Management of Infectious Complications in

Immunocompromised Patients

Abhay Dhand M.D.Director, Transplant Infectious Diseases,

Westchester Medical Center,Valhalla, NY

OBJECTIVES

1. To define an immuno-compromised host.

2. To understand the role of net immune suppression in mediating the risk of infections in susceptible host.

3. To understand the epidemiology and risk factors for infections in immuno-compromised patients.

4. To learn the preventative, and diagnostic strategies for management of infections in immuno-compromised patients

IMMUNOCOMPROMISED HOST

• CONGENITAL IMMUNOSUPPRESSION

• ACQUIRED IMMUNOSUPPRESSION

ACQUIREDIMMUNOSUPPRESSION

• Immunosuppressive Therapy

• Microbial Infection

• Malignancy

• Disorders of biochemical homeostasis

• Autoimmune diseases

• Trauma

ACQUIREDIMMUNOSUPPRESSION:

Immunosuppressive Therapy• Chemotherapy for malignancy- Neutropenia

• Treatment of autoimmune disorders

• Bone marrow transplant- ablation, graft vs. host disease

• Solid organ transplant: induction, maintenance immunosuppression, treatment of rejection

ACQUIREDIMMUNOSUPPRESSION:

Microbial Infection

• HIV/AIDS

• Hepatitis B/C, co-infection with HIV

• Herpes infection, Co-infection with HIV

• Bacterial infection (super antigens)

• Parasitic infections

ACQUIREDIMMUNOSUPPRESSION:

Malignancy• Lymphoma

• Leukemia

• Multiple Myeloma

• Solid tumors

ACQUIREDIMMUNOSUPPRESSION:

Disorders of biochemical homeostasis

• Diabetes Mellius

• ESRD/Hemodialysis

• Cirrhosis/Hepatic insufficiency

• Malnutrition

ACQUIREDIMMUNOSUPPRESSION:

Autoimmune diseases• Systemic Lupus Erythematosis

• Rheumatoid Arthritis

ACQUIREDIMMUNOSUPPRESSION

• Pregnancy

• Stress

• Functional splenia

• Splenectomy

• Aging

Immune Defects and Commonly Associated pathogens

Immune Defect PathogenBarrier breakdown:

Burns Pseudomonas, S. aureusTrauma Streptococcus pyogenes, S. epidermidis

Phagocytic function:Absolute decrease Enteric gram negatives, Pseudomonas,

Aspergillus spp., Candida spp.Chemotaxis S. aureus, Enteric gram negatives

Microbial killing S. aureus, Enteric gram negatives, Aspergillus spp, Burkholderia

Immune Defects and Commonly Associated pathogens

Immune Defect Pathogen

Humoral Immunity:

Hypogammaglobulinemia Streptococcus pneumoniae, Hemophilus IgA deficiency Pyogenic bacteria, Giardia lambia

Asplenia Streptococcus pneumoniae, Hemophilus

Complement deficiency Pyogenic bacteria, Neisseria spp.

Cell mediated immunity: Intracellular organisms (e.g. Listeria)

Viruses (e.g. Herpes family)

Fungi ( e.g. Candida spp., Cryptococcus)

Parasites(e.g. Toxoplasma)

Principles of Infection in Compromised Host: Neutropenia Nosocomial infections in neutropenic cancer

patients occur at a rate of :

46.3 episodes per 1000 neutropenic days

(48.3 episodes per 100 neutropenic patients)• The risk for infection is correlated with the

depth and duration of neutropenia • “Different” presentation

– Abscess– Pulmonary Infiltrate

Principles of Infection in Compromised Host

• Etiology can be ANYTHING

• Polymicrobial Infections can be seen more commonly

• Aggressive approach to diagnosis:

CT scan, Bronchoscopy, Biopsy

• Presumptive treatment

Principles of Infection in Compromised Host

• Serologic testing is generally not useful in the acute diagnostic management of immunocompromised patients.

• They often fail to generate an adequate antibody response to infection.

• Microbiologic testing should include antigen detection and/or nucleic acid detection-based assays as well as cultures.

