17 - Viral Inflections in Transplant Patients

Question 1

_____ _____ are a major source of morbidity and mortality in solid organ transplantation (SOT) and bone marrow transplantation (BMT)

Answer 1

Viral infections

Question 2

What are sources of infection in transplant patients?

Answer 2

1. Present in recipient or acquired from the donor
2. Latent/persistently replicating virus (H’s, polyomavirus)
3. Exposure post-transplant
4. Acutely replicating virus (respiratory, influenza, adenovirus, paramyxo)

Question 3

What are structural characteristics of polyomavirus?

Answer 3

Naked, dsDNA virus with two transcriptional units:

-early region: Large T (LT), splice variants (LT’), and small T (ST) antigens.

-late regions: structural viral proteins VP1-4

miRNA late expression inhibits early gene expression.

Question 4

How many known polyomaviruses are there? Which are the most studied?

Answer 4

11

BK and JC polyomavirus

Question 5

What is the replication cycle of polyomavirus?

Answer 5

1. Endocytosis through unknown mechanisms
2. Genome released into nucleus and replicates early genes and large T antigen is important for replication
3. Late genomes expressed
4. Self-assembly

Question 6

What are components of the Large T-antigen of polyomavirus? What is this referred to as?

Answer 6

“The most potent oncoprotein”

J domain for DNA rep, nuclear localization signal, and DNA binding domain.

LXCXE: binds and disrupts tumor suppressor Rb

Helicase: binds and disrupts tumor suppressor p53

Question 7

What is the function of the small T antigen of polyomavirus?

Answer 7

Alters activity of cellular protein phosphatase

Disrupts aspects of the cell cycle

Question 8

What is the tropism of polyomavirus defined by?

Answer 8

The host cells surface gangliosides:

The type of ganglioside on the outside of cells determines what cells it will infect.

Question 9

What type of infection does BK polyomavirus (BKPyV) cause and in who? How many serotypes are there?

Answer 9

Disease in immunosuppressed; infection occurs at young age and likely persists in proximal renal tubular cells but can infect lymphocytes and other cells.

4 serotpyes

Question 10

What type of disease is caused by BK polyomavirus?

Answer 10

10% of renal transplant-polymovirus associated nephropathy (PVAN)

10-25% of BMT-haemorrhagic cystitis

Induces tumors in animal models

Question 11

What type of infection for JC polyomavirus (JCPyV) cause and in who? How many serotypes are there?

Answer 11

Infects human glial cells and the serotonin receptor in those with immunosupression.

Infection occurs at young age and persists in kidney, lymphocytes, and BM cells.

1 serotype

Question 12

What disease is caused by JC polyomavirus?

Answer 12

Progressive multifocal leuroencephalopathy (PML) 5-8% of all AIDs related encephalopathies: demyelinating disease

Induces multiple types of tumors when inoculated into animals.

Question 13

What type of infection does merkel cell polyomavirus (MCPyV) cause?

Answer 13

Isolated from merkel cell carcinoma; only PyV classified as a causative agent of human malignancy.

Widely prevalent starting in childhood.

Question 14

What disease does Merkal cell polyomavirus (MCPyV) cause? Who does this occur in?

Answer 14

Merkel cell carcinoma: fast-growing, painless, dome-shaped

Risk in imunocompromised, >60 yrs, often on sun-exposed areas.

Integration into host chrom in most MCC and mutation of LgT antigen in DDB (LgT antigen expressed in ~97% of MCC).

Question 15

What is “Phase I” procedure for transplantation?

Answer 15

Screen to identify potential infections that may put pt at risk of death following immunosuppression that precedes transplant.

Donor/recipient screened for:

Hep C, Hep B, HIV, CMV, Epstein-Barr, and Syphilis

Question 16

After being screened, what does a transplant patient do Pre-engraftment? What virses can cause pre-engraftment infections?

Answer 16

Pre-transplant chemotherapy and radiation and post-transplant immune suppression: cyclosporin, tacrolimus which put pt at risk of infeciton.

Pre-engraftment infections due to immunosuppression often due to:

• Respiratory viruses
• Enteric viruses
• HHV6 reactivation
• HSV reactivation

Question 17

What may occur during “phase II” post-engraftment days 30-100?

Answer 17

CMV reactivation, adenovirus infection, HHV6 reactivation, communi acquired viruses such as RSV, influenza, parainfluenza, human metapneumovirus, and picornaviruses.

Question 18

What occurs during phase II post-engraftment >100 days if there’s still presence of chronic graft versus host disease (GVHD)?

Answer 18

Requires continued immunosuppression of the recipient during this phase.

Graft versus host disease: immune response and treatment is prednisone because neutrophil and lymphocyte function sucks

Question 19

What occurs during Phase II post-engraftment >100 days with chronic graft versus host disease? Where do infections during this phase typically occur? What percentage of these infections are viral?

Answer 19

Barrier protection of skin, mucous mmebranes, and GI tract are compromised.

Infection in this phase gernally localized to skin, upper respiratory tract, and lungs.

Viral infections are responsible for >40% of infections.

Question 20

What occurs in phase III late phase? What is the time from by which this occurs?

Answer 20

VZV infections secondary to reactivation: median time is 5 mo post transplant.

85% develope herpes zoster, wherease 15% develop chicken pox.

Those who get chicken pox have an increased risk of systemic dissemination (leading to pneumonia, hepatitis)

Question 21

What can cause hemorrhagic cystitis in transplant pts? When does this occur?

Answer 21

BK, JC, and adenovirus (late onset)

Following irradation, medications in pretransplant regimen, or prolopnged aplasia after transplantation.

Early development associated with high-dose cyclophosphamide before transplant.

Question 22

_______ will successfully treat BK or adenovirus associated hemorrhagic cystitis?

Answer 22

Cidofovir

Question 23

What illnesses can result from adenovirus?

Answer 23

Wide range:

• URI
• Pharyngitis, bronchitis, pneumonia
• Diarrhea
• Conjunctivitis
• Fever
• Cystitis (bladder inflamm)
• Rash
• Hepatitis
• Neurologic disease

This is very bad for transplant patients.

Question 24

What type of infections are we concerned about post-transplant as the months progress?

Answer 24

Immune competent infections are driven by CD4 count

Neutrophil count comes back up at day 21 so risk for bacteria and fungal infection goes way down at day 21

But you are at risk for viral infection until CD4 is back