Download IMMUNE COMPROMISED HOST

IMMUNE COMPROMISED
HOST
Dr. M. A. Sofi MD; FRCP
(London); FRCPEdin;
FRCSEdin
LEARNING 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
Primary immunodeficiencies are disorders in which part of the
body's immune system is missing or does not function normally. To
be considered a primary immunodeficiency, the cause of the
immune deficiency must not be secondary in nature (i.e., caused by
other disease, drug treatment, or environmental exposure to toxins).
Primary immunodeficiency disorder include:






Combined variable
immunodeficiency
disease,
Ataxia-telangiectasia,
Chediak-Higashi
syndrome,
Complement deficiencies,
DiGeorge syndrome,
Hypogammaglobulinemia
,






Job syndrome,
Leukocyte adhesion
defects,
Bruton disease,
Congenital
agammaglobulinemia,
Selective deficiency of IgA,
Wiscott-Aldrich syndrome
Primary immunodeficiency disorder : Symptoms



People PID disorder tend to
have one infection after
another.
Respiratory infections (such
as sinus and lung infections)
develop first and recur often.
Most people eventually
develop severe bacterial
infections that persist, recur,
or lead to complications. For
example, sore throats and
head colds may progress to
pneumonia.





Infections of the mouth, eyes,
and digestive tract.
Thrush/ fungal infection of
the mouth, may be an early
sign of an PID.
Chronic gum disease
(gingivitis) and frequent ear
and skin infections.
Bacterial infections (with
staphylococci) may cause pusfilled sores to form
(pyoderma).
People with certain
immunodeficiency disorders
may have many large,
noticeable warts (caused by
viruses).
ACQUIRED
IMMUNOSUPPRESSION
•
•
•
•
•
•
Immunosuppressive Therapy
Microbial Infection
Malignancy
Disorders of biochemical homeostasis
Autoimmune diseases
Trauma
ACQUIRED IMMUNOSUPPRESSION:
Immunosuppressive Therapy
• Chemotherapy for malignancyNeutropenia
• 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:
Disorders of biochemical homeostasis
•
•
•
•
Diabetes Mellitus
ESRD/Hemodialysis
Cirrhosis/Hepatic insufficiency
Malnutrition
ACQUIRED IMMUNOSUPPRESSION:
Autoimmune diseases
Systemic Lupus Erythematosus
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 negative,
Aspergillus spp., Candida spp.
S. aureus, Enteric gram
negatives
S. aureus, Enteric gram
negatives, Aspergillus spp,
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
Strept. pneumoniae, H. Influen
Pyogenic bacteria, Neisseria Spp
Intracellular organisms:
Listeria,Herpes family
Fungi: Candida spp. Cryptococcus
Parasites: 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:
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
SUPPRESSION
INFECTIONS
IN RECIPIENT
TECHNICAL
COMPLICATIONS
RELATED TO
TRANSPLANT
PROCEDURE
INFECTIONS
IN DONOR
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, Candida 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
Post-transplant 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
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