Micro- Infections in Recipients of Hematopoeitic Cell Transplantation

Question 1

What is a conditioning regimen for hematopoeitic stem cell transplantation?

Answer 1

It is what prepares the recipient for stem cell transplantation.

1. chemo
2. radiation
3. monoclonal antibodies

Question 2

What is GVHD?

Answer 2

when cells from a donated stem cell graft attack the normal tissue in the transplant patient

Question 3

What is myeloablative chemotherapy?

Answer 3

high dose chemo that kills cells in the bone marrow including:

1. cancer cells
2. normal blood-forming cells

Question 4

What value is given to “severe neutropenia”?

Answer 4

an absolute neutrophil count below 500/mm3

Question 5

What 7 factors affect the development of infection in HCT?

Answer 5

1. underlying disease process
2. conditioning regimen
3. autologous v. allogeneic donor source; peripheral stem cell v. umbilical cord blood
4. presence of GVHD
5. pre-transplant exposure history
6. time period after transplantation [intensity of immunosuppression]
7. prophylactic measures

Question 6

What 5 groups of people is HCT an option for?

Of these 5 HCT eligible groups, which have the highest risk of infection?

Answer 6

1. malignancies
2. solid tumors
3. autoimmune diseases [limited number]
4. severe immunodeficiencies
5. bone marrow failure

Immunodeficiency > leukemia/lymphoma/chronic granulomatous disease > solid tumors

Question 7

What are the 5 types of HCT transplant?

Answer 7

1. umbilical cord blood [UCB]
2. peripheral blood stem cell transplant [PBSC]
3. autologous -previously harvested from the recipient
4. allogeneic - from a donor [related or matched-unrelated]
5. syngeneic - from an identical twin

Question 8

What risk of infection is associated with an UBC HCT?

Answer 8

1. prolonged neutropenia [low dose stem cells]
   - bacterial and fungal infections
2. lack of antigen-specific memory T cells
   - viral and opportunistic infections

Question 9

What is the risk of infection with PBSC HCT?

Answer 9

1. shorter neutropenia than UCB

2. more chronic GVHD

Question 10

When getting allogeneic HCT, what does matching refer to?
What problems are associated with higher degrees of mismatch?
What 3 infections specifically are allogeneic HCT recipients at increased risk for?

Answer 10

Matching = HLA matching between donor and recipient

more mismatch –> more immunosuppression required so the transplant doesn’t reject–> delayed immune reconstitution and prolonged engraftment which:
1. increases risk of GVHD
2, increases risk of infection with T-cell immunodeficiency
-PCP
- CMV
-EBV post-transplant proliferative disorder

Question 11

What are the 3 reasons to give conditioning regimens [immunosuppressive and chemo +/- radiation]?

Answer 11

1. eradicate patient disease [malignancy, abnormal cells]
2. make space in the marrow for transplant
3. prevent rejection of new stem cells [by killing old immune cells]

Question 12

What are the 2 forms of conditioning regimens?

Answer 12

1. myeloablative

2. reduced intensity

Question 13

Myeloablative regimens lead to most infections ________ but a similar risk of infections ______________ due to presence of GVHD.

Answer 13

most infections early after transplantation but similar risk late after transplantation

Question 14

During the conditioning regimen, what does total body irradiation cause?

Answer 14

mucositis which is bacterial translocation across the gut wall

Question 15

What is the recovery time of the following cells after HCT?

1. B cells
2. CD4 T cells
3. CD8 T cells
4. monocytes
5. NK cells

Answer 15

1. months to years with abnormal IgG and IgA production for 1-2 years [lower Ab response to vaccinations]
2. 1-3 months
3. 2-3 months
4. one month, but impaired function for a year
5. recover quickly

Question 16

GVHD is when the donor T cells attack the recipients cells [immune, skin, liver, intestinal tract].
What percent of patients with allogeneic HCT will experience this?

Answer 16

40-80%

Question 17

What are the 5 ways GVHD predispose to infection?

Answer 17

1. attack GI which leads to mucositis–> bacterial translocation across the gut
2. alterations of humoral/cellular immunity
3. functional hyposplenism and poor response to vaccines
   - pneumococcal
   - fungal
   - CMV reactivation
4. prophylaxis for GVHD is immunosuppression [cylosporine, methotrexate, steroids, MMF, tacrolimus] for a year
5. acute GVHD is treated with corticosteroids and immunosuppression
   - fungal
   - viral reactivation

Question 18

What 9 tests are routinely done to test pre-transplant exposure history?
What protection will prior immunization provide post-transplant?

Answer 18

1. CMV
2. HSV
3. VZV
4. EBV
5. HIV1/2
6. T. gondii
7. Hep B
8. Hep C
9. TB PPD or Quantiferon

Prior immunization provides LIMITED protection post-transplant

Question 19

What are the 3 risk-periods after transplantation based on differential immune recovery that predispose to certain infections?

Answer 19

1. Pre-engraftment = immediately post transplant until day 20-40
2. Early post-engraftment = until day 100
3. Late post -engraftment = after day 100

Question 20

What type of infection predominates pre-engraftment stage?

