Kaarten: mechanisms of disease 1: theme 3 | Quizlet

virulence factor

any component, product or characteristics that contributes to the ability of a micro-organism to cause disease

virulence factors: structural components -> getting in

· Survival of adverse environment

· Attachment to human structure

· Entry into human body

· Entry into a human cell

· Induce inflammatory response

virulence factors: products -> doing harm

· Toxins

· Enzymes ('-ases')

virulence factors: tricks

-> doing harm (turn off/ hide from defender)

· Kill a cell

· Decreasing normal immune response

· Evading normal immune response

· Latency

gram positive bacteria: lipoteichoic acid

binds to toll like receptors on phagocytes -> they produce cytokines -> mediate inflammation

capsule

interference with complement-mediated phagocytosis

pathogens with capsule

· Streptococcus pneumoniae

· Neisseria meningitis

· Haemophilus influenza B

streptococcus pyogenes

· Primary pathogen

- Transient carrier (throat)

- Cause of disease

· Diagnostics

- Gram positive cocci

- Catalase test

- Beta hemolytic

Local or disseminated infections

· Tonsilitis, otitis media

· Impetigo, erysipelas

· Childbed fever, sepsis, necrotizing fasciitis

Exotoxin-mediated syndromes

· Scarlet fever (NL: roodvonk)

· Streptococcal toxic shock syndrome

Immunological effects

· Acute rheumatic fever

· Acute glomerula-nephritis

Adhesion

Streptolysin

Class of pore-forming exotoxins

Streptokinase (s. pyogenes)

dissolves blood clots (lysis)

Hyaluronidase (s. pyogenes)

spread of infection

C5a peptidase (s. pyogenes)

Inactivates C5a preventing attraction of phagocytes

The M protein of Streptococcus pyogenes:

resists phagocytosis

toxins/ superantigens

· 10% of S. pyogenes

> Erythrogenic toxin -> scarlet fever

> Super antigenic toxin -> toxic shock syndrome

influenza A virus

· Primary pathogen

> Mild disease

> Severe disease

· Increased risk of death in patients with:

> Comorbidity (cardiac, pulmonary, renal)

> Very young or very old age

> Impaired immunity

Hemagglutinin

One of the enzymes found on the surface of the Influenza virus. It is responsible for binding the virus to the cell that is being infected.

Neuraminidase

One of the enzymes found on the surface of the Influenza virus. It promotes the release of progeny viruses from infected cells.

virulence mechanisms (influenza A)

· RNA polymerase: no proofreading

· Mutations are frequent

antigenic drift

Minor change in influenza virus antigens due to gene mutation

antigenic shift

major change in influenza virus antigen due to gene reassortment

human immunodeficiency virus (HIV)

Acquired immunodeficiency syndrome (AIDS) is caused by HIV, which damages the cells in the body's immune system so that the body is unable to fight infection or certain cancers.

reverse transcriptase

An enzyme encoded by some certain viruses (retroviruses) that uses RNA as a template for DNA synthesis.

Integrase

the enzyme responsible for integrating viral DNA into the host cell's DNA

HIV protease

An enzyme that converts immature, noninfectious HIV to its infectious state within the cell

diagnostic test for s. pyogenes

gram stain, blood agar plates

diagnostic test for influenza virus

polymerase chain reaction (PCR), direct immunofluorescence (antigen test)

HIV diagnostic test

PCR, combotest with antigen and antibody detection

Sterile areas of the body

- the inside

- stomach

- deep respiratory tract

- urinary tract

Non-sterile areas of the body

- skin

- ENT

- alimentary tract

commensals

- normally presen t in every person, no symptoms

- harmless unless impaired immune system

opportunistic microorganisms

Would normally not cause disease but do so when immune systems are weakened, suppressed, or deficient.

colonization resistance

presence of bacteria on skin and mucosae -> protects against adherence by other microorganisms

Achieving sterility

· Physical -> barriers: skin and mucosae & airways: ciliar activity, mucus, coughing & urinary tract: voiding, antimicrobial factors

· Chemical -> gastric acid & enzymes (lysozyme in tears)

· Immunological -> keeps the 'inside' sterile

infection

· Structural or functional change caused by:

