Invazivne gljivične infekcije kod hematooških
bolesnika
Prof dr Ana Vidović
Hotel Inn, 20. jun 2018.
O čemu će biti reči
Incidenca IGI kod hematoonkoloških
bolesnika
Najčešći uzročnici IGI kod hematoloških
bolesnika
Nivoi dijagnostike IGI
Nivoi terapije IGI
Vodiči/strategija lečenja hematoonkoloških
bolesnika sa IGI u 2017.godini (NCCN i ECIL 6)
Raspoloživost antmikotika u Srbiji, šta kaže
praksa, šta RFZO?
Incidenca IGI kod hematoonkoloških bolesnika
Princip lečenja bolesnika sa hematološkim
malignitetima (AML, ALL, agresivni NHL)
Dijagnoza
• Intenzivna hemioterapija
• Jatrogena aplazija koštane srži (ANC ≤ 0,5x109/l
Infekcije
• Febrilna neutropenija
• Primena širokospektralnih antibiotika (deeskalaciona terapija)
FN> 72-96h
• Antigljivična terapija:
• Empirijska (vođena febrilnošću); Preemtivna (serologija+ i /ili CT+); Kauzalna terapija (dokazana IGI)
Visoka incidenca IGI kod hematoloških bolesnika
Pagano L et al. Haematologica 2006; 91: 1068-1075
Malignitet Incidenca IFI Incidence Molds Incidence Yeasts
AML 12 % 7.9 % 4.4 %
ALL 6.5 % 4.3 % 2.2 %
CML 2.5 % 2.3 % 0.2 %
CLL 0.5 % 0.4 % 0.1 %
NHL 1.6 % 0.9 % 0.7 %
HD 0.7 % 0.35 % 0.35 %
MM 0.5 % 0.3 % 0.2 %
≤1%
Faktori visokog rizika za razvoj invazivnih gljivičnihinfekcija
Primena visokodozne hemioterapije (AML, ALL, MDS)Imunosupresivna terapija
nakon alogene transplantacije k.srži i posebno razvoja GVHDprimena Anti-TNF-α agenasa (npr. infliximab)
Prethodna primena širokospektralnih antibiotika (posebno neadekvatna)Dugotrajna primena kortikosteroida (30mg/dnevo; 1mg/kg tt)Boravak u jedinicama intenzivne nege duže od 7 dana Neutropenija duže od 7 dana, sa nadirom broje neutrofila ≤100/µlPlasiran Centralni venski kateter- CVK (duže od 14 dana)Bubrežna insuficijencija, hemodijalizaKandidurija (više od 104cfu/ml) ili kolonizacija gljivama > 1 mestaNarušen integritet kože i sluznica (posebno GIT-a).Poremećaj fagocitne funkcije granulocitaPacijenti sa uznapredovalom HIV infekcijom.....
Segal B, Walsh T. Am Resp Crit Care Med 2006; 173: 707-17,
Current Approaches to Diagnosis and Treatment of Invasive Aspergillosis.
Mortalitet kod gljivičnih infekcija
Aspergillus: 32-87%
Candida: 10- 49%
Fusarium: 70- 87%
Zygomycete: 44- 91%
Najčešći uzročnici IGI kod hematoloških
bolesnika
KVASNICE PLESNI
CANDIDA ASPERGILLUS
Porast incidencije!!!
357% (1980-2008)
Invazivne plesni
33 vrste patogene za ljude
A. fumigatus > A. flavus > A. terreus >A. niger
A. terreus i A. nidulans (rezistentni na AmB)
IPA
Aspergillus
180 vrsta
IGI/ Aspergiloza
• A. flavus i A. fumigatus najvažniji patogeni roda Asp.
Dijagnoza IA
Klinička slika
+.......
