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INFECTIONS IN ORGAN

TRANSPLANT PATIENTS
essential learning
Dr.T.V.Rao MD
Transplantation an Emerging
Field in Medicine
Worldwide, 40,000 organ transplants are
performed annually, with very high success
rates (90% 1-year graft survival). In the
United States, 23,288 organ transplantations
were performed in 2008. Renal transplants
were the most common, followed by those of
the liver, heart, lung, and others, including
dual organ, pancreatic, and intestinal
transplantation
Current Challenges in
Organ Transplantation
Over the last several
decades, the field of
solid organ
transplantation (SOT)
science and practice
has advanced
significantly, only to be
continually challenged
by the risks for infection
in ORGAN recipients.
Basic Precepts of Transplant
Infections
Infections occur on a time scale
Type and frequency of infection vary with
transplant type: lung>liver>heart>kidney
More surgery more infection
More immunosuppression more infection
Beware of donor as a source of infection especially
early post-transplant
Transplantation does not protect from
infections normal people get
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Transplant Medicine is
Different
Transplant medicine is a discipline in which,
perhaps more than any other field, practitioners
must maintain a high index of suspicion for
various complications and presentations.
Clinicians must be astute and pay close attention
to details related to epidemiologic clues, historical
features, and physical signs. This helps in the
often-difficult differentiation between infection and
allograft rejection, which may present with similar
symptoms, such as fever, cough, and diarrhoea
Coordination between
Physician and Microbiologist a Need for
success
Although differentiating colonization from
infection is often difficult in the clinical context,
the clinician must exercise both prudence and
vigilance in the approach to the febrile SOT
recipient. The role of Competent Diagnostic Microbiology at
rescue to make a effective diagnosis Only then can a
timely and accurate diagnosis be made while
broad-spectrum empiric antimicrobial therapies
are prescribed.
Patients immunity is guided by the
Immunosuppressive Therapy
The intended therapeutic
effect of suppressing rejection
The deleterious acquired
immunodeficiency that the
host sustains, leading to
increased risk of infection or
neoplasia
The direct or indirect toxicity
to host tissues
Timeframes around transplant-
related infections
For almost 2 decades,
clinicians caring for
SOT recipients have
been able to guide
infection-prevention
and control
management strategies
based on the classic
timetable originally
proposed by Rubin et al.
The guidelines are
changing
Although newer
immunosuppressive
and antimicrobial
prophylactic regimens
have affected the
pattern and timing of
specific infections post
transplantation, certain
general observations
still hold true.
Changing understanding on
Infection possibilities
One of the most important consequences of an
episode of organ rejection or increased
immunosuppression (from regimen modifications) is
that the overall timeframe tends to get reset to an
initial period of vulnerability comparable to the
transplantation itself. Over the subsequent 6 months
post transplantation, periods provide a structural
approach to the infectious disease management
(see image in next page ).
Changing timeline of infection after organ
transplantation (modified from Fishman J.
NEJM. 2007;357(25):2601-14)
Time Scale of Infection after
Transplantation
Types of Infections vary depending on time post-transplant:
0-30 days: mostly surgical infections,
common bacteria, Candida, HSV
1-6 months: opportunistic pathogens, CMV,
Pneumocystis, Nocardia, Aspergillus
6 months onward: common community infections,
occasional opportunists,
endemic fungi (histo, crypto)
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Early Infections
Events of Infection in
Next 30 Days of Transplantation
Events of Infection in Next 30 days
Within the first 30 days
after transplantation,
the patient is at
greatest risk for
healthcare-associated
infections, often due to
antibiotic-resistant
organisms and often
polymicrobial in
aetiology
Events of Infection in Next 30 days
As is the case for healthcare-
acquired infections in general,
are often procedure- or
device-related, such as
catheter-associated infections
(urinary tract, bloodstream
infections), ventilator-
associated pneumonia,
aspiration, surgical wound
infections, or are associated
with anastomotic leaks and
ischemia
Infections can be with
Endogenous Flora
Infections may also result
from modification of
endogenous microbial flora
in the recipient or extant or
new colonization (often
related to the healthcare
environment, including the
hands of healthcare
workers), such as with
Clostridium difficile and
its spore-induced toxins.
Super infection carry Poor
prognosis
Super infections may even develop, and these
may carry a poor prognosis. Specific organisms
across the range of pathogen categories (ie,
opportunistic viruses, bacteria, fungi, and
parasites derived from the donor, recipient, or
both) may cause infection during this first month.
Overall, the types of infection during this period
share patterns with those that routinely occur
after similar operations.
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Second period
(approximately 1-6 months post transplantation)
Second Period
Second period
(approximately 1-6
months post
transplantation) is
characterized by the
presence or absence of
those pathogens selected
for by whether or not
there are ongoing
prophylactic antibiotics
against P jiroveci or
viruses such as CMV or
hepatitis B.