- Micro-organism or its components or its products

causes of fever

infection, allergy, auto-immune, trauma, thrombosis, infarction, malignancy, overheating, intoxications

Exposure vs Infection

Exposure to micro-organism leads to

Colonization on skin or mucosae

· No symptoms

· Commensal or primary pathogens

· Transiently or permanently

· Competition for food and adhesion sites

Infection

· Often, but not always, symptoms and/ or sings

endogenous source

- Commensals: skin (staphylococcus epidermidis), throat (streptococci, neisseria, candida albicans), bowel (escherichia coli, bacteroides fragilis, clostridium)

- Colonization -> staphylococcus aureus, sterptococcus pyogenes/ pneumonia

- Neisseria meningitidis, haemophilus influenza

exogenous source

- Other person

- Zoonosis

- Vector

- Environment

causes impaired barrier function (literally)

- (surgical, traumatic or burn) wounds

- Insect bites

- Penetration of skin by catheters

- Skin/ mucosal toxicity by cytostatic drugs

microorganims on skin or in mucosal membranes

· Staphylococcus aureus -> skin (col. nose)

· Streptococcus pyogenes -> skin (co. throat)

· Staphylococcus epidermidis -> skin

· Escherichia coli -> bowel

· Bacteroides fragilis -> bowel

· Clostridium sp. -> bowel

· Streptococcal sp. -> throat/ vagina

· Candida albicans -> throat/ vagina

S. epidermidis

the most common cause of foreign body infections due to its ability to produce biofilms (polysaccharide)

catheter / chemo can give blood stream infections

causes of impaired barrier function (functionally)

- Urinary catheter, incomplete emptying of bladder -> Escherichia coli

- Lack of gastric acid -> salmonella spp, Vibrio cholera

- Lack of tears (M. Sjörgen: see auto-immune diseases) -> haemophilus influenzae

- Disturbance of normal airway cleaning -> intubation, abnormal mucus, less ciliary function, less coughing, COPD -> streptococcus pneumoniae

Impaired colonization resistance

Candida stomatitis or esophagitis

commensal or colonizing bacteria, yeasts

pseudomembranous enterocolitis

inflammatory condition of both small and large bowels that results in severe watery diarrhea; also commonly called C. diff. colitis

· Pseudo membrane consists of:

- Mucus

- Numerous granulocytes

causes complement deficiency

· Mainly genetic

- Classical pathway

- Alternative pathway

- MB lectin pathway

- Terminal pathway (MAC)

· Iatrogenic

- Eculizumab (anti-C5 antibodies)

· Not always clinically manifest (redundancy of immune system)

· C2, C3, C4 -> extracellular m.o.

· B, D or MBL

· Component of MAC -> Neisseria meningitidis, invasive Neisseria gonorrhoea -> primary pathogens

Conclusion: 'extracellular' bacteria & Neisseria

Neisseria meningitidis

Lipo-polysaccharide (LPS) -> inflammation +++ -> shock * disseminated intravascular coagulation (DIS)

Hypogammaglobulinemia (causes)

· Congenital

- X-linked a-gammaglobulinemia

- As part of SCID (then also cellular defect)

· Acquired

- Common variable immunodeficiency (~immunoglobulin deficiency)

- B cell malignancies -> chronic lymphatic leukemia, myeloma (M. Kahler)

- Iatrogenic: rituximab (anti-CD20)

hypogammaglobulinemia (organisms)

· Capsulated bacteria like

- Streptococcus pneumoniae

- Neisseria meningitidis

- Haemophilus influenzae

· Campylobacter

· Persistent giardia lamblia

· Persistent enterovirus infections

Conclusion: encapsulated bacteria, campylobacter, giardia and enterovirus

splees disorder (causes)

· Asplenia

- Congenital

- Surgical removal

· Functional asplenia

- Chronic hemolysis syndromes

- Infarction

- Other

spleen disorder (organims)

· Often not symptomatic

· Severe sepsis caused by capsulated bacteria like

- Streptococcus pneumoniae

- Neisseria meningitidis

- Haemophiles influenza

· Severe plasmodium infections (malaria)