• CT pluća visoke rezolucije
• Sendvič-ELISA galaktomanan test
(senz i spec > 90%)
• Endoskoposke metode + biopsije
• Direktna mikroskopija (sputum, BAL, uzorak tkiva)
• kulture
• Glukan test
• PCR
Akutna invazivna aspergiloza (IA): oblici
• AKUTNA INVAZIVNA PLUĆNA ASPERGILOZA
- progresivna pneumonija
- simptomi poput drugih pneumonija
- nereagovanje na antibiotik
• AKUTNI INVAZIVNI SINUSITIS
-lokalno širenje u orbite i lobanjsku šupljinu
• DISEMINOVANA ASPERGILOZA
- sek. hematogeno širenje - bilo koji organ (bubreg, jetra, mozak, srce)
-SIRS
- visoka smrtnost
CT pregled u Dg IA
• uraditi ga 48-72h
• preseci na 1 cm a kroz leziju na 1 mm
• Karakteristični nalaz:
– halo (pojas niske atenuacije) oko područja konsolidacije
– vazdusni polumesec unutar konsolidacije
– Kavitacija unutar nodulusa
– nazubljena ivica konsolidacije
– kavitacija ili nodulus uz krvni sud
– Konsolidacija trouglasta sa bazom ka periferiji
Invazivna Aspergiloza pluća
CT
D0: halo D4: promer ↑, halo ↓ D7: vazdušni srp
Caillot D. Et al. J Clin Oncol. 2001.
Tranzitorni halo: <5d; rast infiltrata tokom 7 d → stabilizacija → vazdušni srp
nespecifično Prekasno!!!specifično
Ređi oblici IA (NEJM)
Dijagnoza sistemske kandidoze
• teška
• Dokazati prisustvo u tkivu ili kulturi (npr. krv)
• Serologija: mala poz. prediktivna vrednost
• Obećavaju:
lateks aglut. test na manan (deo glj. zida)
određivanje DNK kandide
Klinički oblici sistemske kandidoze kod
hematoloških bolesnika
• kandidemija
• akutna diseminovana kandidoza
• hronična diseminovana kandidoza
• endokarditis
• kandidoza CNS-a
(mesto ulaska: GIT ili i.v. kateteri)
C.albicans > 50%
Non albicans sojevi:
• C.glabrata
(R) na AmB i triazole
• C.tropicalis
težak klinički tok
• C.krusei
(R) na Flukonazol
• C.lusitaniae i
C.guillermondii
(R) na AmB
Canida četvrti uzročnik sepse u ICU
(kateteri)
Dani
Pro
ca
na
t
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25
C. albicans
C. glabrata
C. tropicalis
C. krusei
C. parapsilosis
others
Viscoli et al. Clin Infect Dis 1999
Preživljavanje u zavisnosti od
soja kandide
Invazivna kandidoza
• teška infekcija
• ugrožava život bolesnika
• zahvata više organa (hematogeno širenje).
• kandidemija + klinički simptomi i znaci teške infekcije
(sepse).
• Prognoza – kao u septičnom šoku.
Diseminovana kandidoza
Akutna
• brzoprogresivni tok
• formiranje abscesa u organima
• smrtni ishod bez brzog lečenja
Hronična
• Sporoprogresivna
• kod bolesnika koji su se oporavili od neutropenije
• tipično hepatosplenična (hepatosplenomegalija, bol u abdomenu, patološki jetreni testovi)
Diseminovana kandidijaza
PATOGENEZA: embolizacija malih k.s., stvaranje
mikroapscesa
Hepatosplenična kandidijaza, N Engl J Med, 2007
Diseminovana kandidijaza
(crvene papule bez eshare i nekroze)
Mays et al. Am J Clin Dermatology, 2006
Patogeneza Zygomycose
Kod zdravih osoba-makrofagi ubijaju intracelularne spore oksidativnim mehanizmom; Neutrofilni granulociti-oštećuju hife gljiva ekstracelularnih mehanizmom.
Neutropenija nakon hemioterapije ili oštećena funkcija neutrofila kod d.mellitusa ili steroidne terapije pogoduju razvoju Zygomycose
Serumsko gvožđe stimuliše rast gljiva (uloga helatora gvožđa u terapiji Zygomycose)
Angioinvazija- glavni faktor u brzoj progresiji infekcije Zygomycetama→nekroza tkiva,uz tromboziranje krvnih sudova
Dijagnostika
high level of laboratory skill for their identification.“Klinički znaci nedovoljno karakteristični, dif. Dg Invazivna aspergilosa
Dijagnoza često tek na autopsiji
Nepostojanje specifičnih seroloških testova (za sada nema spec. biomarkera bolesti)
CT→karakteristične multiple nodularne promene, >10; uz pleuralnuefuziju
Neophodna je biopsija zahvaćenog tkiva, uz pravilnu interpretacijuhistopatološkog nalaza. “The causative fungi are members of the order Mucorales and individual species within this group require a high level of laboratory skill for their identification.“
Lass-Flore, Clin Infect Dis;2007;45:101-4.
