fungi characteristics
more “human-like” (EUK) so tx is v. toxic (amphoteracin B)
heterotrophs, absorb nutrients, parasitic
obligate aerobes, EXCEPT YEAST: facult. anaerobe
cell wall: polysacchs(glucan, chitin) and glycoproteins
cell mem: ergosterol, other sterols (site of drug axn)
some encapsulated: cryptococcus neoformans
fungi disting. based on
morphology of spores and hyphal elements
bac: stain, cell/colony morph., biochem rxns
2 basic fungi growth forms
molds/mycelial (saprobic) growth:
spores germ.–>hyphae (branching or unbranched filaments) +/- septa, (hyphal mass: mycelial)
sexual and asexual spores
yeast OR spherules w. endospores
yeast
round-oval elongated single cell
reprod. by budding, form moist or mucoid colonies (resem. G+ cocci)
pseudohyphae (yeast)
buds remain attached to mom (candida), elongate, lack parallel sides and pinching septa
true hyphae
parallel sides, true horiz. septa, can prod. terminal, thick walled chlamydoconidia
candida albicans (not other spp.) produces a
germ tube in human serum @ 37 degrees C
ddx for c. albicans
yeast cells can convert
into hyphe/pseudohyphae and back again, dimorphic, but not thermally dimorphic
thermally dimorphic fungi
yeast OR spherules/endospores (parasitic) in host/in vitro @ 37 C
mold (saprobic) in environ. @ 21-24 C
therm. dimorph fungi orgs
histoplasma capsulatum
blastomyces dermatitidis
coccidioides immitis, c. posadasii
sporothrix schenckii
molds can produce spores called..
conidia: “naked” spores, unenclosed
macroconidia: large, CANNOT cause RT disease
microconidia: small, can get into alveoli, can cause RT inf. (21-24 C: environ./in vitro)
microconidia-prod. spp.
histoplasma capsulatum
blastomyces dermatitidis
aspergillus spp.
murcormycoses
arthroconidia (arthrospores)
(mold-produced)
thick-walled, fragments of hyphal cells
can cause RT inf.
coccidioides immitis and c. posadasii in environ/in vitro @ 21-24 C
sporangiospores
spores w. in sac-like structures (sporangia)
sporangia prod. spp
coccidiodes immitis and c. posadasii: spherules**
PCP (pneumocystis jiroveci)-cysts w. endospores (8)
c. immitis and c. posadasii produce sporangiospores…
spherules (sporangia) bearing endospores (sporangiospores)
- *spherules is pathognomonic for coccidioidomycoses**
- rupture–>rel. endospores, can dev. into spherule
- neither is infectious*
yeast produce spores called
blastospores: buds
systemic mycoses (mycoses=fungal infections)
most serious, break down int. orgs, viscera (enter via RT, skin break)
orgs:
blastomyces dermatitidis
coccidioides immitis and c. posadasii
histoplasma capsulatum
cryptococcus neoformans var. grubii (CNS)
opportunistic mycoses
human NF or environ. orgs, cause lesions on mucus mem. or in skin, RT, CNS
(@ risk: br-sp abx tx, IC)
orgs:
aspergillus
cryptococcus neoformans var. grubii
candida spp.most important
zygomycetes class: absidia, mucor, rhizomucor, rhizopus (mucormycosis)
fungal pneumo CANNOT be dx by
routine sputum Cx
s/s (no unique)
*does NOT respond to antibiotics
-pay attn to hx, PE, epidemiology
host immune system determines fungal pathogen infections, esp.
T cell deficiencies phagocytic cells (PMNs, macros)
T cell opportunistic fungi
histoplasma capsulatum blastomyces dermatitidis coccidioides immitis and posadasii cryptococcus neoformans candida albicans and other spa. pneumocystis jiroveci
what is required to control fungal inf. and/or disease
CMI: non-immune ppl can be infected, also those w. imp. T cell function: HIV+, glucocorticosteroid/immsupp tx (SOT)
phagocytic cell opportunists
aspergillus
zygomycetes class (mucormycosis)
@ risk:
prol. neutropenia (depressed PMNs
normal functioning phago cells
macros destry conidia
PMS destroy hyphae
causes of iron overload
kidney dialysis
unreg. DM: DKA inhib. iron bind to transferrin: elev. Fe in serum
hemochromatosis
the systemic mycoses (histoplasma apsulatum, blastomyces dermatitidis, coccidioides immitis and posadasii)
primarily pulm. pathogens
most common syst. fungal inf. in immunocompetent and immunocompromised hosts in NA
eukaryotic, thermally dimorphic
H. capsulatum and B. dermatitis produce this in soil (25 C) that are infectious to humans
microconidia (spores)–>yeast in humans: parasitic form (37 C)
C. immitis and C. posadasii produce this in soil (25 C) that are infectious to humans
arthrospores (resistant, barrel-shaped)–>spherule and endospores: parasitic form (37C)
systemic mycoses: transmitted person to person?