Conclusion: sepsis caused by encapsulated bacteria, severe malaria

phagocyte disorder (causes)

· Granulocytopenia

Ø Cytostatic drugs

Ø Immune medicated

- Drug allergy

- Auto-immune mediated

· Granulocyte dysfunction

Ø Chronic granulomatous disease

Ø (chronic glucocorticosteroids)

phagocyte disorder (organims)

same as those associated with defect in barrier function and:

- a-hemolytic streptococci

- asppergillus fumigatus

Granulocytopenia

Necrotizing gingivitis

Aspergillus pneumonia

Conclusion: extracellular bacteria, fungi/ yeasts

Impaired cellular immunity (causes)

· Congenital

Ø SCID

Ø Other (rare) diseases

· Acquired

Ø HIV infection -> less CD4 T cells

Ø Chemotherapy -> less all cell counts

Ø Use of immunosuppressive drugs: T cell function and or counts less

impaired cellular immunity (orgaisms)

Intracellular bacteria

- Salmonella species

- Legionella pneumophila

- Mycobacterium tuberculosis

(herpes) viruses

- CMV, EBV, HSV, VZV

Parasites

- Toxoplasma gondii

- Strongyloides stercoralis (hyperinfection)

Pneumocystis jirovecci -> common as first manifestation of HIV infection whem CD4 < 200

Conclusion: intracellular bacteria/ viruses/ fungi, toxoplasma, strongyloides

suppurative/ (purulent) acute inflammation

bacteria gram +/-

mononuclear/ granulomatous inflammation

mycobacteria, spirochetes, parasites, virus

Cytopathic-Cytoproliferative inflammation

HSV, adenovirus, herpes virus, HPV

chronic inflammation and scarring

hepatitis B

tissue necrosis

clostridium, hepatitis B

no reaction

immune deficient host

empyema

pus in the pleural cavity

Listeria monocytogenes

small gram-positive, non-spore-forming rod is a facultative intracellular parasite that grows in the cold and is associated with unpasteurized milk products

Vibrio cholerae

· Exposure -> drinking water or eating food that is contaminated

· Colonization

· Toxin mediated disease

· Transmission -> passed trough feces

· Prevention -> hygiene

adenylate cyclase

converts ATP to cAMP

Taenia species

Taenia saginata

Taenia solium

Varicella Zoster Virus

chicken pox and shingles

primal infection and reactivation

-> Also a primo-infection or reactivation if you have no T cells (+ CNS, eye, liver)

legionella

· Legionella pneumophila

· Geographical distribution

· Exposure -> inhalation of contaminated aerosols produces in conjunction with water sprays or mists or contaminated water sources

· Pathogenesis:

- Intracellular survival

- T cell immunity!

· Transmission -> cannot go from person to person

· Prevention -> keep the water at a temperature that prevents growth and check regularly

Pontiac fever

Mild flu-like syndrome caused by legionella pneumophilla

treponema pallidum

Syphilis

· Geographical distribution

· Exposure -> sexual contact with an infected individual

· Pathogenesis

· Transmission -> sexual contact with an infected individual

· Prevention -> protected sex

schistosoma

- Schistosoma species

- Geographical distribution

- Exposure -> water in the tropics

- Pathogenesis

- Transmission -> trough snails

- Prevention -> don't swim in water in the tropics

Borrelia burgdorferi

causative agent of lyme disease

stage I: erythema migrans

Stage II: meningitis, arthritis, carditis

Stage III: neuro(psycho)logical, skin (ACA)

microorgansims that can cause pneumonia

- influenza virus

- RSV

- s. pneumonia

- mycoplasma

- m. tuberculosis

- legionella

- aspergillus

- worms

Entamoeba histolytica

causes amoebic dysentery

liver abscess + inflammatory changes caecum

fever without tenderness liver

metronidazol or tinidazol

echinococcosis granulosis

* complaints because of cyst expansion

Typical findings on imaging reflecting cyst structure

Complicated cysts require surgical treatment

Combination therapy in case of (expected) spill

Gram stain

A method for the differential staining of bacteria that involves fixing the bacterial cells to a slide and staining with crystal violet and iodine, then washing with alcohol, and counterstaining with safranin. Results in gram-positive bacteria retaining the purple dye and gram-negative organisms having it decolorized so that the red counterstain shows up.

