera enterotoxin(also named choleragen）。5.C
47、holera enterotoxin acts on the intestinal mucosa and glandular epithelium,provokes intestinal juice secreted excessively,and water diarrhea is seen.typical clinical course Answer：The typical clinical course is：1.Diarrhea and vomit period：Vomit following diarrhea；profuse and frequent stool，appearing“
48、rice water stool”,yellow water stool,blood water stool，no feces foul smell；abdominal pain and fever scarely.2.Dehydration and prostration period：Skin kraurosis；Hoarse sound and thirsty；Sunken eyes；Scaphoid abdomen；Muscle convulsion；Serious patients show blood pressure decrease,breathlessness and con
49、sciousness.3.Recovery and response period：Scare patients have responsive low-grade fever.character of pathogeny，clinic，treatment Answer：Caracters of pathogeny,clinic,and treatment of O139 cholera are：1.Caracters of pathogeny are：having capsule and specific bacterial antigen，no difference with O1 ser
50、ogroup on the aspects of morphology,cultivate character,biochemisty and so on；no agglutination with routine diagnostic serum but specific O139 antiserum.2.Clinic characters：serious symptom；abdominal pain commonly；with the complications of extra-intestinal infections such as bacteremia.3.Main points