Answer 20

Pre-engraftment stage is characterized by:

1. neutropenia
2. lymphopenia
3. mucositis

Therefore, bacterial infections predominate

Question 21

What are the 2 major causes of bacterial infection during the pre-engraftment stage?
Which bacteria predominate?

Answer 21

1. Central Venous Catheter for chemo, blood transfusion, stem cell infusion leads to bacteremia with:
   - skin flora
   - gram positives such as coag. neg staph [epidermitis]
2. Mucositis
   - gram negative enteric bacteria [enterobacteria, pseudomonas]
   - gram positive [viridians strep or enterococci]

Question 22

What is prophylactic treatment for the pre-engraftment stage after HCT?
When should treatment be given until?

Answer 22

Fluoroquinolones are given when absolute neutrophils are below 500.
Give them until neutrophils recover

Question 23

In addition to bacterial infections from mucositis and central line bacteremia, what other 2 infections are likely to occur during the pre-engraftment period?

Answer 23

1. reactivation of HSV [80% of patients]

2. cadidemia and early aspergillosis [rarely]

Question 24

What is prophylaxis for reactivation of HSV during pre-engraftment phase?

Answer 24

acyclovir/valacyclovir

Question 25

Candidemia and early aspergillosis are RARE [5%] infections that occur during pre-engraftment after HCT. What 2 things increase the risk? What is prophylaxis?

Answer 25

Risk is increased by: 1. prolonged neutropenia PRIOR to transplant 2. delayed engraftment Prophylaxis: fluconazole

Question 26

Describe what part of the immune system is recovering during engraftment stage. What type of HCT has the highest risk of infection?

Answer 26

Engraftment is until day 100 after HCT. It occurs after neutrophil recovery. During this stage, B and T lymphocyte functional recovery occurs. Allogeneic transplant is at highest risk for infection because they have to be the most immunosuppressed leading to increased risk of GVHD and CMV reactivation.

Question 27

What specific infections are people in the engraftment stage most at risk for?

Answer 27

1. bacterial - GVHD leading to mucositis and enteric G- - CVC leading to coagulase neg G+ staph, enterococci 2. CMV reactivation 3. late onset fungal or aspergillosis - GVHD, CMV infection 4. PCP

Question 28

What drug prophylaxis is given for aspergillosis/fungal infection and PCP during engraftment stage?

Answer 28

Fungal = voriconazole, posaconazole PCP = TMP-SMX

Question 29

When does late post-engraftment stage occur? What delays full immune recovery? What infections occur during this stage as a result of the delayed recovery?

Answer 29

Day 100 until full immune recovery [18-36 months] cGVHD delays immune recovery because you must use immunosuppression leading to abnormal lymphocytes/macrophages and abnormal Ab function. 1. Respiratory infection predominates - encapsulated [h. flu, S. pneumo] - viruses 2. Filamentous bacteria like Nocardia 3. VZV, CMV 4. aspergillosis and other mold infections

Question 30

Do gram positives or gram negatives cause the majority of bacteremias after HCT? What are the risk factors?

