Fungi detection vaccines

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Fungi detection vaccines
2014-11-19 22:42:01

The junk
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  1. Key fungal cell differences
    • they are eukaryotic but
    • plasma membrane has ergosterol instead of cholesterol
    • cell wall of glucans and chitin
    • virulence factors like exoenzymes and toxins
    • larger than bacteria
    • reproduce by budding or
    • spores grow germ tube, becoming hypha that lace into mycelium (mat)
  2. Fungal Thermotolerance
    • to survive in warm host out of woods
    • more virulent
    • some with thermal dimorphism convert from mycelia form to yeast/sphere
    • increased thermotolerance means go from cutaneous to systemic
    • cell wall, capsule
  3. Fungal Enzymes
    • lots of different proteases, lipases, phospholipases so that they can eat any surface in nature
    • can damage barriers and host cells
    • collagenase, elastase, DNase, protease are better at surviving in the body
  4. Fungal cell wall and capsule
    • made of sugars, which is harder for us to attack than the LPS of bacteria
    • resist phagocytosis
    • adhesion to epithelia and
  5. Mycoses
    chronic, less contagious, delayed/distant responses, tropic, cell mediated immunity
  6. Ringworm
    • underarm ringwrom can manifest distally
    • may appear weeks after infection
    • hard to culture (lab must be notified) but can gram stain and fluoresce (wood’s lamp)
    • usually diagnosed by history and exam
    • biomarkers for polysaccharides (galactomannan)
    • sometimes diagnosed by not responding to antibioitics
  7. Polyenes
    • amphotericin B
    • membrane disruption
    • binds to ergosterol and punches hole in membrane
    • no known resistance
  8. Azoles
    • ketoconazole, fluconazole, itraconazole
    • ergosterol synthesis disruption
    • inhibit cytochrome P-450 3-A4
    • lanosterol 14 alpha demethylase is dependent on CYP3A4
    • cannot convert lanosterol to ergosterol
    • toxicity for drugs that use CYP3A4 (and other CYPs)
  9. Allylamines
    • no examples given
    • ergosterol synthesis disruption
    • earlier in ergosterol synthesis
    • less commonly used
  10. 5-fluorocytosine
    • Flucytosine
    • inhibits DNA replication
    • take up by cytosine permease (not taken up well in our cells)
    • converted to 5-fluorouracil (5-FU)
    • downregulates thymidylate synthetase so there is not enough thymine for DNA replication
    • inserted into RNA to miscode protein
    • chemotherapy agent
  11. Echinocandins
    • capsofungin, micafungin
    • inhibit glucan synthesis
    • lack of glucan weakens cell wall to not tolerate osmotic or mechanical stress
  12. Griseofulvin
    • no examples given
    • dirupts microtubules (spindle formation)
    • concentrates in keratin rich cells by complexing keratin
  13. Superficial mycosis
    • pityriasis (tinea) versicolor, alters pigmentation, involves stratum corneum
    • woods lamp or skin scraping
    • topical therapy or systemic with an azole
  14. Cutaneous mycosis
    • love keratin rich
    • usually itch
    • Trichophyton spp, skin, hair, nails
    • Microsporum spp, skin, hair
    • Epidermophyton floccosum, skin, nails
    • ring worm
    • like warm, moist, glandular, hair shafts (armpits…)
    • distal vesicles aka dermatophytids (hypersensitivity)
    • Dermatophytoses aka the tineae
    • tinea capitis (head), tinea corporis (body), tinea cruris (inguinal), tinea pedis (foot), tinea unguium (nails)
    • if untreated or immunodeficient can cause progressive tissue injury
