Post transplant infections and its management

Introduction

Recognizing the presentation of infections in transplanted patients is paramount

However, immuno-suppressed patients often present atypically, and with far advanced stages of infection

Fever is a non-specific finding, which can be attributed to medications and acute rejection

Invasive testing is often required to make an accurate and timely diagnosis

PATHOGENESIS

DISEASE DETERMINANTS

MicrobeMicrobe HostHost

Inoculum or Inoculum or OrganismsOrganisms

VirulenceVirulence

LatencyLatency

DefenseDefenseMechanismsMechanisms

HOST DEFENSE MECHANISMS

Intact skin and mucous membranes Disrupted due to trauma, burns, ulceration, IV

catheters, surgery Types of infection

Wound infections, burn sepsis, diabetic foot infection, line sepsis

Usual organisms Bacteria – environmental, endogenous Fungi – environmental, nosocomial

HOST DEFENSE MECHANISMS

Physical removal / clearance of micro-organisms Respiratory muco-ciliary clearance Peristalsis and dynamics of hollow viscus (gut, bile

ducts, ureter, fallopian tube) Maybe abnormal due to underlying disease, surgery,

smoking etc. Intact sphincters/valves Types of infection

Pneumonia, urosepsis, biliary sepsis Usual organisms

Bacteria – environmental, endogenous

HOST DEFENSE MECHANISMS

Endogenous microflora Oropharyngeal, gut, skin, vagina Important for preventing colonization with

disease causing organisms (competitive) Antibiotics remove natural flora E.g. C. difficile colitis

Chemical antimicrobial agents Gastric acidity, cutaneous fatty acids

HOST DEFENSE MECHANISMS

Inflammatory response Number (mass) and function of circulating and

tissue phagocytic cells Neutrophils, monocytes, macrophages, spleen

Humoral Mediators Complement, fibronectin

HOST DEFENSE MECHANISMS

Specific Immune response T-lymphocytes

CD4+, CD*+ (helper, cytotoxic) Number, function

B-lymphocytes Make antibodies IgG, IgA

Common problems

Host Defect:Inflammatory response

Common microbes

Neutropenia (<0.5)

Splenectomy

Gram negative bacilli, Staph, Candida, Aspergillus

S. Pneumonia, H. influenza, N. Meningitis

Common problems

Host Defect:Complement

Common microbes

Early (C3, C5)

Late (C6,7,8)

S. Aureus, S. Pneumonia, gram negative bacilli

Neisseria species

Common problems

Host Defect:Immune response

Common microbes

T- Lymphocytee.g. HIV, organ transplant

B-Lymphocyte

Numerous microbes

S. Pneumonia, H. influenza, Giardia

INFECTION: BASIC PRINCIPLES

Inflammatory response attenuated by immunosuppressants

may abolish typical signs/symptoms decreased sensitivity of serological,

radiological tests Effects of established infection may be

devastating Treatment may have more toxicities

Rifampin - decrease CsA Erythromycin, azoles increase CsA Synergistic nephrotoxicity - aminoglycosides,

AmB, septra, cipro, vancomycin, pentamidine

INFECTIONS IN TRANSPLANTATION

Three main determinants of the risk of infectionin transplant recipients

• Infections related to technical / surgical problems

TECHNICAL COMPLICATIONS

Liver - biliary tree - leaks, strictures Lung - bronchial anastomosis necrosis,

dehiscence ; mediastinal fluid collection Kidney - uroterocystostomy - leak,

urinoma Pancreas - duodenum-bladder;

duodenum-bowel: anastomotic leaks, abscess

INFECTIONS IN TRANSPLANTATION

Major determinants of the risk of infection

The net state of The net state of ImmunosuppressionImmunosuppression

EpidemiologicalEpidemiologicalexposuresexposures

NET STATE OF IMMUNOSUPPRESSION

Immunosuppressive therapy: dose, duration, temporal sequence - ‘area under the curve’

Underlying immune deficiency Mucocutaneous barrier integrity: intubation,

drains, catheters, central lines Devitalized tissue, fluid collection Neutropenia, lymphopenia

NET STATE OF IMMUNOSUPPRESSION

Metabolic conditions Uremia Malnutrition Diabetes

Viral infection: Immune modulation Cytomegalovirus Epstein-Barr virus Hepatitis B, C, HIV