Klinički oblici Zygomycosa
Rhinocerebralna→Kod bolesnika sa D. Mellitusom tip 2
Pulmonalna→Najčešće kod imunokompromitovanih bolesnika (akutne leukemije, nakon intenzivne hemioterapije; GVHD nakon BMT; prethodna terapija Voriconasolom; malnutricija)
Diseminovana→kao komplikacije prethodna dva klinička oblika
Radiografska i CT dijagnostika IZ
Cryptococcus
Kriptokokoza
skok incidencije sa pojavom AIDS-a
pad incidencije sa upotrebom HAART
DANASIncidencija 5 obolelih/milion
31
Nivoi dijagnostike IGI
Moguća infekcija “possible”- specifičan CT nalaz - Da, ali Galactomannan/ Mannan test- negativan
Verovatna infekcija “probable”- jasna radiografskapotvrda infekcije +2 ili više pozitivnih uzorka na Galactomannan/ Mannan test
Dokazana- “documented” infekcija - pozitivanhistopatološki pregled tkiva na Aspergilus ili pozitivnakultura dobijena invazivnom procedurom (otvorena biopsija pluća, traheobronhijalna ili perkutana iglena biopsija)- retko izvodljivo kod hematoloških bolesnika zbog trombocitopenije ili lošeg opšteg stanja bolesnika
U rutinskoj٭ dijagnostici IGI preporučene dijagnostičke procedure: visoko rezolutivni CT toraksa, Galactomannan test (ELISA)
Dijagnostikovanje IGI
33
Metode laboratorijske dijagnoze IGI
MIKOLOŠKE
(KONVENCIONALNE
METODE)
1. MIKROSKOPSKI
PREGLED BOLESNICKOG
MATERIJALA
direkni mikroskopski preparat
(DMP)
patohistologija (PH)
2. IZOLACIJA GLJIVA IZ
BOLESNICKOG MATERIJALA
mikološka kultura (MK)-"zlatni
standard"
IMUNOLOŠKE
DOKAZIVANJE ANTITELA
(At)
DOKAZIVANJE
ANTIGENA (Ag)
DOKAZIVANJE
BIOMARKERA
MOLEKULARNE
DOKAZIVANJE DNK
(PCR)
DOKAZANA VEROVATNA GI
34
Nivoi terapije IGI
Kontinium antigljivične strategije
Ciljanaprofilaksa
Empirijska
terapija
Pre-emptivna terapija
Direktna-ciljana
terapija
Maschmeyer G. et al. Eur J Clin Microbiol Infect Dis 2013;32:679-689.
Kada primeniti profilaksu IGI?
• Kada je incidenca za IGI visoka
• Kada je mogući ishod bolesti loš
• Kada je teško dijagnostiikovati ili isključiti IGI
• Kada troškovi lečenja IGI prevazilaze cenu primenjene profilkse/ empirijske terapije
• Kada su dostupni jeftini, dobro tolerabilni i efiksani agensi za profilksu /empirijsku terapiju
• Kada je nizak rizik od indukcije resistencije
Profilaksa nije obavezna kod svih bolesnika sa neutropenijom
ECIL-6 guidelines, Haematologica 2017;102(3):433-444.
Visoko rizični bolesnici, febrilni ali bez dokaza za IGI
Febrilnošću dirigovana- Empirijska terapija:definicija
– Primenjuje se kod prolongirane, izraženeneutropenije (ANC<500)
– Kod persistirajuće febrilnosti (4-7 dana) nepoznatogporekla, refraktarne na lečenje širokospektralnimantibioticima
– Ipak, invasivna gljivična infekcija ne može biti pravilo
Cardonnier C et al. Clin Infect Dis 2009;48:1042-51.