    • diagnoses by history, exam, woods lamp, 10% hydrogen peroxide
    • treat by cleaning and drying and topical azoles
    • systemic azoles or griseofulvin if necassary
  15. Subcutaneous mycosis
    • in soil and plants, can be from penetrating injury
    • rose thorn disease
    • sporotrichosis is canonical of these
    • self limiting unless immunosupressed
    • spreads along cutaneous lymphatics
    • diagnosed by serologic/delayed type hypersensitivity testing or histopathology
    • if not self limited, treated by itraconazole or amphotericin B
  16. Systemic mycosis
    • always dimorphic fungi from birds “nitrogen enriching” soil
    • spores initiate pathology
    • pulmonary focus, breath in while disturbing brush/soil
    • diagnosed by serologic/delayed type hypersensitivity testing or histopathology
    • Coccidioidomycosis
    • Histoplasmosis
    • Blastomycosis
    • Paracoccidioidomycosis
  17. Coccidioidomycosis
    • Coccidioides immitis
    • dimorphic, bird poop
    • SW US and latin america
    • pulmonary focus but disseminates in immunocompromised
    • acute inflammatory response
    • self limiting but if not azoles, amphotericin B
    • virulence factor is proteinases
    • biopsy with stain
  18. Histoplasmosis
    • HIstoplasma capsulatum
    • dimorphic, immitis
    • midwest US
    • pulmonary fous by inhalation of spores (conidia) convert to yeast
    • reside in alveolar macrophages to reticuloendothelial system
    • TB like lesions, walled off parts of lung
    • dissemination in immunosuppressed
    • treat with itraconzole, amphotericin B
    • virulence factor alpha 1,3 glucan (cell wall to avoid macrophage killing)
  19. Blastomycosis
    • Blastomyces dermatitidis
    • dimorphic, bird poop
    • beaver dams in US, asia, africa, S Am
    • pulmonary lesion without walled off (pneumonia)
    • can disseminate to skin, CNS, gonads, bone
    • virulence factor beta-glucan, alpha 1,3 glucan, WI-1 (cell wall)
    • treat with azoles, amphotericin B
  20. Paracoccidioidomycosis
    • Paracoccidioides brasiliensis
    • dimorphic, bird poop
    • south america
    • male predominance (estrogens protect) unless has estrogen binding protein (more virulent)
    • long dormancy with reactivation
    • pulmonary and chronic cutaneous ulcers
    • virulence is alpha 1,3 glucan (cell wall)
    • treat with azoles, amphotericin B
  21. Opportunistic mycosis
    • Candidasis (Candida is most common)
    • Cryptococcosis
    • Aspergillosis
    • Mucormycosis
    • Penumocystosis
  22. Candidiasis
    • Candida albicans, Candida tropicalis, Candida parapsilosis
    • opportunistic
    • pseudohyphae
    • enjoy mucosal surfaces like mouth, vagina etc
    • thrush
    • systemic dissemination in immunocompromised tropic to CNS, retina, kidneys
    • old test is germ tube test
    • many virulence factors
    • treat local or systemic with azoles, amphotericin B
  23. Cryptoccosis
    • Cryptococcus neoformans
    • opportunistic
    • bird poop soil, inhaled
    • can cause meningitis
    • virulence is surface capsule (not phagocytosable), melanin synthesis genes, myristoyl-CoA transferase
    • diangose by india ink, latex agglutination, brain biopsy
    • difficult to treat, amphotericin B and 5-fluorocytosine
  24. Aspergillosis
    • Aspergillus spp.
    • opportunistic
    • inhalation, asthma like hypersensitivity
    • virulence by protease and aflatoxin common contaminate of grains, carcinogen, hepatic failure
    • diagnosed by skin test
    • treat with steroids, surgery, azoles, amphotericin B
  25. Mucormycosis
    • Absidia, Rhizomucor, Mucor spp.