Epidemiology

The risk, rate, and type of infection vary over time from transplantation

Currently, there are no assays to measure risk/susceptibility to infection

Risk of infection is an interplay between Exposure history (of donor and recipient) Intensity and quality of immunosuppression Use of prophylactic medications

Classification of Infections

Donor-derived

Recipient-derived

Nosocomial

Community-acquired

Donor-derived Infection Most are latent

CMV, TB, T.cruzi

Rarely can be acute Bacteremia/viremia at time of procurement West Nile, rabies, HIV, hepatitis, LCV

The majority of these are sub-clinical in healthy patients, but can be catastrophic when transplanted into an immuno-suppressed patient

At present, routine evaluations of donors for infectious diseases relies upon serologic antibody testing, and thus sensitivity is not 100% for those that may not have had time to seroconvert

Donor-derived

Transplantation of organs from deceased donors with viral syndromes is controversial

Livers with known Chagas or Hep B infection may be used as there are effective treatments for these infections

Hep C infected organs are sometimes transplanted into Hep C(+) donors

Fishman J. N Engl J Med 2007;357:2601-2614

Recipient-derived Infections

Infections that can be treated or controlled do not necessarily preclude transplantation

Most commonly screened for: TB syphilis Viral: CMV, EBV, VZV, HSV, HIV, HBV, HCV

Other things to think of T.cruzi, strongyloides, cryptococcus Endemic fungi: histoplasma, coccidioides,

paracoccidioides, aspergillus, blastomycosis

Polyoma Viruses

2 major clinical manifestations are known BK virus JC virus both of these are members of the papovaviridae family

JC virus is primarily associated with progressive multifocal leukoencephalopathy in AIDS pt’s

BK virus is primarily associated with nephropathy and ureteral obstruction

Both are asymptomatic infections acquired in childhood that remain latent

BK virus

First recognized in 1971, not truly appreciated until mid 1990’s when recognized as a cause for renal allograft loss (~5% incidence)

Has a tropism for the uro-genital tract, tends to affect “diseased” kidneys

Clinical manifestations asymptomatic hematuria hemorrhagic cystitis ureteral stenosis interstitial nephritis (nephropathy)

BK virus

Viruria can be detected in many populations, but the most clinically important is renal transplant recipients

Exact pathogenesis of the infection is poorly understood

Diagnosis must be made histologically (biopsy) Special stains and PCR can help solidify the diagnosis

BK virus

Treatment Only effective therapy is immune reconstitution (i.e.

reduction of immunno-suppressant therapy) Cedofivir and leflunomide are effective in reducing viral

load, but do very little to change the course of disease, and are both nephrotoxic

One must effectively walk the tightrope between progressive renal destruction secondary to infection, and acute rejection causing graft loss

BK virus

Several case reports exist for BK nephropathy in non-renal transplant recipients Bone marrow Heart Lung

However, these are rare, and are at level of case report

Fishman J. N Engl J Med 2007;357:2601-2614

Immunizations Pt’s should be current on the following

vaccines MMR HBV Influenza Strep pneumoniae Tetanus Diphtheria Pertussis Polio VZV – if never infected

Consideration should be given to boosters for any of the above prior to transplantation as live vaccines are generally contraindicated post-transplant, and immunologic memory will become impaired

Peri-operative Prophylaxis

Liver Skin, enterococcus, anaerobes, enterobacteriaceae Most common site of invasive fungal infection

Lung GNR, molds, endemic fungi MRSA and VRE according to antiobiogram prevalence Second most common site of invasive fungal infection

Nosocomial Infections

MRSA VRE fluconazole-resistant Candida species

associated with surgical site and indwelling catheters

C.diff Resistant gram-negative bacilli,

Pseudomonas, Aspergillus

Community Infections

Aspergillus Nocardia Cryptococcus neoformans (birds) Respiratory viruses Community acquired pneumonia pathogen HIV, hepatitis viruses Environmental fungi Secondary bacterial superinfection

Enteric bacterial pathogens (salmonella) TB, zoonosis,

Monitoring Immunosuppression

There are no specific tests currently available to determine the overall susceptibility of patients to infection…

…but they are on the horizon

Currently, the known determinants contributing to the overall risk of infection are the dose, duration, and sequence of immunosuppressive therapies

Fishman J. N Engl J Med 2007;357:2601-2614

Dynamic Assessment of the Risk of Infection after Transplantation

Fishman J. N Engl J Med 2007;357:2601-2614

Changing Timeline of Infection after Organ Transplantation

Early post-transplant period (30d)