Principles of Infection in Compromised Host:

Risk of Infection

• Timing post transplant

• Type of immunosuppression

• Net state of immunosuppression

• Pathogen-pathogen interaction (role of CMV)

• Type of transplant

Immunosuppressive Drugs and Mechanism of Action

Antigenpresenting

cell

AACCTTIIVVAATTIIOONN

HelperT

Lymphocyte

ILIL--2 R (High affinity)2 R (High affinity)

Calcineurin inhibitorsCiclosporinTacrolimus

ActivatedT

Lymphocyte

Anti-IL2 receptor AntibodiesBasiliximabDaclizumab

Mycophenolic acidAzathioprine

Antigen /T-cellreceptor/ MHC II

IL-2IL-2

Corticosteroids

DNAsynthesis

EverolimusSirolimus

PPRROOLLIIFFEERRAATTIIOONN

TLymphocyte

TLymphocyte

Morbidity and Mortality in Organ Transplant Recipients - Major Causes

• Allograft Loss

– life-long requirement - exogenous immunosuppression

– major threat - chronic rejection - immunologically mediated, but poorly responsive to immunosuppression

• Life threatening infection– ~ 67% transplant recipients develop infection in

first year post - transplant; – ~ 25% eventually die of infection

• Malignancy

• Cardiovascular complications

Infections in Solid Organ Transplantation patients

What are the Risk Factors for Infection in Organ Transplantation?

• Exposure to infectious pathogens (endogenous and exogenous)

• “Net State of Immunosuppression”

IMMUNOSUPPRESSION

LESS

- MORE REJECTION- LESS INFECTION/ MALIGNANCY

- LESS REJECTION- MORE INFECTION/ MALIGNANCY

MORE

Relationship between Infection and Immunosuppression

INFECTIONS IN RECIPIENT

INFECTIONS IN DONOR

TECHNICAL COMPLICATIONS

RELATED TO TRANSPLANTPROCEDURE

PRE-TRANSPLANT

IMMUNOSUPPRESSIO

N

INFECTIOUS EXPOSURES

POST-TRANSPLANT

RISK OF INFECTION

Complications of Transplantation that Predispose to Infection

• Contamination of the allograft during harvesting, transport or implantation

• Anastomotic leak• Hematoma, infarcted tissue• Presence of vascular access devices• Presence and mismanagement of endotracheal tubes• Presence of urinary, biliary or other drainage catheters

Net State of Immunosuppression

• Complex, poorly explained, combination of– exogenous immunosuppression – neutropenia– metabolic abnormalities (protein calorie

malnutrition, uremia, etc.)– infection with immunomodulating viruses (Herpes

group viruses particularly CMV, EBV, hepatitis viruses, HIV)

Potential Exposures - Post-transplant

• Nosocomial organisms (bacteria, fungi)

• Opportunistic organisms from environment (e.g. cryptococcus, aspergillus)

• Respiratory viruses and bacteria in the community

• Organisms in contaminated food and water (e.g. salmonella, listeria)

Immunosuppressive Therapy - what you need to know

• What was used for induction immunosuppression – induction with polyclonal, MAB preparations – increased

risk for opportunistic infection

• What was used as maintenance immunosuppression– How quickly did the patient get to maintenance

• What and when was anti-rejection therapy used– The trouble makers

Induction Immunosuppression

• Anti-T/B cell preparations– Used in patients with highest risk of rejection,

multiple prior transplants

• Allows delay in use of nephrotoxic immunosuppression (CyA, Tacrolimus)

• Result – Watch out - increase in infection

Maintenance Immunosuppression

• Renal– CyA/FK + mycophenolate + prednisone– problem = drug toxicities …organ dysfunction...infection

• Other solid organ transplants– FK + mycophenolate + prednisone– problem = drug toxicities …organ dysfunction...infection

Anti-rejection therapy

• Aggressive immunosuppression– higher doses of usual immunosuppression (e.g.

steroid pulses, etc.)– Polyclonal AB and MABs

• Result – significant increase in infection – need for

additional prophylaxis

When do Infections Occur in Transplant Recipients?

0 1 2 3 4 5 6 7

BACTERIAL

VIRAL

FUNGAL

Wound, pneumonia, line sepsis

Bacteremia, urosepsis, biliary, etc

Listeria

CMV

EBV, Hepatitis C

Aspergillus, PCP

Cryptococcus

HSV

Months post-transplant

First Month, Post-transplantation

• Infection that was present pre-transplant (pneumonia, bacteremia/line sepsis, etc.)

• Infection from contaminated allograft

• Typical bacterial, Candidal infections seen in post-operative patients

• NOTE - NO OPPORTUNISTIC INFECTIONS - UNLESS UNUSUAL HAZARD PRESENT

Month 2-6, Post-transplantation

• Immunomodulating viruses - particularly CMV, EBV, hepatitis B, C

• Opportunistic pathogens - Listeria, PCP, Aspergillus

• Residual bacterial, fungal infections from transplant complications

• NOTE - MOSTLY OPPORTUNISTIC INFECTIONS

> 6 Months, Post-transplantation

• 80% patients - good allograft function, minimal immunosuppression - usual community acquired ID

• 10% patients - chronic viral infections ….. Progress to end organ failure, sepsis, etc.

• 10% patients - continuing acute, chronic rejection, more immunosuppression, continuing risk of opportunistic infection

What Type of Infections Occur in Transplant Recipients?

