Transplantation Infectious Disease/Immunocompromised Host Service
Massachusetts General Hospital
2013-2014
I.
Structure
The Transplantation Infectious Disease and Compromised Host Program developed as a
part of the comprehensive and life-long care provided to transplant recipients and other
immunocompromised individuals with unique susceptibility to infection. The program in
Transplantation Infectious Disease was established as an integral part of the surgical
Transplantation Unit to facilitate the evaluation, prevention, and treatment of infectious
disease in Liver, Kidney, and Pancreas transplant recipients at the Massachusetts General
Hospital. This service now includes the Heart, Lung and Bone Marrow and Stem Cell
Transplantation Programs and acute leukemia, lymphoma and other oncology patients with
complications of chemotherapy. In addition to providing clinical care on a longitudinal basis for
this unique “at risk” population, this service also provides an educational opportunity for
Infectious Disease Fellows and other trainees in the area of infectious disease management of
immunocompromised individuals.
The Compromised Host Program allows the rapid communication of clinical
recommendations to the primary care medical and surgical teams on a continuous basis. As
participants in the primary care of these patients, we are afforded a unique opportunity to
participate in the development of antimicrobial and immunosuppressive protocols on the
clinical service. This provides a valuable venue for clinical research. There is an ongoing
relationship with basic research scientists studying models of transplantation (in the Infectious
Disease Division, Transplant Unit and Transplantation Biology Research Center), with particular
interests in xenograft transplantation and in the development of preclinical models of tolerance
induction for clinical use.
II.
Clinical Activities
One attending physician and one first year Infectious Disease Fellow and a second year
Transplant Infectious Disease Fellow staff the inpatient Transplant ID Service, with physicians
from outside institutions participating on the service by special arrangement. Transplantation
Infectious Disease participates in the pre-transplant evaluation of new patients. The Fellows
and Attending round with the Transplant team each morning and participate in the outpatient
care of Transplant recipients (see below). The Abdominal Transplant team is responsible for
renal, liver, pancreas, and bowel transplants as well as ancillary surgical procedures (dialysis
access, general surgery) in solid organ transplant recipients. This team generally includes the
Transplant Surgery Attending, 2-3 Surgical Residents, a rotating first year Infectious Disease
Fellow from the combined Partners Infectious Disease Program, a Nephrology Fellow and
Nephrology Attending, an Attending Gastroenterologist and Fellow, and participation of
representatives from Nursing, Pharmacy and Social Service. Consultations on patients on the
1
Cardiac (Heart Failure and Transplant), Pulmonary, Bone Marrow Transplantation and Leukemia
and Lymphoma services are also seen in consultation on a routine basis. Visiting fellows who
have generally completed Infectious Disease training elsewhere may apply to attend this
program as observers.
Weekly activities include:
 Friday morning (8 AM) conference on clinically related topics and Morbidity and Mortality
Conference monthly
 Tuesday morning ‘Compromised Host Conference” (ID Library, 8:00-9:00) to discuss ID
issues from active patients and present journal articles weekly
 Wednesday morning Transplant “Chief’s Rounds (8:30 AM, Blake 6) and Transplant Center
Grand Rounds (7:30 or 8:00 AM in Bigelow Amphitheater)
 Special Transplant Immunology (noon Friday) and Immunology (Thursday noon, CNY)
 Special lectures and Visiting Faculty.
Outpatient Experience
A variety of patients are seen in the Transplant Infectious Disease and
Immunocompromised Host outpatient clinic:
 Pre-transplant evaluation for all patients undergoing kidney, liver, pancreas, heart, and
lung transplant (over 200 patients in 2012)
 Follow-up after inpatient stays (or emergency room/observation) for active infectious
disease issues (over 300 visits in 2012)
 Urgent access for transplant recipients with acute issues appropriate for outpatient
evaluation (~50 visits in 2012)
 Monitoring via OPAT (Outpatient Antibiotic Therapy) is performed on many transplant
patients per year to ensure safety and enhance therapeutic efficacy
 “Travel after Transplant Clinic” provides focused travel advice and care for solid organ
and bone marrow transplant recipients
Infectious disease fellows and internal medicine residents in the out-patient clinic enhance their
knowledge of:
 Pre-immunosuppression evaluation
 Acute evaluation of illness in immunocompromised hosts
 Routine follow-up of inpatients with active infectious disease issues
 Vaccines in immunocompromised hosts
 Mitigation of risk of side effects from antibiotic therapy
 Enhancing lifestyle safety after transplant, including travel medicine
Patient educational tools regarding transplant infectious diseases topics (including vaccines,
pets, food safety, arboviral avoidance).
2
To the degree possible, ID Fellows participate in the teaching activities of the Infectious
Disease Unit during their participation on the Transplant Service. All Transplant I.D. Attending