Dijagnostikom-dirigovana terapija Pre-emtivne terapija
Započinje kada je invazivna gljivična infekcija vrlo izvesna
•Klinički dokaziIli halo znak
ili• mikološki dokazi
Ili Aspergillus galactomannan pozitivan
Visok-rizični bolesnici + klinički ilimikrobiološki dokaz za IFI
Pre-emptive Antifungal Therapy (ECIL3)
• Pre-emptivna antigljivična strategija je “izvodljiva”– Klinički znaci + GM/CT-scan bazirana strategija: ukupno
preživljavanje kao sa empirijskom terapijom- samo u centrima sa brzom dg IGI
– Smanjenje obima antigljivične terapije u odnosu na empirijsku (↓ toksičnost, interakcije, rezistencija, troškovi?)
– Rizik od povećanja incidence IFI (Aspergillus, Candida)u odnosu na empirijsku terapiju, posebno kod bolesnika sa neutropenijom > 15 dana: uticaj na prognozu IFI?
– Mogućnost rane terapije IFI u odsustvu febrilnosti, pre-emptivnim pristupom (propušteno kod empirijske terapije koja je dirigovana febrilnošću)
– Nema gradiranja pouzdanosti/preporuka za pre-emptivnu terapiju usled nepostojanja definisanih standardnih kriterijuma i usled varijabilnosti rezultata u različitim studijama
UPDATE ECIL-3 2009
9,0%
*2.7%
0%
5%
10%
15%
20%
Empirical, n=150 Pre-emptive, n=143
% o
f p
ati
en
ts
97,0% 95,0%
0%
20%
40%
60%
80%
100%
Empirical, n=150 Pre-emptive, n=143
% o
f p
ati
en
ts
Empirijska v. Preemptivna antigljivičnaterapija
(n =293)
*p<0.02p=ns
Ukupno preživljavanje Dokazana i verovatna IGI
Cordonnier et al. CID 2009; 48: 1042-1051
SVI PACIJENTIPrimena
antimikotika tokom
perioda postojanja
rizika infekcije
SPECIFIČNA
TERAPIJA
FEBRILNI
PACIJENTI
Posle 48h
primene
antibiotika
POZITIVNI
DG.
TESTOVIDOKAZANO
NIJE
PRISUTNANIJE
ISKLJUČENASUSPEKTNA PRISUTNA
GM esej ili CT;
bez simptoma
IFI/EORTC/MSG
PROFILAKSA EMPIRIJSKA TERAPIJA PREEMPTIVNA Th
Terapijske strategije u IGI
IZGLEDI DA OBOLJENJE POSTOJI
42
Vodiči/strategija lečenja
hematoonkoloških bolesnika sa IGI u
2017.godini (NCCN i ECIL 6) i
raspoloživi antimikotici
1950~ 1970~80 1997~ 2002~ 2004
Early AzolesClotrimazoleMiconazole
Ketoconazole
AmbisomeAbelcet
Amphocil
2nd Tri-azole: VfendEchinocandins: Cancidas
PolyenesNystatin
Amphotericin B
1st Tri-azolesFluconazoleitraconazole
Micafungin
Posaconazole
1990~
Antigljivični lekovi
-(1,3)-D-glukan
Analozi nukleozida
Ergosterol
Polieni
Azoli
Fosfolipidni dvosloj
Ćelijske membrane
Ćelijski zid
-(1,6)-glukan
Sintaza -(1,3)-D-glukana
Inhibitor sinteze glukana
(ehinokandini)
jedro
Mehanizmi delovanja antimikotika
45
NCCN Guidelines Version 1.2017
Prevention and Treatment of Cancer-Related Infections
NCCN Guidelines IndexTable of Contents
Discussion
KEY: ALL = acute lymphoblastic leukemia, AML = acute myeloid leukemia, MDS = myelodysplastic syndromes, GVHD = graft-versus-host disease, HCT = hematopoietic cell transplant, HSV = herpes simplex virus
OVERALL INFECTION
RISK IN PATIENTS WITH
CANCERa
DISEASE/THERAPY EXAMPLES ANTIFUNGAL PROPHYLAXISf,l DURATION
ALL Consider:
• Fluconazolem or Micafunginn
• Amphotericin B productso (category 2B)
Until
resolution
of
neutropenia
INTERMEDIATE
TO
HIGH MDS (neutropenic)
AML (neutropenic)
Consider:
• Posaconazolem (category 1)