• Sources of infection – limitless, but usually follow a timetable

– bacterial > viral > fungal

• Presentation of infection – infection difficult to recognize - signs blunted because of

impaired immune response

– unusual presentations

– chronic or relapsing infection

• Therapy challenging– prolonged courses

– adverse interactions with immunosuppressive agents

CMV and Solid Organ Transplantation• CMV is still among the most important

infectious complications after transplant

• In the absence of prophylaxis, CMV reactivation can occur in over 75% of solid organ transplant recipients depending on other risk factors

• Once CMV infection is established, then its replication is highly dynamic with rapid increases in viral load

Risk of Symptomatic CMV Disease

• Serologic status of donor and recipient

• Type of organ transplanted

• Type of immunosuppression

CMV Infection: Risk Categories in Solid Organ Transplant Recipients

Risk CategoryDonor (D) or Recipient (R)

Seropositivity (+/-)

High D+/R-

Intermediate* D+/R+, D-/R+

Low D-/R-* D+/R+ generally at higher risk than D-/R+

0

10

20

30

40

50

Kidney Heart Liver Heart-Lung orLung

Risk of Developing CMV Disease

Percent with CMV Disease

CMV Disease in SOT

Indirect Effects of CMV Infection

Altered host immune response

• Graft rejection; graft dysfunction

• Opportunistic infections: Bacterial fungal superinfection

• Decreased graft and patient survival

• Herpesvirus interactions: EBV/PTLD

Indirect Effects

Strategies for Prevention of Infection in Transplant Patients

• Pre-transplant

• Peri-transplant

• Post-transplant

Strategies for Prevention of Infection in Transplant Patients: PRE-TRANSPLANT

• Evaluate for active infection

• Evaluate for colonization with MDROs

• Evaluate for latent infections

• Vaccination

Strategies for Prevention of Infection in Transplant Patients: PERI-TRANSPLANT

Antibiotic prophylaxis:

• Goal: decrease the risk of surgical site infection, donor derived infection, disseminated infection, active treatment of latent/occult infection

• Type of transplant, h/o colonization, active localized infection, infection/colonization in the donor, antibiotic allergies

Strategies for Prevention of Infection in Transplant Patients: POST-TRANSPLANT

Prophylaxis:Antibiotics: bactrim, ciprofloxacin

Anti-viral: herpes viruses (CMV): valganciclovir

Anti-fungal: candida, aspergillus, endemic funguses

Candida Prophylaxis

• Liver transplant:

Atleast 2 risk factors: re-transplantation, Cr>2mg/dl, choledochojejunostomy, prolonged intra-operative time,

use of >40 U of blood products, fungal colonization 2 days before and 3 days after transplant.

• Heart/Kidney: not required

• Pancreas, Small bowel

Aspergillosis Prophylaxis

• Heart transplant recipients:

Isolation of aspergillus in airway cultures

Repeat thoracic surgery

CMV disease

Posttransplant renal replacement therapy• Liver transplant recipients:

Retransplantation, renal replacement therapy

Repeat intra-abdominal or thoracic surgery

4 weeks post transplant

Transplant for fulminant hepatic failure

Prevention of Nosocomial Infections

“Ventilator Bundle”

Head of bed elevation > 30 degrees*

Daily “sedation vacation” and assessment of readiness to extubate*

Oral care (chlorhexidine)

Peptic ulcer disease prophylaxis*

Deep vein thrombosis prophylaxis*

*Institute for Healthcare Improvement

Reduction in VAP from 6.6 to 2.7 (59%) per 1000 ventilator-days with > 95%

compliance

Hospital-Acquired UTI

40% of healthcare-associated infections80% due to indwelling urethral catheter

Potential Strategies Insertion/care

Catheter reminders/automatic stop ordersBladder US scanners

Condom cathetersAntimicrobial catheters

Clin Infect Dis 2008;46:243-50

- Multimodal intervention- Bundle approach- The “last mile” may require the use of

some technical device (chlorhexidine patch, coated catheters, antibiotic impregnated device, lock solutions…)

Zero Central Line Associated Bloodstream Infections:

…how to get there…

Colonization with Antibiotic Resistant Organisms:

Risk of Nosocomial Infections

Decolonization and its Role in Prevention of Nosocomial Infections

Arch Intern Med 2006; 166:306-12

Chlorhexidine Body Wash in the ICU

Arch Intern med 2007;167:2073-79

Decreased Acquisition of VREBefore and after, compared with soap and water

Decreased Bloodstream InfectionsCross-over, compared with soap and water

6.4 vs. 16.8 BSI per 1000 catheter-days

Selective Colonization: CDI

Selective Colonization: CDI

• Restore microbiota: fecal bacteriotherapy

• Nontoxigenic Clostridium Difficle