Role of Antimicrobial agents
The preventive antimicrobial agents used for these
organisms also have efficacy against other
opportunistic pathogens, such as common bacteria,
Listeria, Nocardia, Strongyloides, and herpes viruses
such as herpes simplex virus, varicella-zoster virus,
and EBV. Importantly, concurrent CMV infection during
these 5 months may have an independent
immunosuppressive effect, placing SOT recipients at
risk for opportunistic organisms and contributing to
almost two thirds of febrile episodes during this
period.
CMV Infection an Emerging
Infection
CMV
infection/illness may
manifest as
systemic symptoms
such as fever,
arthralgia, myalgia's,
or organ-specific
symptoms.
What are possibilities
after 6 months
After 6 months, patients fall into
the following 3 groups:
1Eighty percent have adequate allograft functioning
(and minimal immunosuppression characterized by
the absence of chronic viral infection)
2 Approximately 15% have chronic viral infections.
3 About 10% have frequent rejection episodes,
immunosuppression due to treatment regimens,
infections with viruses such as CMV, or a combination
of these.
After 6 months
Infections most commonly found in the first
group include community-acquired viral
infections (eg, influenza, parainfluenza,
respiratory syncytial virus, human
metapneumovirus), bacterial infections (eg,
Streptococcus pneumoniae, Haemophilus
influenza), urinary tract infections, and
asymptomatic cryptococcal infection (eg,
asymptomatic pulmonary nodules)
The Second Group is
Risk with
The second group is at
special risk for infections
with adenovirus,
polyomavirus BK,
recurrent hepatitis C,
human papillomavirus
(HPV), and HIV. Chronic
viral infections may also
lead to different types of
allograft dysfunction.
Third group often presents
The third group often
presents with severe
opportunistic infections
involving P jiroveci,
Cryptococcus
neoformans, Nocardia,
Rhodococcus, and
invasive fungi such as
Aspergillus, Mucor, and
other molds
Malignant Neoplastic Diseases is
Serious Concern
Malignant neoplastic diseases that originate from or
are modulated through infectious organisms can
develop during periods of immunosuppression, albeit
in the later post transplantation period (eg, EBV-
related PTLD, HPV-related skin or anogenital
squamous cell cancers, and human herpes virus
(HHV)8related Kaposi sarcoma. ) SOT in survivors
of hematopoietic cell transplantation has been the
subject of a recent article at a single institution
INFECTION RISK MANAGEMENT
High level of suspicion will
reduce Mortality and Morbidity
Remaining vigilant to the concept of
net state of immunosuppression, the
clinician is advised to approach solid
organ transplantation (SOT)related
infections using a framework of
infection risk assessment based on
exposure to organisms potentially
acquired through the following 6
different paths
High level of suspicion will
reduce Mortality and Morbidity
Community-acquired
pathogens
Reactivation of previous
infections (either from donor
or recipient)
Specific epidemiologic
exposures, including hobbies,
food and water, work,
recreational activities, pets,
zoonotic infections, or sexual
activit
High level of suspicion will
reduce Mortality and Morbidity
Infection specific to
donor organ
Iatrogenic or
healthcare-associated
infections
Specific travel-
associated pathogens,
including a range of
tropical diseases
Risk assessment with
CREDIT
Risk Assessment with
CREDIT Protocols
The framework for
infection risk
assessment in the
solid organ
transplant
recipient is
discussed below,
with CREDIT used
as a mnemonic
device.
C - Community-acquired
Community-acquired infections are common and
include cold viruses, lower respiratory viruses
and bacteria, and gastrointestinal pathogens.
With the increasing complexity of epidemiologic
patterns affecting communities, pathogens such
as methicillin-resistant S aureus (MRSA) and
drug-resistant S pneumoniae may also fall into
this general group.
C - Community-acquired
Atypical organisms such as Mycoplasma, Legionella,
and Chlamydia species, as well as prevalent vaccine-
preventable diseases, may also cause disease in SOT
recipients. Specific viral pathogens include influenza,
parainfluenza, respiratory syncytial virus, adenovirus,
human metapneumovirus, rhinoviruses, and
coronaviruses
R - Reactivation
Several organisms can lead to clinical infection and even
endogenous immunosuppression (eg, CMV) from a
process of reactivation within the SOT recipient, including
M tuberculosis, atypical mycobacteria, parasites
(Strongyloides stercoralis, Trypanosoma cruzii, Leishmania
species), the herpesviridae (CMV, EBV, herpes simplex
virus, varicella-zoster virus), other viruses (HIV, hepatitis B,
hepatitis C, papillomavirus, BK virus), and endemic fungi
(Histoplasma capsulatum, Coccidioides immitis,
Paracoccidioides brasiliensis). Donor-specific reactivation-
related disease is largely mediated through transmission
via the donated organ.