Opportunistic infections are rare in the first month post-transplant

>1 month of medical therapy is required to effectively deplete cell-mediated therapy

One exception is large, prolonged doses of corticosteroids

Infections are generally donor-derived or associated with complications from the surgery itself

TIMETABLE: 0-1 MONTH

Infections usual to post-op patients nosocomial pneumonia, wound, line sepsis, UTI

Key factors: nature of the operation, technical skill

Lung, heart, liver at highest risk longer intubation, ICU stay, lines, catheters

Most OI’s (eg. PCP) absent in the first month Exceptions – HSV, HHV6, Candida, Aspergillus

TIMETABLE: 0-1 MONTH

Also may see Infection transmitted with the allograft: eg.

lung transplant with pneumonia or a donor bacteremia which seeds the vascular anastamosis

Pre-existing infection within the recipient made worse by the transplant

Intermediate period (1-6mos) Viral infections and allograft rejection account for

the majority of febrile episodes

Adherence to Cotrimoxazole and antiviral prophylaxis renders infections such as PCP, UTI’s, listeria, toxoplasmosis, and herpes very unlikely

Fungi, cryptococcus, T.cruzi, strongyloides can surface

Other: polyoma virus (BK and JC), recurrent HCV

TIMETABLE OF INFECTION

One to 6 months post-Tx Maximal period of immunosuppression Effect of sustained immunosuppression or

‘area under the curve’ Opportunistic infections in the absence of

excessive epidemiological hazard

TIMETABLE - 1 TO 6 MONTHS

VIRAL CMV, EBV, VZV, HHV-6, Adenovirus, Influenza, RSV

BACTERIAL Nocardia, Legionella, Listeria, TB

FUNGAL PCP, Aspergillus, Cryptococcus, endemic mycosis

PARASITIC Toxoplasma, Strongyloides

Late post-transplant period (>6mos)

Risk wanes as immunosuppressive therapy is tapered

Risk profile however, is “reset” with each episode of acute rejection

Chronic viral infections can cause allograft injury HCV cirrhosis BOOP in lungs CMV coronary vasculopathy PTLD Skin/anogenital cancers

Fungi/molds, viruses and “typical” bugs still remain on radar

TIMETABLE - > 6 MONTHS

GROUP 1: Good graft function, minimal immunosuppression Community acquired pneumonia, UTI, OI based

on intense exposure

GROUP 2: Recurrent or chronic rejection, high level immunosuppression, chronic viral replication Continued risk of opportunistic infections

Long-term Prophylaxis

Co-trimoxazole for at least 3 months, sometimes for life

CMV and HSV prophylaxis is not standardized, and varies according to immunno-suppressive regimen and institution

Rarely chronic suppressive antifungal Rx for pt’s with history of significant disease

CMV PREVENTION

Universal prophylaxis: anti-viral therapy to all ‘at-risk’ patients

Pre-emptive therapy: anti-viral therapy to subgroups of ‘at-risk’ patients usually based on further diagnostic tests aimed at identifying early viral reactivation

PRE-EMPTIVE THERAPY

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00 44 88 12 weeks12 weeks

Could have initiated pre-emptive therapyCould have initiated pre-emptive therapy

CMV diseaseCMV disease

TESTTEST

CMV IN LIVER TRANSPLANT RECIPIENTS

PRE-TRANSPLANT: Donor and recipient CMV serology

POST-TRANSPLANT: D+/R+, D-/R+

Week 2-12: Every clinic visit: CMV antigenemia CMV quantitative PCR

D+/R-: Ganciclovir prophylaxis 12 weeks

Bloodwork at week 12, 14, 16, 18. CMV antigenemia and quantitative PCR testing

General Lifestyle Recommendations

Avoid sick contacts, esp respiratory Avoid dusty sites (i.e. construction sites) Avoid ingestion of well and lake water Avoid undercooked meats Avoid soft cheeses and unpasteurized dairy

products Avoid unwashed fruits/veggies

Summary

Be aware of the time frame from transplant leading you to the most likely type of infection

<30d think nosocomial or donor-derived

1-6mos, reactivation of viruses and atypical infections “classic” for transplant pt’s

>6mos, think of “typical” or community-acquired bugs as their risk returns to somewhat normal

Fishman J. N Engl J Med 2007;357:2601-2614

Assessment of the Risk of Infection at the Time of Transplantation