NO, via inhalation of aerosolized microconidia/arthrospores (not via resp. droplets)
(target is LRT)
histoplasma capsulatum (histoplasmosis, Darling’s disease, spelunker’s)
Ohio-Miss. river valley, guano
blastomyces dermatitidis (blastomycosis, Chicago disease)
soil near lakes, rivers of Missouri, Arkansas, St. Lawrence, overlaps w. histo but larger
coccidoides immitis and c. posadasii (coccidioidomycosis, desert rheumatism, valley fever, san joaquin valley fever)
American SW, Latin America
C. immitis: San Joaquin Valley
syst. mycoses patho
sev. immsuppr pts @ risk
* asymptomatic more common
- micro/arthr are phago by non-act. macros
* only histo grows IC
- ->all may dissem. via blood–>extrapulm. inf.
syst. mycoses patho: host response to inf
sp. CD4+ T cells required for control of inf., need activated macros (transplant, HIV pts @ risk)
effective CMI forms tubercle-like lesion where repo. happens–>calcify
incubation period: 1-3 wks
syst. mycoses s/s (sev. options)
- flu-like/bronchitis: fever, malaise, dry, non prod. cough
- flu-like w. anything from atypical pneumo–>chronic granulomatous disease in lungs (indist. from pulmonary tb) and cavitary lesions (+/- night sweats, anorexia/W.L., dry non prod. cough or prod. +/- hemoptysis, CP (p/np), SOB, dyspnea
-
progressive dissem./systemic disease: EITHER
- gen. systemic inf/dis
- extrapulm. inf. of sp. orgs. or tissues +/- pulm. involvement (each organ has sp. targets)
progressive disseminated targets of histoplasmosis
liver, spleen, adrenals
progressive disseminated targets of blastomycosis
skin, soft tissue, bone (osteolytic), GU tract
progressive disseminated targets of coccidioidomycosis
skin, soft tissue (rashes), bones (osteolytic, skel. pain), joint/synovium, CNS (meningitis)
systemic mycosal infections CXR
heal by fibrosis–>necrotic “coin-like” lesions (like TB/neoplasm) *esp. histoplasmosis
systemic mycosis s/s in sev. immsuppr. pts
fever, w.l., night sweats, pulm. sympts (cough, dyspnea), anemia in many pts, loc. or gen. lymphadenopathy, hepatosplenomegaly, skin/colon ulcers
syst. mycoses dx: stain/Cx
KOH-sample stain shows parasitic form (yeast or spherule)
Cx: variable growth, alert lab (esp. C. immitis, C. posadasii- dangerous!)
DNA probs/exoantigen tests
syst. mycoses dx: serology?
Yes, for b, h, c
syst. mycoses dx: DTH skin testing
histoplasmin (mycelial Ag) : epi studies of histoplasmosis
spheruline: dx/px of coccidioidomycosis
syst. mycoses CXR:
variable; coin-like lesions/nodular masses diffuse bilateral alveolar infiltrates consolidation combos of above
syst. mycoses tx
Amphotericin B lipid formulation- may be prolonged
histoplasma capsulatum epi
wood w/ bird poop
histo cap patho
asymptomatic, may observed calcified tubercle-like lesions on XR: liver, spleen, adrenals, lungs
histo cap: progressive disseminated disease (Darling’s)
in adults: like military TB; lesions in liver, spleen, adrenals–>may result in Addison’s
in infant: persist. fever, hepatosplenomegaly, death in 6 wks if unto
charac. by massive parasitism of macros
histo cap dx:
like TB (infiltr/consol. on XR) rounded-oval yeast forms in macros
histo cap dx: serology
-complement fixation (mycelial Ag and whole yeast cell Ags (histolyn)
-immunodiffusion test:
H Ag+: active histo, primary dis.
M Ag+: acute or chronic dis.