    • opportunistic
    • classic in diabetes because likes high sugar high acid
    • rhino to cerebral or pulmonary
    • difficult to diagnose and culture
    • virulence is endoprotease Arp
    • treat with surgery and amphotericin B
  26. Pneumocystosis
    • Pneumocystis jiroveci
    • opportunistic
    • likes air water interface so lungs
    • classic is pneumonia patient (therefore immunocompromised)
    • diagnosed by bronchoscopy
    • treat with trimethoprim-sulfamethoxazole or pentamideine isethionate
  27. Direct specimen stain
    • very fast around 30 minutes
    • gram stain, blood smear for malaria, acid fast for mycobacteria, antigen detection
  28. Microbial culture
    • grow the specimen, can take days or weeks
    • bacteria 1-3 days
    • blood culture 1-2 then gram stain then subculture a few days (phenotypic ID and susceptibility) and 5 day minimum
    • fungi take 4 weeks
    • virus culture 2 weeks
    • mycobacteria 6-8 weeks
    • cannot culture HCV or herpes simplex from spinal fluid
  29. Antibody detection
    • aka serological assay
    • for things that can’t grow like viruses
    • hours for turn around
  30. Nucleic acid testing
    becoming standard of care
  31. Commensal relationship
    exist together, no reward or damage
  32. Saprobe relationship
    agent benefits from host without harming
  33. Parasite relationship
    • agent causes damage
    • also a general term
  34. Keys to sample
    • know flora of that body region
    • for lower respiratory sputum <10 epithelial cells per low power field and ≥25 leukocytes is good
    • time of collection in the course of infection determines where to get sample
    • adequate volume/size
    • don’t swab
    • very careful with blood stream collection, less than 3% skin contaminants (expensive false positives/bad for pt) get lots of blood
  35. Assay turnaround time
    • usually batch testing
    • delayed by lots of samples coming in and what times you can do it
    • suggested move to random access aka on demand
  36. New technologies
    • immunological methods detect antigens cheap fast easy but low sensitivity
    • DNA on culture is easy cheap fast but requires culture
    • DNA with amplification (PCR, LAMP, HDA TMA) sensitive, specific, costly
    • Matrix assisted laser desorption ionization time of flight mass spectometry still need culture
    • Film array uses blood culture ID panel with PCR
    • rapid detection is not useful for bacteria or respiratory viruses, but it really improves patient care
  37. Live attenuated
    • repeated pass through subculture
    • loss of function in our environment
    • possible severe reactions
    • fragile (careful storage/handling)
  38. Innactivated vaccine
    • whole killed or fractional subunit
    • cannot replicate
    • less effective, requiring multiple doses
    • diminishing response
  39. Smallpox vaccine
    • highest rates of adverse events of any current vaccine
    • usually for military
    • only makes sense when small pox was really bad
    • eradicated 1979
    • live attenuated
  40. Measles vaccine
    • 2011 still 158k deaths per year worldwide (generally low income countries)
    • long immunity after two doses (5% dont respond to first dose)
    • MMR (false autism link) live attenuated
    • recent increase in measles in US
  41. Varicella Vaccine
    • two doses for efficacy
    • live attenuated
    • chicken pox can be fatal and lead to shingles (50% effective vaccine for this)
    • few adverse effects
  42. Polio vaccine
    • Polio destroys nuerons in anterior horn with .1% of infections leading to frank paralysis
    • 1955 inactivated polio vaccine by Salk through monkeys and formaldehyde, 3 doses (injection) and 3 serotypes
    • 1963 oral polio through monkey, shed in stool, 3 doses, 3 serotypes, lifelong coverage
    • live attenuated
    • last case in US 1979, India 2011 still in afghanistan, pakistan, nigeria
  43. Bacillus Calmette-Guérin (BCG)
    • TB vaccine through cows (improved)
    • single intradermal injection (repeat unhelpful)
    • not super effective
    • live attenuated
  44. Pertussis vaccine
    • fractional inactivated acellular bacteria
    • mainly seen in adults, who can give to chlidren
    • less effective long term than whole cell but less local reactions
  45. Tetanus vaccine
    • fantastic efficacy, booster every 10 years
    • toxoid fractional inactivated
    • cases only in unvaccinated or oldies who wear off vaccine
  46. Influenza A
    • gene changer leading to different mix and match strains H#N#
    • guess what strain every year
    • inactivated subunit (tri/quadravalent) intramuscular/intradermal
    • live attenuated vaccine (nasal)
    • decent in young people, less good the older you get
    • rare adverse reactions, mainly local (few fever, malaise) for inactivated
    • live attenuated vaccine has URI symptoms in adults and asthma increase in children
    • Guillain-Barré syndrome 10x as likely from flu than vaccine
    • risk for pregnant women
  47. HPV vaccine
    • fractional inactivated subunit
    • quadrivalent for 6, 11, 16, 18
    • bivalent 16,18
  48. Polysaccharide vaccines
    • pure polysaccharide are not consistently immunogenic in children <2 yrs
    • no booster response
    • polysaccharide conjugate vaccines are covalently bound to diptheria toxoid (immunogenic but non toxic)
    • more robust immune response, booster response
    • difference shown by pneumococcal vaccine PPV23 v PCV13
    • Haemophilus influenzae type b (Hib) is also polysaccharide conjugate
    • pure has more local reactions and conjugate has more fever/myalgia reactions because it is stronger
  49. Other fractional vaccines
    • hepatitis B
    • typhoid
  50. No vaccines
    • HIV
    • hepatitis C
    • lyme disease
    • herpes simplex
    • staphylococcus aureus