Infections in Transplant Recipients

Learning Objectives

• General concepts – Solid Organ Transplantation (SOT)– Hematopoietic Stem Cell Transplantation (HSCT)

• Chronology of infections

• Clinical evaluation– Approach to the patient with SOT– Approach to the patient with HSCT

• Specific transplant infections

50F with history of [solid organ] transplant presents with fever and chills x 1week. No localizing symptoms.

• How immunosuppressed is she?– What infections do I need to worry about– Inpatient or outpatient– Empiric antibiotics

• What do I need to look for in my evaluation?

Solid Organ Transplantation

• Type– Kidney < Heart, Liver, Pancreas < Intestine, Lung

– Anatomic/Technical considerations• Anastomotic leak• Fluid collections – blood, bile, lymph, urine• Surgical incision / poor wound healing• ICU-related infections• Organ specific

– Kidney: complicated UTI. SPK: enteric vs bladder drainage– Heart: mediastinitis, LVAD-associated, aortic suture line– Liver: R-en-Y vs biliary anastomosis, HAT, biliary stricture– Lung: airway anastomosis, ischemia-reperfusion injury

• Net State of Immunosuppression– Pre-transplant immunosuppression– Induction

• Varies with institution – no set standard• Anti-lymphocyte therapy

– Depleting: ATG, OKT3, alemtuzumab– Non-depleting: anti-CD25

– Maintenance• Corticosteroids, Azathioprine, MMF, CNI, Rapamycin

– Rejection– Duration

• Allograft function: good, injured, poor

Solid Organ Transplantation

50F with history of kidney transplant presents with fever and chills x 1week. No localizing symptoms.

• Kidney transplant 1 year ago• ATG induction• Rejection at 4 months and 11 months post-transplant –

each treated with high dose corticosteroids• Maintained on tacrolimus, MMF, and prednisone

• Assessment High degree of immunosuppression– Inpatient evaluation– Empiric antibiotics probably warranted

Chronology - SOT

NEJM 2007; 357: 2601-14

SOT – Early

• Vast majority of infections are surgical / ICU related– Nosocomial / MDR bacteria– Candida– C.diff

• Donor-derived infections– Unexplained infectious syndrome

• Recipient-derived infections– HSV reactivation [Prophylaxis]– Prior colonization or undiagnosed infection

• Opportunistic infections – very rare

SOT – Intermediate• Classic opportunistic infections

– CMV [Prophylaxis]– Nocardia, Listeria [Prophylaxis]– Pneumocystis [Prophylaxis]– Endemic mycoses– Toxoplasma [Prophylaxis]– Aspergillus

• Most common causes of fever– Viral infections: Respiratory viruses– Rejection

• Donor or Recipient derived– Mycobacteria, endemic mycoses, HCV, BK, other exotics

• Complicated / Persistent bacterial infections

SOT - Late

• Good graft function– Typical community acquired infections

• Severe presentation– VZV

• Poor graft function– Classic opportunistic infections during intermediate period– Exotic opportunistic infections – atypical molds

• Late infections– Delayed CMV– JCV - PML– EBV - PTLD

Clinical Evaluation

• Induction– May not be relevant if transplantation several years prior

• Rejection

• Prophylaxis– TMP/SMX vs Other [6 - 12 months]– Ganciclovir [3 - 12 months]

• Pre-transplant evaluation– HSV/VZV, CMV/EBV, HIV, HBV/HCV, RPR, Toxoplasma– Endemic mycoses, TB

• Immunosuppression = lack of inflammation– UTI without pyuria– Appendicitis without peritoneal signs

Donor Screening

Am J Transplant 2009; 9(S4):S19-26

Donor-Derived Infections

Am J Transplant 2009; 9(S4):

Case

56M s/p OLT 17 days ago for ESLD 20 NASH.• No anti-lymphocyte induction• Post-op course uncomplicated. No rejection episodes.• Maintenance: Prograf, Cellcept, Prednisone• Prophylaxis: Bactrim, Valcyte, Fluconazole• Presents with 2 days of progressive ataxia, diplopia,

decreasing alertness obtunded, bladder and bowel incontinence.

