Micro- Infections in Recipients of Hematopoeitic Cell Transplantation Flashcards
What is a conditioning regimen for hematopoeitic stem cell transplantation?
It is what prepares the recipient for stem cell transplantation.
- chemo
- radiation
- monoclonal antibodies
What is GVHD?
when cells from a donated stem cell graft attack the normal tissue in the transplant patient
What is myeloablative chemotherapy?
high dose chemo that kills cells in the bone marrow including:
- cancer cells
- normal blood-forming cells
What value is given to “severe neutropenia”?
an absolute neutrophil count below 500/mm3
What 7 factors affect the development of infection in HCT?
- underlying disease process
- conditioning regimen
- autologous v. allogeneic donor source; peripheral stem cell v. umbilical cord blood
- presence of GVHD
- pre-transplant exposure history
- time period after transplantation [intensity of immunosuppression]
- prophylactic measures
What 5 groups of people is HCT an option for?
Of these 5 HCT eligible groups, which have the highest risk of infection?
- malignancies
- solid tumors
- autoimmune diseases [limited number]
- severe immunodeficiencies
- bone marrow failure
Immunodeficiency > leukemia/lymphoma/chronic granulomatous disease > solid tumors
What are the 5 types of HCT transplant?
- umbilical cord blood [UCB]
- peripheral blood stem cell transplant [PBSC]
- autologous -previously harvested from the recipient
- allogeneic - from a donor [related or matched-unrelated]
- syngeneic - from an identical twin
What risk of infection is associated with an UBC HCT?
- prolonged neutropenia [low dose stem cells]
- bacterial and fungal infections - lack of antigen-specific memory T cells
- viral and opportunistic infections
What is the risk of infection with PBSC HCT?
- shorter neutropenia than UCB
2. more chronic GVHD
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?
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
What are the 3 reasons to give conditioning regimens [immunosuppressive and chemo +/- radiation]?
- eradicate patient disease [malignancy, abnormal cells]
- make space in the marrow for transplant
- prevent rejection of new stem cells [by killing old immune cells]
What are the 2 forms of conditioning regimens?
- myeloablative
2. reduced intensity
Myeloablative regimens lead to most infections ________ but a similar risk of infections ______________ due to presence of GVHD.
most infections early after transplantation but similar risk late after transplantation
During the conditioning regimen, what does total body irradiation cause?
mucositis which is bacterial translocation across the gut wall
What is the recovery time of the following cells after HCT?
- B cells
- CD4 T cells
- CD8 T cells
- monocytes
- NK cells
- months to years with abnormal IgG and IgA production for 1-2 years [lower Ab response to vaccinations]
- 1-3 months
- 2-3 months
- one month, but impaired function for a year
- recover quickly
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?
40-80%
What are the 5 ways GVHD predispose to infection?
- attack GI which leads to mucositis–> bacterial translocation across the gut
- alterations of humoral/cellular immunity
- functional hyposplenism and poor response to vaccines
- pneumococcal
- fungal
- CMV reactivation - prophylaxis for GVHD is immunosuppression [cylosporine, methotrexate, steroids, MMF, tacrolimus] for a year
- acute GVHD is treated with corticosteroids and immunosuppression
- fungal
- viral reactivation
What 9 tests are routinely done to test pre-transplant exposure history?
What protection will prior immunization provide post-transplant?
- CMV
- HSV
- VZV
- EBV
- HIV1/2
- T. gondii
- Hep B
- Hep C
- TB PPD or Quantiferon
Prior immunization provides LIMITED protection post-transplant
What are the 3 risk-periods after transplantation based on differential immune recovery that predispose to certain infections?
- Pre-engraftment = immediately post transplant until day 20-40
- Early post-engraftment = until day 100
- Late post -engraftment = after day 100
What type of infection predominates pre-engraftment stage?
Pre-engraftment stage is characterized by:
- neutropenia
- lymphopenia
- mucositis
Therefore, bacterial infections predominate
What are the 2 major causes of bacterial infection during the pre-engraftment stage?
Which bacteria predominate?
- Central Venous Catheter for chemo, blood transfusion, stem cell infusion leads to bacteremia with:
- skin flora
- gram positives such as coag. neg staph [epidermitis] - Mucositis
- gram negative enteric bacteria [enterobacteria, pseudomonas]
- gram positive [viridians strep or enterococci]
What is prophylactic treatment for the pre-engraftment stage after HCT?
When should treatment be given until?
Fluoroquinolones are given when absolute neutrophils are below 500.
Give them until neutrophils recover
In addition to bacterial infections from mucositis and central line bacteremia, what other 2 infections are likely to occur during the pre-engraftment period?
- reactivation of HSV [80% of patients]
2. cadidemia and early aspergillosis [rarely]
What is prophylaxis for reactivation of HSV during pre-engraftment phase?
acyclovir/valacyclovir
Candidemia and early aspergillosis are RARE [5%] infections that occur during pre-engraftment after HCT.
What 2 things increase the risk?
What is prophylaxis?
Risk is increased by:
- prolonged neutropenia PRIOR to transplant
- delayed engraftment
Prophylaxis: fluconazole
Describe what part of the immune system is recovering during engraftment stage.
What type of HCT has the highest risk of infection?
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.
What specific infections are people in the engraftment stage most at risk for?
- bacterial
- GVHD leading to mucositis and enteric G-
- CVC leading to coagulase neg G+ staph, enterococci - CMV reactivation
- late onset fungal or aspergillosis
- GVHD, CMV infection - PCP
What drug prophylaxis is given for aspergillosis/fungal infection and PCP during engraftment stage?