staining mycobacteria (tuberculosis)

- ziehl neelsen stain

- Auramine stain

Giemsa stain

Chlamydia, Borrelia, Rickettsia, Trypanosomes, Plasmodium

Rapid antigen test

an immunologic test in which antigens are detected in a patient specimen by visualizing an Ag-Ab complex

- lower sensitivity

- highest load are most significant

bacterial culture

* time dependent

* specimen quality is important

- further analysis required

- some bacteria and many viruses cannot be cultured

MALDI-TOF mass spectrometry

matrix assisted laser desorption ionization time of flight mass spectrometry

PCR (polymerase chain reaction)

technique that allows molecular biologists to make many copies of a particular gene

- nucleic acid amplification

Serology

The study of reactions between antibodies and antigens

IgM -> recent infection

IgG -> past infection

ELISA test

enzyme-linked immunosorbent assay

complement fixation

activation of the classical complement pathway can result in the specific rupturing of cells and some viruses

haemophilus influenzae

gram negative rods

- encapsulated

- if causes recurrent pneumonia: B cell deficiency ?

good syndrome

Immune deficiency associated with thymoma

· Hypogammaglobulinemia

· Low or absent B-cells

· CD4-penia

· Immune deficiency can become manifest after thymectomy

treatmet hypogammablobulinemia

azithromycin / amoxicillin

Case 1

18 jaar, man, bloody diarrhea, india trip, cysten gezien

1 protozoa: entamoeba histolitica (dyspar geeft geen klachten)

2 cytotoxine, overleving cysten buiten mens, resistentie tegen maagzuur, vermogen om aan darmslijmvlies te hechten

3 geen, iedereen kan het krijgen

4 infasief -> valt darmcellen aan -> bloed gaat eruit ; komt via poortader in lever terecht

5 serologie 's onderzoek, directe diagnostiek op ontlasting

6 metronidazole + paramonisine (tegen de cysten)

Kan het krijgen door fecaal verontreinigd eten/ water

Case 2

A 44-y-old woman is treated with prednisone for systemic lupus erythematodes (auto-immune disease) since two years. In the past she has had a cold sore (fever blister) a few times but during the past two years she has more frequent attacks. During the past six months it occurred five times. It always starts with a tingling feeling, followed by painful vesicles on the left upper lip which makes eating difficult. It takes almost two weeks before the lesions heal. During the last episodes the lesions extended up to her nostril.

1 Which microorganism caused the disease?

Virus, herpes simplex type 1 (type 2 is de soa)

2 Which virulence mechanisms played a crucial role?

(Capsid), infectie slijmvliezen, virus blijft latent in ganglion cellen aanwezig

3 Which host defenses failed?

Cytotoxic T cells, NK cells (t cell immuniteit, chemo, langdurig op IC, HIV, stress/ zonlicht (gezonde mensen))

4 What mechanisms caused the clinical signs and symptoms of the disease?

No capsule -> virus mediated endocytose -> making copies -> exit by lysis

Via zenuwstelsel -> naar huid ->

Reactive van immuun system -> schade aan cellen

5 Which (additional) diagnostic test(s) are indicated, if any?

PCR/ serology

Kweek -> als het vaak terugkomt -> resistentie ?

6 Is antimicrobial therapy indicated and, if yes, what would be a rational choice?

Valaciclovir (alleen bij mensen met verminderde afweer), profilacs

HPS -> reactiveert, tintelingen , impetigo niet

Casus 3

Zwelling op rug

1 stapholococcus aureus

2 alfa toxines -> maken gaten in neutrofielen; peptidoglycaan in celwand -> enorme inflammatoire reactie; protein a als belemmering voor opzonisatie, coagulase -> vertraagt migratie van granulocyten

3 granulocyten/ macrofagen; geen falen nodig iedereen kan er ziek van worden

4 haarklier talgklier

Toxine -> roodheid,

Pus: witte bloedcellen, dood weefsel, bacterie

5 resistentie uitsluiten (als je uit het buitenland komt) met kweek , ook van bloed als er ook koorts is