• ER Vitals: T38.80C, P88, BP 120/54, RR25 • Exam – abdominal incision intact, opens eyes to verbal,

non-communicative, intermittently obeys commands.

MRI Brain

Differential? Next Steps?

Chronology - SOT

NEJM 2007; 357: 2601-14

• Brain biopsy – necrosis and abscess formation

• Family withdraws care hospital day #8

• Donor-derived infection– Kidney-pancreas recipient with encephalitis / brain

abscesses and hospitalized– Donor is a 27M landscaper with large skin lesion x6

months, cause of death was presumed stroke– Balamuthia identified from brain biopsy of liver and

KP recipients & also donor liver.

SOT - Summary• Variable infection risk

– Type of transplant– Duration from transplant– Induction immunosuppression, rejection

• Chronology– Early (1 mo)– anatomic, technical, nosocomial– Intermediate (6 mo)– opportunistic infections– Late (6+ mo)– good vs poor graft function

• Prophylaxis– PJP, CMV, secondary prophylaxis

• Clinical presentation– Absence of inflammation – Severe manifestation

Hematopoietic Stem Cell Transplantation

• Graft type– Bone-marrow derived– Peripheral blood stem cell– Cord blood

• Donor type– Autologous– Allogeneic

• Matched sibling• Matched unrelated

Hematopoietic Stem Cell Transplantation

• Conditioning– Myeloablative– Reduced intensity / Non-myeloablative

• Graft manipulation– T-cell depletion

• GVHD– Acute– Chronic

Chronology - HSCT

BMT 2009; 44: 457-62

HSCT – Pre-engraftment

• R marrow suppression D marrow reconstitution– Pathogenesis

• Mucositis, translocation, nosocomial• HSV reactivation [Prophylaxis]• Respiratory viral infections• Engraftment syndrome

• Typical chemo-induced neutropenic infections– Neutropenic fever– Nosocomial / MDR bacteria [Prophylaxis]– C.diff – Neutropenic enterocolitis– Candida [Prophylaxis]– Aspergillus (prolonged neutropenia) [Prophylaxis]

HSCT – Post-engraftment

• Bacterial– Nosocomial– Translocation (Acute GVHD gut)

• Fungal – Candida [Prophylaxis]– Invasive molds [Prophylaxis] Acute GVHD– Pneumocystis [Prophylaxis]

• Viral– CMV [Pre-emptive] Acute GVHD– Respiratory viruses– HHV– BK Conditioning / Acute GVHD

HSCT – Late Phase

• Low risk– Matched allo-HSCT without GVHD– Infections:

• Encapsulated bacteria• VZV, Respiratory viruses

• High risk– Acute / Chronic GVHD, active CMV, T-cell depleted graft– Infections:

• Encapsulated bacteria, Nocardia• CMV, VZV, Respiratory viruses• Invasive molds, Pneumocystis

Clinical Evaluation• Infection risk

– Time from transplant– GVHD– Ask your friendly BMT practitioner

• Prophylaxis– Bacterial Quinolone [Pre-engraftment]– Viral

• HSV / VZV Acyclovir [1 year]• CMV Pre-emptive [Post-engraftment]

– Fungal• Candida Fluconazole [Pre-engraftment]• Invasive Molds Variable [GVHD]• PJP Bactrim [Pre-engraftment to 6 months]

• Pre-transplant evaluation– Same as for SOT– Hematologic malignancy associated infections

Antifungals 101

• Azoles– Fluconazole: Candida, Cryptococcus, Coccidioides– Itraconazole: above, and Aspergillus, Blastomyces, Histoplasma– Voriconazole: above, first line for Aspergillus– Posaconazole: above, and Mucor

• Echinocandins– Candida and Aspergillus

• Amphotericin– Broad spectrum antifungal– Lipid formulations: Abelcet and Ambisome

Case

36M s/p MUD-BMT for ALL Day +64• Myeloablative conditioning, engraftment at Day +14• Acute GVHD (gut & skin) at Day +24• Discharged from hospital at Day +33• CMV viremia detected at Day +41• Medications: Pred 70mg qd, Prograf, Bactrim, Valcyte, Vori

• Presents with fever, cough productive of frothy white sputum and SOB x 1 week.