-RIA (polysac. Ag in urine/serum), ELISA (Ab to histo Ag 69-70kDa in serum)
histo cap tx
Amphotericin B, oral itraconazole after
blastomyces dermatitidis epi
also dis. in dogs
blasto derm patho
chronic necr. pneumo + coin-like lesions extrapulm manifests: *skin lesions-like SCC* bone lesions GU- less common, prostate, epidid.
blasto derm dx:
- BROAD-BASED, budding yeast form w/ v. THICK WALLS*
- ELISA (screen), immunodiffustion (confirm)
blasto derm tx:
Amphotericin B, oral itraconazol after
coccidioides immitis and posadasii virulence factor
estrogen-binding proteins (progesterone, testosterone, 17B-estradiol)
inc. steroid hormone levels–>stim. growth and maturation of spherules
c. immi and posa epi
SW US (immitis), Latin America
rains-germinate in soil-mycelia grow-form arthroconidia-dust stirred up-epidemics
*dissem: males, preggos (3rd trimester), immsuppr, minorities?
SUMMER!
c. immi and posa patho
60% asymptomatic, (DTH test + to spherulin)
40% inf.: symptomatic 2 wks (10-16d)
c. immin and posa s/s
see earlier for gen. manifest.
cutaneous: macpap rash (esp. kiddos), erythema nodosum/multiform (white women, good px)
-traids
most self-limiting, not all, dissemination is rare (0.5%) but insidious and fulminant
desert rheumatism: 2 triads
c. immi and posa
fever, erythema nodosom, arthralgias
conjunctivitis, erythema nodosum, arthralgias
c. immi and posa pathognomonic dx
spherules: 5-40 um and/or endospores in tissue
c. immi and posa serology dx
IgM: + 1st mo, neg by 2 mos (prim. inf)
IgG titers: +2-3 wks-8mos, dx and px (high-disseminated, drop w/ succ. tx)
c. immi/posa most likely if
+ spherulin rxn (w.in 3 wks, good px)
s/s consistent
resident/travel to endemic area (SW, LA)
(w. disseminated, may be DTH -: high relapse rates, converts to + w/ succ. tx)
c. immi/posa tx
amphotericin B, then oral itraconazol
aspergillosis and mucormycosis/zygomycetes epi
both: ubiquitous distribution (geography), POE is RT (inhalation of microconidia)
(inhale sev. 100 A. fumigatus conidia/day)
asperg. patho
allergic bronchopulm. aspergillosis (ABPA): in bronchial asthmatic pt
aspergilloma (“fungus ball”) lung parenchymal displacing mass
invasive aspergillosis (IA)
asperg and mucor dx (both)
clin. features depend on organ, XR, Cx/microscopic evidence
asperg dx
resence of aspergillus galactomannan (GM) in BAL specimen or serum
halo sign by lung CT scan
asperg and mucor tx
voriconazole (broad-spec triazole) followed by amphotericin B
asperg and mucor ppx
posaconazole (not fluconazole, itraconazole)
aspergillosis: dimorphic fungus?
no
aspergillosis spp.
a. fumigatus (most common), a. flavus, a. niger
asperg cell morph
non-pigmented, harry septate hyphae (“soldiers marching in a row”), acute angle branching (45-90 degrees)
asperg epi
ubiquitous geo, POE RT, inhale lots a. fumigatus conidia/day
asperg risk factors
(gen ones) +
lung structural abnormalities
over-exuberant IR (hypersens, atopy?) in allergic asperg.
severely immcompromised
asperg: syndromes involving mycelia growth in body, req. tx
ABPA: allergic bronchopulmonary aspergillosis
aspergilloma
IA: invasive aspergillosis
ABPA
most sev. allergic pulm comp caused by aspergillus spp.
