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)13

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)–8–related 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 posttransplanthistory 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, Taeniasolium, 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.

BacteriaGram-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.

VirusesHerpesviridae 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.

FungiOpportunistic 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, Fusariumspecies, 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 system–related 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 InfectionHospital 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

68

Prevention of Exposure to Infection

Respiratory

viruses: avoid

persons with colds,

public places during

flu outbreaks,

vaccinate family

members 69

Prevention of Exposure to Infection-Continued

Airborne molds: avoid barns, silos, chicken coops etc.

STD’s: 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

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