E - Epidemiologic exposure
Realizing that accurate and timely assessment of the
SOT recipient's risk of infection is directly related to
his or her involvement in specific activities may be of
great epidemiologic significance in the evaluation of
the febrile SOT recipient. In fact, such an assessment
is of importance on a preventive basis, since proactive
identification of epidemiologic exposure that increases
the SOT recipient's risk may represent a cost-effective
way to mitigate against infection in the first place.
D - Donor-derived infections
Donor-derived
infections are of
particular
significance, as
evidenced by several
reports of infectious
diseases transmitted
through transplanted
organs.
D - Donor-derived infections
They include viruses (hepatitis B and C,[37] herpes
viruses, human T-cell lymphotropic viruses (HTLV) 1 and 2,
West Nile virus, rabies, LCMV, polyomavirus BK/JC, HPV,
parvovirus B19, HIV), mycobacteria (tuberculous and
nontuberculous mycobacteria), meningococcus, syphilis,
parasites (malaria, Babesia, Toxoplasma gondii,
Trypanosoma cruzi [Chagas disease], S stercoralis), and
several fungal organisms. Donor-derived drug-resistant
bacteria may also be transmitted, including vancomycin-
resistant enterococci, MRSA, and fluconazole-resistant
Candida species
I - Iatrogenic considerations
Invigorated efforts toward increasing patient safety,
minimizing errors, and increasing adherence to hand
hygiene reinforce the vigilance required of healthcare
workers and patients in their efforts to mitigate the risk
of acquiring iatrogenic or healthcare-acquired
infections. As noted above, there are specific patterns
of infection, especially in the first month after
transplantation, that are also carried forward
throughout all phases in the natural posttransplant
history whenever the SOT recipient interfaces with the
healthcare setting.
T - Travel considerations
Attention to recent and remote travel is an important
component of infection risk assessment.[39] There are
many emerging and re-emerging infectious diseases
across a range of pathogen categories. Some
important pathogens in this category of exposure
include Escherichia coli (eg, enterotoxigenic E coli),
Mycobacterium leprae (leprosy), HTLV 1 and 2,
Penicillium marneffei, Plasmodium species, filarial
species, Echinococcus species, Schistosoma species,
Clonorchis species, Trypanosoma brucei, Taenia
solium, and Entamoeba histolytica.
Most significant organisms
(common and uncommon)
observed in solid organ transplant
recipients
American Society for Microbiology
guides on Infections
The information is largely tabulated from the American
Society of Microbiology (ASM) monograph "Infections
in Solid-Organ Transplant Recipients, as well as other
sources (eg, case reports) for completeness. Although
the list is not all-inclusive, it does attempt to capture
the common and uncommon pathogens that are of
clinical significance to practicing clinicians who
manage infections in SOT recipients.
Bacteria
Gram-negative organisms
include Acinetobacter species ,
Burkholderia species,
Enterobacteriaceae (E coli,
Klebsiella, Enterobacter
species), Pseudomonas
species, Proteus species,
Salmonella and other potentially
foodborne pathogens (eg,
Campylobacter, Plesiomonas,
Shigella species, Vibrio species,
Yersinia species), H pylori, and
Bacteroides species
Gram-positive organism
Gram-positive organisms include S aureus (including
MRSA), Staphylococcus epidermidis, enterococci, S
pneumoniae, group B Streptococcus, Streptococcus
milleri, Streptococcus suis, Rhodococcus equi,
Corynebacterium urealyticum , Lactobacillus species,
Rothia species (eg, Rothia dentocariosa), C difficile, M
tuberculosis,Mycobacterium bovis, and atypical
mycobacteria.
Other Important Bacteria
Other respiratory pathogens include H influenzae,
Moraxella catarrhalis, Mycoplasma species,
Legionella, and Bordetella.
Other bacteria include Listeria species, Nocardia
species, Borrelia species, Neisseria meningitidis,
Treponema pallidum species (syphilis), Rickettsia
species, Anaplasma phagocytophilum, Bartonella,
Coxiella burnetii, Ehrlichia species, Francisella
tularensis, and Leptospira species.
Viruses
Herpesviridae include CMV, EBV, HHV-6, HHV-7, HHV-8, and
varicella-zoster virus
Zoonotic viruses include Nipah virus, rabies, arenavirus, LCMV,
West Nile virus and other arboviruses, and parapox virus.
Gastrointestinal/viral hepatitis viruses include hepatitis C virus,
hepatitis A virus, hepatitis B virus, hepatitis E virus, rotavirus[ ,
and noroviruses.