• VITALS: T38.80C P120 BP149/80 RR32 O2 90%RA• Exam – Diffuse lung crackles.

CT Chest

Differential? Next Steps?

Chronology - HSCT

BMT 2009; 44: 457-62

• Labs: WBC 2.1 73% N

• Blood cultures– AFB positive

• Lung biopsy– Path: Acute lung injury with inflammatory necrosis, no

granulomas. AFB smear positive.– Micro: Mycobacterium chelonae

• Tunneled CVC finally removed– IR notes that the CVC is green and slimy.

HSCT - Summary• Variable infection risk

– Type of donor, type of graft– Duration from transplant– Conditioning, GVHD

• Chronology– Pre-engraftment (30 d) – neutropenic infections– Post-engraftment (100 d) – opportunistic infections– Late phase (100+ d) – low risk vs high risk

• Prophylaxis– You bet… and lots of it!– Breakthrough or resistant infections

• Clinical presentation– Severe manifestation – particularly viral infections– Need aggressive diagnostics

Case

34F s/p LDKT 20 yrs ago for ESRD 20 chronic VUR• No episodes of rejection, good graft function. CMV D neg / R neg.• Medications: Azathioprine, Cyclosporin – stable dosing• PMH: S/P TAH for menorrhagia• Married, monogamous. No children. No sick contacts.

• Presents with low-grade fevers, night sweats, myalgias and severe malaise x1 month. Also with odynophagia, epigastric pain, nausea, vomiting and diarrhea x 2 weeks. No urinary symptoms.

• VITALS: T38.40C P89 BP117/82 RR14• Exam: comfortable appearing, no LAN, OP clear, + epigastric

tenderness, lungs clear, no rash, no tenderness over allograft.

• Labs: WBC 1.9 43%N, LFTs normal

Chronology - SOT

NEJM 2007; 357: 2601-14

CMV IgG & IgM positive

CMV quantitative PCR:

576K copies/mL (NL < 200)

Duodenal biopsy:

+ CMV inclusions

+ CMV immunostains

How did she get CMV?

CMV

• Seroprevalence 40-70%. Latent infection G-M cell lines.

• Transplant recipients– Most common viral infection

– Definitions:• CMV infection – asymptomatic viral replication• CMV disease

– CMV syndrome– End-organ disease

– Timing:• Solid organ at 1-3 months• HSCT at 40-50 days• Late disease due to prophylaxis / pre-emptive therapy

CMV

– Risk factors:• Donor positive / Recipient negative• Use of anti-lymphocyte antibodies, T-cell depletion

– Diagnosis:• Serum PCR sensitive and specific, test of choice• Pathology - CMV immunostains• Serologic testing not useful for active infection

– Treatment:• Ganciclovir / Valganciclovir (Valcyte)

– Outcomes:• SOT – increased risk of rejection and infections• HSCT – CMV pneumonia with 50% mortality

Case

57F s/p OLT 15 months ago for PBC.• No rejection. CMV D+/R+. EBV R+.• Choledocholithiasis s/p ERCP 3 months ago.• Presents with intermittent fevers/chills x 3 mo & RUQ pain.

Chronology - SOT

NEJM 2007; 357: 2601-14

Monomorphic PTLD

EBV

• Seroprevalence 90%. Latent infection of B-cells.

• Post-transplant lymphoproliferative disorder– Clinical manifestations

• Benign polyclonal lymphoproliferation– Asymptomatic, mononucleosis-like illness

• Polymorphic or Monomorphic PTLD– Extra-nodal involvement: GI, liver, spleen, BM, allograft, lungs

– Risk factors• EBV 10 infection, EBV D pos / R neg• Transplant type

– SOT: Intestinal / Lung >> Kidney / Liver– HSCT: MUD, Cord, T-cell depletion

BK Virus

• Seroprevalence 80%.

• Latent infection – kidney, bladder, ureters.

• Kidney transplantation– BKV associated nephropathy

• Usually within 1st year post-transplant (28-40 wks)• Screening – Urine BK PCR Serum BK PCR• Diagnosis – Biopsy with immunostain

• HSCT– BKV associated hemorrhagic cystitis

• Usually within first 2 months of transplant (post-engraftment)• Acute, late-onset, long duration (2 wks)