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
ACQUIRED
IMMUNOSUPPRESSION
•
•
•
•
•
•
Immunosuppressive Therapy
Microbial Infection
Malignancy
Disorders of biochemical homeostasis
Autoimmune diseases
Trauma
ACQUIRED
IMMUNOSUPPRESSION:
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
ACQUIRED
IMMUNOSUPPRESSION:
Microbial Infection
•
•
•
•
•
HIV/AIDS
Hepatitis B/C, co-infection with HIV
Herpes infection, Co-infection with HIV
Bacterial infection (super antigens)
Parasitic infections
ACQUIRED
IMMUNOSUPPRESSION:
Malignancy
•
•
•
•
Lymphoma
Leukemia
Multiple Myeloma
Solid tumors
ACQUIRED
IMMUNOSUPPRESSION:
Disorders of biochemical homeostasis
•
•
•
•
Diabetes Mellius
ESRD/Hemodialysis
Cirrhosis/Hepatic insufficiency
Malnutrition
ACQUIRED
IMMUNOSUPPRESSION:
Autoimmune diseases
• Systemic Lupus Erythematosis
• Rheumatoid Arthritis
ACQUIRED
IMMUNOSUPPRESSION
•
•
•
•
•
Pregnancy
Stress
Functional splenia
Splenectomy
Aging
Immune Defects and Commonly
Associated pathogens
Immune Defect
Barrier breakdown:
Burns
Trauma
Phagocytic function:
Absolute decrease
Chemotaxis
Microbial killing
Pathogen
Pseudomonas, S. aureus
Streptococcus pyogenes, S. epidermidis
Enteric gram negatives, Pseudomonas,
Aspergillus spp., Candida spp.
S. aureus, Enteric gram negatives
S. aureus, Enteric gram negatives,
Aspergillus spp, Burkholderia
Immune Defects and Commonly
Associated pathogens
Immune Defect
Humoral Immunity:
Hypogammaglobulinemia
IgA deficiency
Asplenia
Complement deficiency
Cell mediated immunity:
Pathogen
Streptococcus pneumoniae, Hemophilus
Pyogenic bacteria, Giardia lambia
Streptococcus pneumoniae, Hemophilus
Pyogenic bacteria, Neisseria spp.
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
Calcineurin inhibitors Anti-IL2 receptor Antibodies
Corticosteroids
Antigen
presenting
cell
Basiliximab
Daclizumab
Ciclosporin
Tacrolimus
Helper
T
Lymphocyte
A
C
T
I
V
A
T
I
O
N
Activated
T
Lymphocyte
IL-2
IL-2
ILIL-2 R (High affinity)
Antigen /T-cell
receptor/ MHC II
Everolimus
Sirolimus
P
R
O
L
I
F
E
R
A
T
I
O
N
T
Lymphocyte
DNA
synthesis
T
Lymphocyte
Mycophenolic acid
Azathioprine
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”
Relationship between Infection and
Immunosuppression
- MORE REJECTION
- LESS INFECTION/
MALIGNANCY
- LESS REJECTION
- MORE INFECTION/
MALIGNANCY
LESS
MORE
IMMUNOSUPPRESSION
PRE-TRANSPLANT
POST-TRANSPLANT
IMMUNO
SUPPRESSIO
N
INFECTIONS
IN RECIPIENT
INFECTIONS
IN DONOR
TECHNICAL
COMPLICATIONS
RELATED TO
TRANSPLANT
PROCEDURE
INFECTIOUS
EXPOSURES
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?
Cryptococcus
FUNGAL
Aspergillus, PCP
HSV
EBV, Hepatitis C
VIRAL
CMV
Listeria
Bacteremia, urosepsis, biliary, etc
BACTERIAL
Wound, pneumonia, line sepsis
0
1
2
3
4
5
Months post-transplant
6
7
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 Category
High
Intermediate*
Donor (D) or Recipient (R)
Seropositivity (+/-)
D+/RD+/R+, D-/R+
* D+/R+ generally at higher risk than D-/R+
Low
D-/R-
CMV Disease in SOT
Percent with CMV Disease
50
40
30
20
10
0
Kidney
Heart
Liver
Risk of Developing CMV Disease
Heart-Lung or
Lung
Indirect Effects of CMV Infection
Indirect Effects
Altered host immune response
• Graft rejection; graft dysfunction
• Opportunistic infections: Bacterial fungal superinfection
• Decreased graft and patient survival
• Herpesvirus interactions: EBV/PTLD
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 infections
80% due to indwelling urethral catheter
Potential Strategies
Insertion/care
Catheter reminders/automatic stop orders
Bladder US scanners
Condom catheters
Antimicrobial catheters
Clin Infect Dis 2008;46:243-50
Zero Central Line Associated
Bloodstream Infections:
…how to get there…
- Multimodal intervention
- Bundle approach
- The “last mile” may require the use of
some technical device (chlorhexidine
patch, coated catheters, antibiotic
impregnated device, lock solutions…)
Colonization with Antibiotic
Resistant Organisms:
Risk of Nosocomial Infections
Decolonization and its Role in
Prevention of Nosocomial Infections
Chlorhexidine Body Wash in the ICU
Decreased Acquisition of VRE
Decreased Bloodstream Infections
Before and after, compared with soap and water
Cross-over, compared with soap and water
6.4 vs. 16.8 BSI per 1000 catheter-days
Arch Intern Med 2006; 166:306-12
Arch Intern med 2007;167:2073-79
Selective Colonization: CDI
Selective Colonization: CDI
• Restore microbiota: fecal bacteriotherapy
• Nontoxigenic Clostridium Difficle