Transcript What is a host?

Comorbosità infettive nel
paziente oncoematologico
Giuseppe Gentile
Responsabile UO Prevenzione e Terapia delle Infezioni in
Oncologia ed Ematologia
Dip Biotecnologie Cellulari ed Ematologia
Università Sapienza, Roma
INFECTION -- DISEASE
Infectious diseases specialist, Microbiologist, Haematologist,.......
Carrier
Infection
Disease
DAMAGE OF DEFENSE
MECHANISMS
SKIN PENETRATIONS:
-PUNCTURES
-CENTRAL VENOUS LINES
-SURGERY
Ben De Pauw
-SKIN
-MUCOUS MEMBRANES
-CILIARY SYSTEM
BLADDER CATHETERS
CHEMOTHERAPY
RADIOTHERAPY
CORTICOSTEROIDS
UNDERLYING
MALIGNANCY
GRANULOCYTES
MONOCYTE /
MACROPHAGE
SYSTEM
COMMENSAL FLORA
CELLULAR IMMUNITY
ANTACIDS
ANTIBIOTICS
CATABOLISM
HUMORAL IMMUNITY
ORGAN FUNCTION
Beta-herpesvirus in HSCT and solid organ
transplant
• Beta herpesvirus (CMV, HHV-6, HHV-7)
-Direct effect
° Diseases: colitis, pneumonia, retinitis
°Classic syndromes (mononuclesosis, fever of
undetermined origin)
-Indirect effect
°Oncogenesis
°Contributes to net state of immunosuppression
°Allograft injury
Effetti immunosoppressivo e
immunomodulatorio di beta-herpesvirus in
HSCT e trapianto d’organo solido
• Citomegalovirus
- ↑ infezioni batteriche e fungine
- ↑GVHD
Randomised
- ↑ mortalità
studies, case• Human herpesvirus-6
control studies,
- ↑rischio infezioni da CMV meta-analyses
Gentile G. Herpes 2000 , Boeckh M. Herpes 2003
Gentile G, Antonelli G. Future Virology 2015
Immunosuppressive effects of
infections
Indirect Effects
Increased rate of graft rejection
Opportunistic infections
Malignancies
Effects mediated by innate or adaptive immune
mechanisms
Viral effects on cellular proliferations, functions of
immune cells, inflammatory networks
Freeman Am J Transplant 2009
....the host-virus interactions are modulated
by co-infections, emphasizing the relevance
of co-infections in determining the clinical
expression (from asymptomatic to
symptomatic infection) and the severity of
herpesvirus-associated diseases (either
neoplastic or infectious diseases)...
Gentile G. Clin Microbiol Infect 2016
Thakker S. Frontiers in Microbiology 2016
Reese TA. J Virol 2016
Lichtner M. J Infect Dis
6111 HIV patients from the ICONA study
CMV serology
CMV seropositivity was an indipendent risk factor for
cardiovascular and cerebrovascular diseases
Restimulating interest in Cytomegalovirus as a cofactor for HIV
infection
Emery VC. J Infect Dis 2015
Cytomegalovirus continues to
cause major complications
after hematopoietic cell
transplantation..........
Impact of long term acyclovir on cytomegalovirus
infection and survival after allogeneic bobe
marrow transplantation
Randomized, double blind, placebo controlled study
303 patients receiving allogegeneic stem cell transplant
High doses of acyclovir significantly improved survival and
reduced episodes of CMV viremia.
Mortality due to fungal and bacterial infections was lower in the
group receving acyclovir compared with patients receiving
placebo
Prentice HG, et al. Lancet 1994
Prentice HG, et al. Bone Marrow Transplantation 1997
Randomized, double blind, placebo controlled study
616 patients receiving kidney transplant
Valacyclovir significantly reduced
Episodes of
candidemia
the incidence of CMV
infection and disease
Epidodes
of
rejection
Episodes of
bacterial
infections
Lowance D, et al. N Engl J Med 1999
Meta-analysis: the efficacy of strategies to prevent organ disease
by cytomegalovirus in solid organ transplant recipients.
Randomized, controlled trials
17 trials involving 1980 patients.
Universal prophylaxis reduced CMV organ disease in subgroups of
patients at highest risk (donors with positive CMV serostatus and
recipients with negative CMV serostatus and induction with
antibodies).