Answer 30

``` G+ Risks: 1. mucositis 2. GVHD 3. indwelling CVC 4. prolonged or severe neutropenia ```

Question 31

What G+ bacteria are most commonly associated with the following: 1. bloodstream infections esp with CVC 2. poor dentition, mucositis, HSV-oral ulcers 3. catheter-related bacteremia in neutropenic patients

Answer 31

1. coagulase negative staph 2. S. pyogenes [GABHS], strep mitis, enterococcus 3. MRSA

Question 32

What G- cause the most problems in neutropenic patients with HCT? What is prophylaxis? Which 3 G- have developed drug-resistance? What are the risk factors for infection with these G-?

Answer 32

1. Enterobacteriaciae and non-lactose fermentors 2. prophylaxis = fluoroquinolones 3. pseudomonas, acinetobacter, stenotrophomonas 4. mucositis, GVHD, neutropenia, CVC

Question 33

What is likely to lead to infection by encapsulated bacteria? Which bacteria are most common? What is prevention for this?

Answer 33

cGVHD--> functional asplenia leading to infection by: 1. strep pneumo 2. haemophilus influenza 3. nisseria meningitidis Prevention: pneumococcal vaccination, penicillin, macrolides, fluoroquinolones

Question 34

What diseases can rare legionella infections cause in patients after HCT? How is diagnosis made?

Answer 34

1. Pneumonia, pulmonary nodules 2. legionella monocytogenes --> meningitis, bacteremia Diagnosis is with direct fluorescence Ab, but it can lead to false neg because it doesn't have all serotypes

Question 35

What disease presentation is associated with Nocardia in patients after HCT? What is prophylaxis? What is treatment?

Answer 35

1. pneumonia, pulmonary nodules 2. brain abscesses Prophylaxis: TMP-SMX Treatment: surgical debridement and antibiotics [sulfonamide]

Question 36

What are the 3 modes of acquiring rapidly growing mycobacterial infections post-HCT? What 2 techniques can be used for diagnosis?

Answer 36

1. CVC exit site wound 2. bacteremia 3. pneumonia Diagnose with: 1. AFB culture 2. mycobacterial DNA probes

Question 37

What is prophylaxis for TB? | How long is treatment?

Answer 37

Prophylaxis: isoniazid, pyridoxine Treatment: 6 to 12 months depending on species and site/severity of infection

Question 38

What percent of patients have reactivation of HSV1/2 after HCT? What does it cause? How is diagnosis made? What is prophylaxis?

Answer 38

80% Causes: oropharyngeal, esophageal, perianal ulcers Dx: DFA, PCR, culture Prophylaxis: acyclovir

Question 39

Reactivation of CMV depends on the serocompatability of the donor and recipient. Which combo has the highest rate of reactivation?

Answer 39

D-/R+ > D+/R+ >> D+R->D-R-

Question 40

What are the 2 main risk factors for CMV reactivation post-HCT?

Answer 40

1. GVHD | 2. lymphopenia

Question 41

What diseases are caused by CMV post -HCT? | What does it also predispose to?

Answer 41

CMV predisposes to other bacterial/fungal infections. It presents with : 1. pneumonitis [different from HIV] 2. enteritis 3. bone marrow suppression 4. retinitis [rare. but most common in HIV]

Question 42

How is CMV diagnosed? What is prevention? What is treatment?

Answer 42

Dx: CMV pp65 leukocyte antigen assay [cannot be performed with neutropenia], PCR Prevention: 1. if seronegative--> CMV safe blood products [leukoreduced] Tx: ganciclovir/valanciclovir with CMV Ig

Question 43

What are the 5 main risk factors for a EBV reactivation?

Answer 43

1. GVHD 2. treated with anti-thymocyte globulin 3. given T cell depleted graft 4. mismatched transplant recipient 5. UCB

Question 44

What type of transplant predisposes to HHV6? What is the presentation? How is it diagnosed? Treatment?

Answer 44

1. UCB 2. most cases are asymptomatic but can present with: - meningoencephalitis - interstitial pneumonitis - bone marrow suppression 3. PCR 4. ganciclovir or foscarnet

Question 45

What are the risk factors for adenovirus post HCT? What is clinical presentation? What is dx? tx?

Answer 45

1. GVHD, lymphopenia, recipient of UCB or unrelated 2. hemorrhagic cystitis, pneumonitis, enteritis, hepatitis, nephritis 3. Dx: PCR, viral culture, DFA 4. Tx: no effective therapy

Question 46

What viral family is BK virus? How does an infection present? Dx? Tx?

Answer 46

Polyomavirus [same as JC] It causes hemorrhagic cystitis, but NOT BK-induced nephropathy like with renal transplants Dx: PCR Tx: reduce immunosuppression, cidofovir

Question 47

When after HCT are infections by respiratory viruses most common? What is the seasonal preference? How does clinical syndrome progress? Why? What are 2 techniques to prevent this?

Answer 47

Within the first 3 months esp in the winter [except parainfluenza which is year round] URI--> pneumonia-->respiratory failure and death because of lymphopenia Prevention: 1. proper hand hygiene and covering coughs/sneezes 2. vaccination of family and close contacts

Question 48

What drugs used as prophylaxis have drastically decreased the rate of candida and aspergillosis post-HCT? What is the drawback of these drugs as prophylaxis?

Answer 48

fluconazole/voriconazole drawback: increases rise of non-aspergillus filamentous molds

Question 49

What is the clinical presentation of candida infection post-HCT? What are the 3 major risk factors? What is Dx?

Answer 49

Hepatosplenic candidiasis with multiple liver and spleen microabscesses. Risks: 1. neutropenia 2. broad spectrum antibiotics and steroids allow for overgrowth 3. CVC, GVHD, mucositis Dx: - culture, biopsy w/ histology, b-d-glucan assay

Question 50

Describe how aspergillus causes infection post HCT. What time frame?

Answer 50

Aspergillus spores are inhaled in the respiratory tract-->pulmonary and sinus infections [fungal ball] --> dissemination--> skin nodules/brain abscesses Peak 1 at 2-3 wks Peak 2 at 3-4 months Peak 3 late during cGVHD

Question 51

What are the risk factors for aspergillosis?

Answer 51

1. older patient 2. construction near hospital 3. lymphopenia 4. CMV, respiratory viruses 5. mult. myeloma

Question 52

What is treatment for aspergillosis?

Answer 52

Amphotericin or voriconazole +/- echinocandin

Question 53

What increases the risk of non-aspergillus mold infections?

Answer 53

empiric fluconazole/voriconazole prophylaxis in HCT

Question 54

What does PCP cause? | Dx? Tx?

Answer 54

Pneumonia Dx: DFA prophylaxis and Tx: TMP-SMX

Question 55

What is the most common parasite infection post HCT [although only 2-7% get it]? When is the highest risk period? Dx? Tx?

Answer 55

T. gondii mostly due to reactivation disease Highest risk: 2-8wks Dx: tissue culture, PCR Tx: TMP-SMX