physicians also participate in the Clinical and Teaching activities of the M.G.H. Infectious
Disease Division. Activities include Management Conference (Monday A.M.), Intercity Rounds
with the ID physicians of other Boston Centers (Wednesday AM), and a didactic seminar series.
There are additional clinical conferences and journal clubs that are available for those with
special interests in the field.
III.
General Strategies in the Care of Transplant Patients
Drug therapy in transplantation revolves around a highly immunosuppressive regimen,
which entails multiple drugs with frequent interactions in terms of toxicities as well as
immunosuppressive effects. Therapy is individualized for each patient based on clinical data
and unique risk factors. The basic principle of antimicrobial therapy in this population is that
established infection is poorly tolerated -- requiring that emphasis be placed on prevention
whenever possible. The preventative antimicrobial strategies are linked to the
immunosuppressive regimens required to control rejection or graft-vs-host- disease (GvHD).
In general, the use of empiric antimicrobials for immunocompromised patients with infectious
“syndromes” is routine; the spectrum must be narrowed based on microbiologic data as soon as
is possible.
Some general observations are possible:
1. The progression of infectious disease is generally more rapid in the
immunocompromised host than in other individuals. As a result, early and effective
antimicrobial therapy is essential. Appropriate microbiologic specimens should be obtained,
when possible, prior to the initiation of antimicrobial therapy, which is then selectively
adjusted based on microbiologic data. Serologic tests are not often useful for acute diagnosis in
these hosts after transplantation, but pre-transplant testing often provides a basis for specific
prophylaxis (cytomegalovirus, toxoplasmosis, tuberculosis) following transplantation.
2. Nephrotoxicity is a major concern in all patients who are receiving calcineurin
inhibitors (cyclosporine or tacrolimus/FK506). Certain agents are routinely avoided (except for
treatment of life-threatening infections) including: aminoglycosides, amphotericin, and high
dose trimethoprim-sulfamethoxazole. Interactions are generally shared between cyclosporine,
tacrolimus (FK506), and sirolimus via the P450 hepatic enzyme system; special caution should
be used when starting erythromycin, rifampin, and the azoles (ketoconazole, itraconazole,
voriconazole, posaconazole). The organ most often targeted for significant toxicity from
calcineurin inhibitors is the kidney, but neurotoxicity, hypertension, hypergycemia, hemolytic
uremic syndrome, hirsutism, liver function abnormalities and other problems are also common.
As a result, the differential diagnosis of unexplained rejection or organ dysfunction includes
drug toxicity. Rapamycin (sirolimus) will generate a separate set of side effects including poor
wound healing, proteinuria, peripheral edema, and pulmonary interstitial edema. Drug dosages
3
must be adjusted as appropriate for altered metabolic function or clearance. Specific agents
and their effects include:
a. The oral antifungal (azole) agents are used with appropriate adjustments made for
hepatic and renal function and for drug levels (CyA, Tacrolimus). CyA and tacrolimus and
rapamycin are generally reduced when initiating voriconazole or itraconazole and, to a
lesser extent, fluconazole therapy. Adjustments are also made to increase these drugs
to therapeutic levels when discontinuing azole therapy.
b. Drugs metabolized via the hepatic P450 systems will increase cyclosporine and
tacrolimus levels and include ciprofloxacin (and levofloxacin to a lesser extent).
c. Rifampin increases metabolism of cyclosporine and tacrolimus and decreases
absorption of the same drugs.
d. Erythromycin increases cyclosporine A absorption and decreases cyclosporine
metabolism (as does clarithromycin).
e. Synergistic bone marrow toxicities occur with many agents including azathioprine,
allopurinol, cyclophosphamide, valganciclovir, acyclovir, TMX-SMZ, and occasionally
warfarin.
f. Prolongation of the QT interval may be seen with calcineurin inhibitors, azoles,
macrolides, fluoroquinolones, some psychiatric drugs, and other medications, especially
when use din combination.
3. Indwelling drainage catheters (e.g. JP drains, T-tubes) are cultured routinely but only
as a guide to empiric therapy should evidence of clinical deterioration or infection develop.
The use of central venous catheters and PICC lines are avoided whenever possible.
IV.
Routine Prophylaxis: Prophylaxis is to be adjusted based on present or prior
microbiologic data suggesting particular microbial resistance patterns or prior colonization
risks (e.g. vancomycin-resistant enterococci, MRSA, yeasts, other nosocomially-acquired
bacteria). Prophylactic agents are used for 24 - 48 hours unless longer-term therapy is desired.
V.
Pretransplant Evaluations:
1. Routine Recipient Serologies: HIV, treponemal antibody, CMV, VZV, EBV, Hepatitis B and C,
, Toxoplasma (hearts only), T SPOT TB, mumps, measles, and rubella. Quantitative molecular
diagnostic strategies are often employed in the evaluation of transplant donors or
recipients.
The Pre-transplant Laboratory Evaluation
Test
Serologies
All patients
4
Patients in endemic area
CMV
VZV