6 Flucloxacillin (voor patiënten met kunstmateriaal, of als het zich bevindt in het gelaat)

casus 4 54 jaar, plekjes in de mond, recente antibiotica kuur

1 candida albicans (80% van de mensen heeft het)

2 geen virulent organisme want iedereen heeft het

Pseudohypea -> vasthechten aan mondslijmvlies -> mogelijk pijn

3 kolonisatie resistentie

4 pseudohypae -> zorgt voor invasie -> witte slag en soms ulcera met eventueel pijn

5 uitstrijkje van witte uitslag bij twijfel of als het niet opknapt met de therapie

6 Fluconazole (kleinste spectrum)

Casus 5

4 jaar oud, hoge koorts, wisselend bewustzijn, nekstijfheid, petechiae, gram negatieve diplococci

1 Neisseria meningitis

2 lipopolysacharidden (LPS) -> schade zenuwcellen + enorme inflammatie respons

Pili -> hechten aan nasopharynxepitheel

Kapsel -> phagocytose weerstaan

Kan zich binden aan ijzer

3 hoeft niet, maar als complement deficiëntie, geen milt, immunoglobuline verhoogde kans

4 LPS -> veel inflammatie

5 wel bevestigen zodat je gerichter kan behandelen, kweek liquor/ bloed, PCR

6 meteen: hoge dosering penicilline + steroiden om inflammatoire respons te drukken (als je het nog niet zeker weet)

Casus 6

57, turks, bovenbuikklachten, pijn bij palpatie lever, lab normaal, echo, 15 cm cyste

1 echinococcus granulosis -> cyste + gebrek aan andere symptomen

2 cyste vorming -> overleven in darm en daar hechten -> via vena porta naar lever

3 kan bij iedereen voorkomen

4 cyste -> rek op kapsel van lever (kan pijn in rechterschouder geven) + druk op galwegen

Als ie kapot gaat -> door lichaam verspreiden -> anifilaxie

5 bloedonderzoek -> serologie

Cyste opsturen naar lab (ontlasting onderzoek niet zinvol)

6 ja, heel groot dus gevaarlijk, kan openscheuren

Albendazol + operatie (PEAR techniek)

Casus 7

62, man, wond met tinteling + pijnlijke spierspasmen

1. Clostrini tetanus

2. Sporen vormt

Toxine werkt op neurotransmitter

3. Iedereen kan het krijgen, vaccinatie beschermt, ouderen kunnen niet gevaccineerd zijn

Vaccinatie of niet maakt verschil voor behandeling

4. Toxine -> verliest inhibitie -> spasmes door continue prikkel

Specifiek = kaakklem

5. Klinisch beeld, liquor (gevaarlijk)

6. Verpleegarm verplegen -> weinig prikkels

Soort immunoglobuline (als de persoon niet gevaccineerd is)

Belangrijk = preventie

Beta-lactam and glycopeptides

· Cell wall: inhibition of peptidoglycan synthesis (periplasmatic space)

· Competitive inhibition penicillin binding protein

· Ongoing autolysis bacterial wall

penicillin

kills susceptible bacteria by specifically inhibiting the transpeptidase that catalyzes the final step in cell wall biosynthesis, the cross-linking of peptidoglycan

Inhibitors of cell wall synthesis

Penicillins

· Penicillin G

· Flucloxacillin

· Amoxicillin

· Amoxicillin + clavulanic acid

Cephalosporins -> beta lactam antibiotics

· Cefuroxime

· Many others

Glycopeptides

· Vancomyin

inhibiton of DNA synthesis

· Quinolones (ciprofloxacin)

· Metronidazole

inhibitors of ribosomes

- aminoglycosides

- macrolides

- tetracyclins

- clindamycine

Bacteriostatic

inhibits growth of bacteria

(macrolides, tetracyclins)

- Often sufficient

- Even preferred if exotoxin is major virulence factor

Bactericidal

kills bacteria

(betalactam, aminoglycoside, chinolone)

- Infection blood stream: sepsis, endocarditis

- Sites outside reach of immune system: CNS

- Lack of immune cells: granulocytopenia