• Voriconazolem, Fluconazolem, Micafunginn, or
Amphotericin B productso (all category 2B)
Autologous HCT with mucositisj Consider:
• Fluconazolem or Micafunginn (both category 1)
Autologous HCT without mucositis Consider no prophylaxis (category 2B) N/A
Allogeneic HCT (neutropenic)
See Antipneumocystis Prophylaxis (INF-6)
Consider:
• Fluconazolem or Micafunginn (both category 1)
• Voriconazolem, Posaconazolem, or Amphotericin B
productso (all category 2B)
Continue
during
neutropeniap
Significant GVHDk
See Antipneumocystis Prophylaxis (INF-6)
Consider:
• Posaconazolem (category 1)
• Voriconazolem, Echinocandin, Amphotericin B productso
(all category 2B)
Until
resolution
of
significant
GVHD
NCCN Guidelines Version 1.2017
Prevention and Treatment of Cancer-Related Infections
NCCN Guidelines IndexTable of Contents
Discussion
ANTIFUNGAL AGENTS: AZOLES
AZOLESa DOSE SPECTRUM COMMENTS/CAUTIONS
Fluconazole In adults with normal
renal function: 400
mg IV/PO daily
• Active against Candida
• Active against coccidioidomycosis
and C. neoformans
• Candida glabrata is associated with variable resistance
in vitro and Candida krusei is always resistant
• Inactive against molds (eg, Aspergillus
sp., Zygomycetes)
Isavuconazonium
sulfateLoading dose 372 mg IV/
PO every 8 h x 6 doses
then maintenance dose
372 mg IV/PO daily
• Active against invasive
aspergillosis and mucormycosis
in patients with cancer and in
HCT recipients1,2,3
• Can be considered in patients intolerant or refractory
to first-line anti-mold therapy
• Potential drug interactions are important to consider
Itraconazoleb 400 mg PO daily;
Loading dose 200 mg PO
TID x 3 days, then
maintenance dose 200 mg
PO BID
• Active against Candida, Aspergillus
sp., and some of the rarer molds
• Active against dimorphic fungi and
C. neoformans
• Itraconazole has negative inotropic properties and
is contraindicated in patients with significant
cardiac systolic dysfunction
• Use with caution in the capsule formul ation with
H2 blockers and PPIs
NCCN Guidelines Version 1.2017
Prevention and Treatment of Cancer-Related Infections
NCCN Guidelines IndexTable of Contents
Discussion
ANTIFUNGAL AGENTS: AZOLES (continued)
AZOLESa DOSE SPECTRUM COMMENTS/CAUTIONS
Posaconazoleb • Prophylaxis:
Loading dose 300 mg PO
tablet BID on day 1 and
then maintenance dose
300 mg PO daily
Loading dose 300 mg IV
every 12 h on day 1 and
then maintenance dose
300 mg IV daily
• Effective as prophylaxis in
neutropenic patients with
myelodysplastic syndrome and
acute myeloid leukemia7, and
in HCT recipients with
significant GVHD8
• Active against
Candida, Aspergillus
sp., some
Zygomycetes sp., and
some of the rarer
molds
• Active against dimorphic
fungi and C. neoformans
• Evaluated as treatment of refractory infection (but
not FDA-approved) in several invasive fungal
diseases
• Data on posaconazole as primary therapy for invasive
fungal infections are limited
• Liquid formulation should be administered with a
full meal or liquid nutritional supplement or an
acidic carbonated beverage. Tablet is better
absorbed, though it should be taken with food.