Fungal = voriconazole, posaconazole
PCP = TMP-SMX
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?
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.
- Respiratory infection predominates
- encapsulated [h. flu, S. pneumo]
- viruses - Filamentous bacteria like Nocardia
- VZV, CMV
- aspergillosis and other mold infections
Do gram positives or gram negatives cause the majority of bacteremias after HCT?
What are the risk factors?
G+ Risks: 1. mucositis 2. GVHD 3. indwelling CVC 4. prolonged or severe neutropenia
What G+ bacteria are most commonly associated with the following:
- bloodstream infections esp with CVC
- poor dentition, mucositis, HSV-oral ulcers
- catheter-related bacteremia in neutropenic patients
- coagulase negative staph
- S. pyogenes [GABHS], strep mitis, enterococcus
- MRSA
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-?
- Enterobacteriaciae and non-lactose fermentors
- prophylaxis = fluoroquinolones
- pseudomonas, acinetobacter, stenotrophomonas
- mucositis, GVHD, neutropenia, CVC
What is likely to lead to infection by encapsulated bacteria?
Which bacteria are most common?
What is prevention for this?
cGVHD–> functional asplenia leading to infection by:
- strep pneumo
- haemophilus influenza
- nisseria meningitidis
Prevention: pneumococcal vaccination, penicillin, macrolides, fluoroquinolones
What diseases can rare legionella infections cause in patients after HCT?
How is diagnosis made?
- Pneumonia, pulmonary nodules
- legionella monocytogenes –> meningitis, bacteremia
Diagnosis is with direct fluorescence Ab, but it can lead to false neg because it doesn’t have all serotypes
What disease presentation is associated with Nocardia in patients after HCT?
What is prophylaxis?
What is treatment?
- pneumonia, pulmonary nodules
- brain abscesses
Prophylaxis: TMP-SMX
Treatment: surgical debridement and antibiotics [sulfonamide]
What are the 3 modes of acquiring rapidly growing mycobacterial infections post-HCT?
What 2 techniques can be used for diagnosis?
- CVC exit site wound
- bacteremia
- pneumonia
Diagnose with:
- AFB culture
- mycobacterial DNA probes
What is prophylaxis for TB?
How long is treatment?
Prophylaxis: isoniazid, pyridoxine
Treatment: 6 to 12 months depending on species and site/severity of infection
What percent of patients have reactivation of HSV1/2 after HCT?
What does it cause?
How is diagnosis made?
What is prophylaxis?
80%
Causes: oropharyngeal, esophageal, perianal ulcers
Dx: DFA, PCR, culture
Prophylaxis: acyclovir
Reactivation of CMV depends on the serocompatability of the donor and recipient. Which combo has the highest rate of reactivation?
D-/R+ > D+/R+»_space; D+R->D-R-
What are the 2 main risk factors for CMV reactivation post-HCT?
- GVHD
2. lymphopenia
What diseases are caused by CMV post -HCT?
What does it also predispose to?
CMV predisposes to other bacterial/fungal infections.
It presents with :
- pneumonitis [different from HIV]
- enteritis
- bone marrow suppression
- retinitis [rare. but most common in HIV]
How is CMV diagnosed?
What is prevention?
What is treatment?
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
What are the 5 main risk factors for a EBV reactivation?
- GVHD
- treated with anti-thymocyte globulin
- given T cell depleted graft
- mismatched transplant recipient
- UCB
What type of transplant predisposes to HHV6?
What is the presentation?
How is it diagnosed?
Treatment?
- UCB
- most cases are asymptomatic but can present with:
- meningoencephalitis
- interstitial pneumonitis
- bone marrow suppression - PCR
- ganciclovir or foscarnet
What are the risk factors for adenovirus post HCT?
What is clinical presentation?
What is dx? tx?
- GVHD, lymphopenia, recipient of UCB or unrelated
- hemorrhagic cystitis, pneumonitis, enteritis, hepatitis, nephritis
- Dx: PCR, viral culture, DFA
- Tx: no effective therapy
What viral family is BK virus?
How does an infection present?
Dx? Tx?
Polyomavirus [same as JC]
It causes hemorrhagic cystitis, but NOT BK-induced nephropathy like with renal transplants
Dx: PCR
Tx: reduce immunosuppression, cidofovir
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?
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:
- proper hand hygiene and covering coughs/sneezes
- vaccination of family and close contacts
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?
fluconazole/voriconazole
drawback: increases rise of non-aspergillus filamentous molds
What is the clinical presentation of candida infection post-HCT?
What are the 3 major risk factors?
What is Dx?
Hepatosplenic candidiasis with multiple liver and spleen microabscesses.
Risks:
- neutropenia
- broad spectrum antibiotics and steroids allow for overgrowth
- CVC, GVHD, mucositis
Dx:
- culture, biopsy w/ histology, b-d-glucan assay
Describe how aspergillus causes infection post HCT. What time frame?
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
What are the risk factors for aspergillosis?
- older patient
- construction near hospital
- lymphopenia
- CMV, respiratory viruses
- mult. myeloma
What is treatment for aspergillosis?
Amphotericin
or
voriconazole +/- echinocandin
What increases the risk of non-aspergillus mold infections?
empiric fluconazole/voriconazole prophylaxis in HCT
What does PCP cause?
Dx? Tx?
Pneumonia
Dx: DFA
prophylaxis and Tx: TMP-SMX
What is the most common parasite infection post HCT [although only 2-7% get it]?
When is the highest risk period?
Dx? Tx?
T. gondii mostly due to reactivation disease
Highest risk: 2-8wks
Dx: tissue culture, PCR
Tx: TMP-SMX