Respiratory viruses include adenovirus, bocavirus,
coronaviruses (severe acute respiratory syndrome),influenza ,
H5N1, metapneumovirus, respiratory syncytial virus,
parainfluenza, enteroviruses, HIV, HTLV 1 and 2, and parvovirus
B19.
Polyomavirus Infection of the Transplanted
Kidney: Decoy Cells in the Urine
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CMV Retinitis - Early
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Labial Herpes
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Intraoral Herpes Simplex
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Other possible Infection with Virus
Other viruses
(vaccine-
preventable)
include measles,
mumps, rubella,
polio, and
Japanese
encephalitis
virus.
Fungi
Opportunistic systemic
fungi include Candida
species and
Cryptococcus.
Geographically endemic
species include
coccidioidomycosis,
histoplasmosis,
blastomycosis, and
paracoccidioidomycosis.
Cysts of Pneumocystis in a Lung
Biopsy
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Radiographic Picture of Pneumocystis Pneumonia
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Budding Cryptococcus
neoformans
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Pulmonary Cryptococcosis
Strongly Positive India Ink Smear
Invasive moulds
Highly Pathogenic
Invasive molds include
Aspergillus species, Fusarium
species, Scedosporium,
zygomycosis, Mucor species,
entomophthoramycosis (eg,
Basidiobolus), P jiroveci
(previously P carinii),
penicilliosis (P marneffei),
phaeohyphomycetes
(dematiaceous fungi),
Sporothrix schenckii,
Malassezia species, and
Trichosporon.
Parasites in
Transplantation
Protozoa include
Toxoplasma species,
trypanosomiasis (T cruzi
[Chagas disease], T brucei
[sleeping sickness]
[primarily in heart and
lung recipients),
Acanthamoeba,
Cryptosporidium
infection, Giardia species,
Microsporidia species,
and Isospora
Parasites
issue and blood protozoa
include leishmaniasis
(visceral), Plasmodia species
(malaria), and Babesia
species.
Helminths include
Strongyloides stercoralis,
Clonorchis sinensis,
Echinococcus species, T
solium, amebiasis, and
Schistosoma species
A strategic approach to fever
(and associated organ systemrelated manifestations)
in the SOT recipient
Turn to next page
Infections increase with increased intensity of
immunosuppression
Two major immunosuppressive drugs introduced since 1980,
cyclosporine and tacrolimus, have similar infectious risk but are
associated with less infection than the earlier regimen of
azathioprine/steroids
Two cell cycle inhibiting agents, azathioprine and mycophenylate
mofetil, have similar infectious risk
Risk of post transplant malignancy and CMV may be reduced
with rapamycin
Immunosuppression and Infection
Dummer JS, PPID, 2000
Infection Control Practices
Infection-control practices must be optimized for SOT
recipients and providers. The CDC provides several
guidelines for effective infection control measures here.
Although many of the policies and procedures relate to
specific setting and types of exposure, the most important
and cost-effective tool available to all individuals, especially
SOT recipients and their families and loved ones, is hand
hygiene. A great deal of information on proper technique is
available from the CDC here, in addition to guidance for the
range of questions that concern hand hygiene methods,
materials, and best practices.
Prevention of Exposure to Infection
Hospital exposures: usually just standard infection control.
Bone marrow units may HEPA filter air and restrict visitors
with colds
Enteric pathogens: avoid raw eggs, unpasteurized milk and
juices, certain soft cheeses, water from streams or lakes
Varicella: if seronegative avoid contact with chickenpox or
shingles
Zoonosis: avoid cat litter, bird cages, avoid jobs with frequent
animal contact
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Prevention of Exposure to
Infection
Respiratory
viruses: avoid
persons with colds,
public places during
flu outbreaks,
vaccinate family
members
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Prevention of Exposure to Infection-
Continued
Airborne molds: avoid
barns, silos, chicken
coops etc.
STDs: Practice safer sex
Exotic infections: Before
international travel
outside Canada or W.
Europe, confer with
infectious disease expert
Vaccination after
Transplantation
No clear evidence connecting vaccination to rejection episodes
Inactivated vaccines safe to use starting 3 months after
transplant if at baseline immunosuppression
Avoid live virus vaccines after transplant (minimum 4 weeks from
live vaccine to transplantation)
Influenza: inactivated seasonal vaccine recommended,
insufficient data to support use of high dose influenza vaccine,
adjuvant, or booster dose
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In spite of Many Advances Hand
Washing still can save many
References
Infections After Solid Organ
Transplantation Author: Asim A
Jani, MD, MPH, FACP; Chief Editor:
Ron Shapiro, MD etal
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Program created by Dr.T.V.Rao MD for Basic
issues on Infections in Organ Transplant
patients and a Time to Think about Importance
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