• Alternative antifungal therapy should be
considered for patients who cannot eat a full meal
or tolerate an oral nutritional supplement
• Proton pump inhibitors decrease
posaconazole plasma concentration with oral
solution
• Potential drug interactions are important to considerVoriconazoleb • Loading dose 200 mg PO BID
for patients >40 kg or 100 mg
PO BID for patients <40 kg IV 6
mg/kg every 12 h x 2 doses,
then maintenance dose 4 mg/
kg IV every 12 h (for invasive
aspergillosis);4
• Loading dose 6 mg/kg IV every
12 h x 2 doses, then
maintenance dose 3–4 mg/kg
IV every 12 h 200 mg PO BID
for patients >40 kg or 100 mg
PO BID for patients <40 kg for
non-neutropenic patients with
candidemia5
• Active against Candida, Aspergillus
sp., and some of the rarer molds
• Active against dimorphic fungi and
C. neoformans
• Standard of care as primary therapy
for invasive aspergillosis (category
1)4,6
• Effective in candidemia in non-
neutropenic patients5
• Poor activity against Zygomycetes
• Long-term complications resulting from metabolic
irregularities may include increased risk for squamous
cell carcinoma and hyperphosphatemia
• Fluorosis may occur with prolonged use and
is associated with bone/muscle pain
• Evidence for combination therapy remains limited9
• IV formulation should be used with caution in patients
with significant renal dysfunction
• Potential drug interactions are important to consider
NCCN Guidelines Version 1.2017
Prevention and Treatment of Cancer-Related Infections
NCCN Guidelines IndexTable of Contents
Discussion
ANTIFUNGAL AGENTS: EMPIRIC AMPHOTERICIN B FORMULATIONSc
AMPHOTERICIN B
FORMULATIONSdDOSE SPECTRUM COMMENTS/CAUTIONSf
Amphotericin B
deoxycholate
(AmB-D)
Varies by indication,
generally 0.5–1.5
mg/kg IV daily
Broad spectrum of
antifungal activity
including Candida
Aspergillus sp.,
(excluding Aspergillus
terreus) Zygomycetes,
rarer molds,
C. neoformans,
and dimorphic
fungi
• Substantial infusional and renal toxicity
including electrolyte wasting
• Saline loading may reduce nephrotoxicity
• Infusional toxicity may be managed with anti-pyretics,
an anti-histamine, and meperidine (for rigors)
Amphotericin B lipid
complex (ABLC)
5 mg/kg/IV daily for
invasive mold
infections
Reduced infusional and renal toxicity
compared to AmB-D
Liposomal amphotericin
B (L-AMB)
3–5 mg/kg IV daily10,e Reduced infusional and renal toxicity
compared to AmB-D
NCCN Guidelines Version 1.2017
Prevention and Treatment of Cancer-Related Infections
NCCN Guidelines IndexTable of Contents
Discussion
ANTIFUNGAL AGENTS: ECHINOCANDINS
ECHINOCANDINS9,g DOSE SPECTRUM COMMENTS/CAUTIONS
Anidulafungin 200 mg IV x 1 dose,
then 100 mg/IV daily
Active against Candida
and Aspergillus sp.
Not reliable or effective
against other fungal
pathogens.
• Empiric therapy for candidemia and invasive
candidiasis (category 1), pending susceptibility
data
• Efficacy established compared to fluconazole
as primary therapy for candidemia and
invasive candidiasis15
• Excellent safety profileCaspofungin • 70 mg IV x 1 dose, then 50 mg IV
daily; (35 mg IV daily for patients
with moderate liver disease)
• Some investigators use 70 mg IV
daily as therapy for aspergillosis
in second-line therapy
• Primary therapy for candidemia and
invasive candidiasis (category 1)11
• Treatment for invasive, refractory aspergillosis.
Similar efficacy compared to AmB-D as primary
therapy for candidemia and invasive
candidiasis but significantly less toxic11
• 45% success rate as therapy for invasive,
refractory aspergillosis12
• Similar efficacy, but less toxic compared with L-AMB
as empiric therapy for persistent neutropenic fever11
• Excellent safety profile
Micafungin • 100 mg IV daily for
candidemia and 50–100
mg/d IV as prophylaxis
• 150 mg IV daily used at
some centers for
Aspergillus sp. infection in
second-line therapy
• Primary therapy for candidemia and
invasive candidiasis (category 1)
• Similar efficacy compared to caspofungin13
and compared to L-AMB14 as primary therapy
for candidemia and invasive candidiasis
• Excellent safety profile
Evolution over time of the grading system used for treatment of invasive Candida and
Aspergillus infections
ECIL-6 recommendations for initial first-line treatment of candidemia
ECIL-6 recommendations for first-line treatment of candidemia after species identification
ECIL-6 recommendations for first-line treatment of invasive aspergillosis
ECIL-6 recommendations for salvage therapy of invasive aspergillosis
ECIL-6 recommendations for first-line therapy of mucormycosis
Imajući u vidu sve napred rečeno, šta je ipak najvažnije....?
HVALA VAM NA PAŽNJI !
Hematolog, mikolog, infektolog, epidemiolog, intenzivista, klinički farmakolog, radiolog,
pulmolog, hirurg.......
Hvala na pažnji
Top Related