in some pts w. atopic asthma (1-2%) or CF (7-35%)
immunopathology hurts host more than fungal growth
ABPA clin manifests
worsening bronch. asthma (brown mucus plugs in prod. cough + wheezing), transient pulm. infilt.–> fatal lung destruction
ABPA: Loeffler’s syndrome
fever, cough, *urticaria, wheezing, inter. infilt. on CXR, sputum + eosinophilia (>500/mm3) + Charcot-Leyden crystals (deg. eosinophil granules), peripheral eosino. w. CBC
ABPA: 5 major definitive dx
asthma hx
immediate (15mm+/-5mm) skin reactivity to A. fumigatus Ag extract
elevated serum levels IgM, IgG, IgE against A. fumigates
elevated total IgE serum levels (>1 ug/mL)
central (proximal) bronchiectasis
aspergilloma
“fungus ball” of fungal hyphae
- displaces lung parenchyma
- in 10-15% of cavities from lung dis (TB, sarcoid)
- chronically obstr. paranasal sinuses
aspergilloma patho
- spheroid mass of hyphae in proteinaceous matrix w. sporulating structures @ periphery
- balls external to cavity lining (i.e. airway)
- as hyphae grow, rel. enzymes–>destroy human tissue and break down macromol (protein, aas)–>disrupt BVs in cavity wall/bronchial supply–>1 or both: massive internal bleeding +/- hemoptysis (bleed in airway) (either can be fatal)
aspergilloma symps
hemoptysis, bronchiectases in late disease
aspergilloma dx
CATscan: spherical mass surrounded by radioluscent crescent
bronchioscope: fungal ball
invasive aspergillosis (IA)
acute or chronic pulmonary IA* most
- other: tracheobronchitis, obstructive dis. (AIDS), acute/chronic invasive rhinosinusitis
- dissem. sites: brain, skin, eyes
IA risk factors
*leading COD among*: blood Ca: lymphoma, leukemia pts sev. neutrophenic pts tx w. cytotoxin for blood dis BM transplant, SOT kiddos w. chronic granulomatous disease AIDS pts
IA patho
growth of fungus in lung tissue–>hemorrh. infection–>dissem via blood–>fungal hyphae grow in tissue (not ball in cavity)
(histo reveals 1/few short segments of larger hyphal elements)
IA presentation in neutropenic pt
persistant fever, fails to respond to br. spec abx
+/- cough, min sputum prod.
hemoptysis is uncommon
aspergillosis dx: imaging
(depends on organ location)
+ CT scan: large nodules w. “halo sign” (hazy, nonobstruc. ground glass attenuation)
–>invasion of vascu.–>hemorrhage (1st 10d), early sign
-air crescent sign–>later (IA), invasion-necrosis, host mounts an inflammatory resp
aspergillosis dx: Cx
narrow, septate hyphae w. acute angle (45-90) branching, in tissue
aspergillosis dx: serum
aspergillus galactomannan (GM) in BAL spec./serum, (not for SOTs) -detectable 5-8 days before s/s, correlates to fungal tissue burden, serial assays 2x/week + CT/Cx -also: LAtest for GM, ELISA (using MAb sp. for 1-5-B-D-galactofuranose) side chains of GM
aspergillosis tx
voriconazol (b-spec triazole) then amphotericin B
- *survival rates POOR** (>80% mortality w. CMI suppression)
ppx: posaconazole
mucormycosis/zygomycosis: dimorphic?
NO
mucormycosis/zygomycosis orgs
absidia, mucor, rhizomucor, rhizopus
mucor cell morph
variable width (6-25 um), broad, ribbon-like
thin walled
infreq. septat or aseptate hyphae
irregular branching (includes wide angle 90)
mucor patho
typ: progressive and fatal w.in 2-3 wks
risks: abn. +/- LOW #s PMNs
infection from inhale. of spores into bronchioles and alveoli leading to prim. infarc/necrosis w. cavitation–>blood dissem to other orgs (brain)
mucor manifests
persistant fever, rap. prog. pneumo w. hemoptysis, pleuritic CP
mucor dx
need to make early!
ID ribbon-like, aseptate hyphae in tissue and Cx
microscopy is most rapid dx
“prominent infacrcts, angioinvasion and perineural invasion*: both aspergillus and mucormycoses
Dx typically made on autopsy
mucor tx
voriconazole then amphotericin B
no ppx
5-fluorocytosine (5-Fc)
nucleoside analog
interferes w. DNA and RNA syn/func
griseofulvin
mitosis inhibitor
inhibition of fungal cell mitosis at metaphase by interaction w. polymerized microtubules
echinocaandins, pneumocandins, caspofungin
inhib. cell wall syn. by inhib. syn. of 1,3-B-D-glucan in fungal cell walls
amphotericin B-lipid formulations
polyene antibiotics
interaction w. ergosterol, formation of aqueous channels, inc. mem. perm to univalent cations and –>cell death
ketoconazole
imidazole/azole
causes ergosterol depletion and accum. of aberrant and toxic sterols in cell mem
flucanozole
imidazole/azole
causes ergosterol depletion and accum. of aberrant and toxic sterols in cell mem
itraconazole
imidazole/azole
causes ergosterol depletion and accum. of aberrant and toxic sterols in cell mem
voriconazole
imidazole/azole
causes ergosterol depletion and accum. of aberrant and toxic sterols in cell mem
amorolfine
morpholine
inhib. sterol reductase and isomerase
terbinafine
allylamines/thiocarbamates
causes ergosterol depletion and accum. of aberrant and toxic sterols in the mem