Universal prophylaxis significantly reduced bacterial and fungal
infections (OR, 0.49 [CI, 0.36 to 0.67]) and death (OR, 0.62 [CI,
0.40 to 0.96]).
Both acyclovir and ganciclovir significantly prevented CMV organ
disease in the universal prophylaxis trials.
Kalil Ann Intern Med 2005
CMV serostatus still has an important prognostic impact in de novo
acute leukemia patients after allogeneic stem cell transplantation:
a report from the Acute Leukemia Working Party of EBMT
16628 de novo acute leukemia patients after allogeneic stem cell transplantation
CMV seropositivity of the donor and/or the recipient showed
a significantly↓ 2-year leukemia-free survival (44% vs 49%,P < .001)
↑overall survival (50% vs 56%, P < .001)
↑nonrelapse mortality (23% vs 20%, P < .001)
Donor and/or recipient CMV seropositivity is still associated with an adverse
prognosis in de novo acute leukemia patients after allo-SCT despite the
implementation of sophisticated strategies for prophylaxis, monitoring, and
(preemptive) treatment of CMV.
Schmidt-Hieber M, et al. Blood 2014
Iori AP. Bone Marrow Transplantation 2004
9469 patients
2003-2010
CMV reactivation was
associated with higher
non relapse mortality
for patients with AML,
ALL, CML MDS
Teira et al. Blood 2016
117 pazienti riceventi trapianto allogenico di cellule staminali
Probabilità di sopravvivenza in pazienti con riattivazione di CMV
rispetto a pazienti senza riattivazione
94.4% vs 77% p=0.011
Gentile G Unpublished data
421 cases of CMV pneumonia
1986-2011
Overall survival at 6 months: 30%
Outcome improved after the year 2000
Outcome of CMV pneumonia showed a
modest improvement over the past 25
years. However, the advance seem to be
due to antiviral treatment and changes
in transplant practices rather than
immunoglobulin based treatments. Novel
treatment strategies for CMV pneumonia
are needed
Erard V. et al. Clin Infect Dis 2015
Gentile G, Antonelli G. Future Virol 2015
Microbiome
Sum of colonizing organisms
(bacteria, fungi, protozoa, viruses)
Acute and chronic infections
Reflects alterations in the microbial flora by
the immune system
vaccination
antimicrobial agents
Fishman JA Cold Spring Harb Perspect Med 2013
Science 2016
What is a host? Incorporating the
microbiota into the damage-response
framework
Microbe-centric
Disease
Microbes that cause disease.
Pathogens
Commensalism
Commensal microbes adapted
to host niches
Colonization
Colonizing microbes identified
Microbe-on
centric
the basis on their
propensity to reside in host
( Staph aureus in nares)
Casadevall A. Infect Immun 2015
What is a host? Incorporating the
microbiota into the damage-response
framework
Host-centric
Disease
Host susceptibility allows microbes to
cause disease. Depends on host
immunity
Commensalism
Host defense sregulate and maintain
microbial flora
Colonization
Microbes related on host immunity
Transient colonization: microbe persists
until the immune system responds
Persistent colonization: host unable to
eradicate
Casadevall A. Infect Immun 2015
What is a host? Incorporating the
microbiota into the damage-response
framework
Damage-response framework
Disease
Commensalism
Colonization
There are microbes and hosts: disease is one
state resulting from the host-microbe
interaction where there is sufficient damage
to affect host homeostasis
State of the host-microbe interaction where
there is not damage to the host.
The amount of damage incurred by the host is not
sufficient to affect homeostasis.
Host damage can trigger an immune response that
eradicates the microbe
The interaction can progress to disease
Norman JM et al. Gastroenterology 2014
Maizels RM et al. Science 2014
Future challenges
Chemotherapy, immunity, and microbiota: a new
triumvirate (Nature Medicine 2014;20,126)
The microbiome, systemic immune function, and
allotransplatation
(Nellore A, Clin Microbiol Rev 2015)
Gut microbiota and hematopoietic stem cell
transplantation: where do we stand?
(Zama D. Bone Marrow Transplantation 2016)
Transkingdom control of viral infection and immunity in
the mammalian intestine
( Pfeiffer JK. Science 2016)