Micro- Infections in Recipients of Solid Organ Transplantation Flashcards
What is presensitization for SOT?
when the transplant recipient has a high number of preformed circulating anti-HLA antibodies leading to increased risk of rejection of the transplanted organ
What do antiproliferative agents used for immunosuppression do?
Which drugs are anti-proliferatives?
Anti-proliferative drugs inhibit purine synthesis which limits B and T cell division and proliferation blunting CELL-MEDIATED immunity
- azathioprine
- Mycophenolate Mofetil [MMF]
What is the mechanism of action of MMF?
What 2 infections does it put patients at an increased risk for?
It is inosine monophosphate dehydrogenase inhibitor which disrupts de novo purine synthesis
[disrupts guanine synthesis]
It puts patients at increased risk for:
- BK nephropathy
- CMV
How do corticosteroids cause immunosuppression?
They block T-cell and APC cytokine expression:
- impairing T-cell activation/proliferation [IL-2]
- inhibiting inflammatory response [IL-1]
What is the ultimate result of using corticosteroids?
- lymphocytopenia, monocytopenia, neutrophilia
2. antibody suppression only occurs at high doses for long periods of time
What is the MOA of polyclonal anti-lymphocyte antibodies?
Opsonize leukocytes and platelets and elicit immune suppression via T-cell inactivation
For how long does lymphopenia last after giving a patient polyclonal anti-lymphocyte antibodies?
What syndrome can be caused by this?
What infections are patients at an increased risk for?
lymphopenia lasts for a year and has increased infection risk for over 3 months after administration.
Cytokine release syndrome due to ativation of T-cell before it is destroyed:
fever, chills, pulm edema, aseptic meningitis
Increased risk of:
- viral infection
- lymphoid malignancy
What are the 2 main polyclonal anti-lymphocyte antibodies?
- ATG [anti-thymocyte globulin] = rabbit
2. ATGAM [anti-human thymocyte globulin] = equine
What are the 5 monoclonal antibodies used in host immunosuppression?
What specifically do they each attack?
- OKT3 = anti-CD3
- Basiliximab, Daclizumab = anti CD25
- Alemtuzumab = anti CD52
- belatacept = CTLA4-Ig complex that binds to APCs
- rituximab = anti CD20
What is the MOA of OKT3?
What is the major side effect?
It is anti-CD3 and depresses T-cells via TCR transduction blockade
[Does not allow activation of T-cells]
SIDE EFFECT = cytokine release syndrome
What is MOA of basiliximab, daclizumab?
They are anti CD-25 so they block IL-2R inhibiting clonal proliferation and differentiation of activated T cells.
- no cytokine storm
What is the MOA of alemtuzumab? What is the major side effect?
It is anti-CD52, so it binds T, B, NK, monocytes and macrophages that have CD52.
This leads to Ab-dependent, cell-mediated lysis.
Side effect: neutropenia
What is the MOA of rituximab?
What is it specifically used for?
It is anti-CD20 and targets B cell lymphocytes.
It is used to reduce presensitization
What is the MOA of calcineurin inhibitors?
What are the 2?
Block calcineurin and inhibit T-cell activation and IL-2 production
- Cyclosporine
- isolated from tolypocladium - tacrolimus
- isolated from streptomyces
What is the MOA of mTOR inhibitors?
How do they compare to calcineurin inhibitors?
What is the main example?
What 2 side effects?
They inhibit mTOR thus blocking G0 to G1 transition and G1-S phase of T-cell activation.
They are more selective than CIs.
Sirolimus
Side effects: delayed wound healing, oral ulcers
What 4 factors affect risk of infection in SOT?
- time period after transplant
- type of transplant
- pre-transplant exposure
- donor-derived infections
What factors contribute to a patients “net state of immunosuppression”?
- type, dose, timing of immunosuppressive meds
- Immunomodulatory viruses:
- CMV, EBV, HIV, HBV, HCV - diabetes or renal insufficiency
What epidemiologic exposures affect a patients risk of infection post-transplant?
- nosocomial vs. CA
- exposure pre and post transplant
- prophylaxis
What is given as prophylaxis if the patient has:
- CMV
- PCP
- Fungal infection
- TB
- ganciclovir/valganciclovir
- TMP- SMX or [dapsone, atovaquone, inhaled pentamide]
- nystatin, fluconazole, ampho B
- pyridoxine, isoniazid
What are the 3 most common infections that occur in the first month after SOT?
- Nosocomial infections predominate
- ventilator pneumo, CVC bacteremia, UTIs - Bacterial & Candida from surgical technique and post-op care
- donor-derived infection
What time period after SOT has the highest net state of immunosuppression?
1-6 months
What infections are most common in the intermediate post-transplant stage [1-6 months]?
- viral reactivation - CMV, EBV, HBV, HCV
- opportunistic infections
- aspergillus
- Cryptococcus
- nocardia
- listeria
- t. gondii
What causes reactivation of CMV during intermediate posttransplant stage?
discontinuation of gangiclovir prophylaxis
What type of infection predominates the late post-transplant stage [over 6 months]?
community-acquired infections because not the patient is at home with a good allograft and minimal suppression.
- Viral respiratory infections: Flu, parainfluenza, RSV, adenovirus, human metapneumovirus
- bacterial respiratory infections: legionella, pneumococcus
Which organ when transplanted has the lowest number of incidence of infection with scarce deep fungal infection?
Renal
What infection is most associated with renal transplant?
- UTIs
2. pyelonephritis [if within the first 3 months, reduced graft survival]
What type of transplant carries the highest risk of bacteremia and the second highest rate of deep fungal infections?
Liver transplant
What types of infections predominate liver transplants?
What are the infections related to?
What organisms are most present?
- biliary tract
- abdominal
These infections are related to surgical complications like:
abscesses, peritonitis, cholangitis
Enteric G-, enterococci, anaerobes, staph, candida
What increases the risk of bacterial infection with liver transplant?
- prolonged surgery duration
- multiple transfusions
- repeated transplants
- CMV
What increases the risk of a deep fungal infection post liver transplant?
- elevated Cr
- long surgery
- repeated transplant
- Fe overload
- candida
Which organ transplant has the highest rate of infection OVERALL? Why?
Heart-Lung or Lung
- decreased mucocililary clearance
- decreased lymphatic drainage
- absent cough reflex
- environmental exposure
- ischemia at anastomoses
- allograft rejection –> bronchiolitis obliterans
Which transplant has:
- second highest rate of bacteremia
- highest rate of mediastinitis
- highest rate of deep fungal infections
- highest rate of CMV reactivation
- highest mortality from infection?
lung
What is bronchiolitis obliterans syndrome?
Chronic allograft rejection with decreased FEV1
What infections predominate with heart transplants?
- lung infections
2. endocarditis within the first month
With a heart transplant, what infectious agents are associated with mediastinitis and sternal wound infections?
- s. aureus
2. s. epidermitis [coag neg staph]
What 4 infections can occur in heart transplants?
- mediastinitis, sternal wound = staph aureus, coag neg staph
- Toxo from infected donor
- nocardiasis
- chaga’s - reactivation of T. cruzi
What 10 things are studied for pre-transplant history for the recipient?
1, HSV
- CMV
- EBV
- HBV
- HCV
- RPR [syphilis]
- VZV
- T. gondii
- TB
- HIV
What tests are done on donors to see if they are eligible to donate organs?
- HIV 1/2, PCR to “catch” window period
- RPR/VDRL
- HepB
- Hep C
- EBV
- CMV
- tracheal swabs for lung transplants
- urine/blood culture if febrile or with leukocytosis