EBV

HIV

HBV:
HbsAg
anti-HBs
core antibody
HCV
Mumps
Measles
Rubella
Treponemal antibody
T SPOT TB
Toxoplasma gondii
Strongyloides stercoralis
Schistosomiasis
HTLV I/II (esp if Strongyloides positive)
Leishmania spp.
Trypanosoma cruzi
Coccidioides immitis









 (all hearts)





2. History of exposures to: Tuberculosis, Endemic Fungi (Histoplasma, Coccidioides,
Blastomycosis), Strongyloides stercoralis, Trypanosoma cruzi (Chagas disease), and
Leishmania merit special consideration. Patients from endemic areas should have serologic
tests performed and stool evaluations for ova and parasites where appropriate; generally
individuals with exposures to endemic regions are treated with ivermectin for Strongyloides
while awaiting serologic studies. Chagas’ may be managed with monitoring and preemptive therapy in patients receiving heart transplants. Toxoplasma seronegative
recipients of seropositive hearts require life-long TMP-SMZ prophylaxis. Unusual exposures
might include sushi, raw seafood, well water, raw meats, unpasteurized milk products,
home made sausage, unwashed vegetables, farm animals, or wild game. Prior blood testing
for clinical hepatitis and previous blood transfusions should be ascertained.
3. Routine dental evaluations and treatment are mandatory for all transplant recipients. ENT
evaluations are performed for cystic fibrosis patients prior to lung transplantation.
4. Immunizations: Pneumovax/Prevnar, Influenza, Varicella/Zoster, MMR, Tdap, and Hepatitis
A & B vaccines as appropriate. Tetanus toxoid booster is given for tetanus-prone wounds.
Live vaccines are generally avoided in the transplant recipient following transplantation.
Particular attention must be paid to pretransplant vaccinations in individuals expected to
5
undergo splenectomy during surgery. In general, hyperimmune globulins (i.e. hepatitis B,
rabies, tetanus) are employed, but toxoids are avoided.
Vaccinations to Consider Prior to Transplantation
Measles/mumps/rubella (MMR)
Diphteria/tetanus/pertussis (DTP) (or update tetanus)
Poliovirus (inactivated)
Varicella (if seronegative) or zoster if >50 yo
Hepatitis B (consider Hepatitis A with risk factors)
Pneumococcal and Prevnar vaccines
Influenza (usual indications)- yearly
Haemophilus influenzae B and meningococcus
(splenectomy, plasmapheresis, eculizumab)
5. Patients on chronic steroids or immunosuppression should generally be started on
trimethoprim-sulfamethoxazole prophylaxis prior to transplantation. Patients on long term
steroids or broad spectrum antimicrobials need pre-transplant antifungal prophylaxis.
6. Bowel decontamination is not employed routinely outside of pancreas transplantation.
7. Eradication of pre-existing infections (e.g., sinus surgery in CF patients, colectomy for
repeated episodes of diverticulitis)
8. Surgical and Procedure-based prophylaxis (Full protocols are available for prophylaxis in each
organ type)
Background: The incidence of infection in surgical patients is determined by the nature of
the surgery, the duration of the procedures, complications, and patient-specific factors. In an
immunologically normal host, the rate of infection in a “clean-contaminated” wound (minor
breaks in GI, GU, or respiratory tracts without obvious spillage) is reduced form ~ 10% to 1.3%
by use of perioperative antibiotics. The optimal timing of antimicrobial prophylaxis has been
demonstrated to be ~30 minutes prior to skin incision. Thus, optimal prophylaxis is
individualized (e.g., if a patient is colonized with resistant flora) and given in the operating
room. General: Aminoglycosides and Amphotericin are to be avoided whenever possible
(exception – liposomal amphotericin B for post-lung transplant prophylaxis or oral regimens)
Routine prophylaxis is based on those organisms commonly found in each body site:
 Routine kidney transplant: Cefazolin 1 gm iv at OR +/- in 6 hours(re-dose if procedure is ongoing) and x 1 post-op (alternative for PCN allergy: Vancomycin 1 gram x 1 and Aztreonam 1
gram q 8 x 2); post-op TMP-SMZ/Nystatin/ganciclovir or famciclovir
 GI Procedures: ERCP, Liver or GI biopsy: Piperacillin-tazobactam 3.375 gm iv x 1 (repeat for
bleeding) +/- fluconazole 400 mg x 1 – all ERCPs include bacterial cultures of biliary drainage.
 Liver transplant : Unasyn or Piperacillin-tazobactam 3.375 gm iv q6h +/- fluconazole 400 mg
daily (alternative for PCN allergy: Vancomycin 1 gram x 1 and Aztreonam 1 gram q 8 x 2). For
VRE colonization add linezolid 600 mg po/iv q12h x 2.
 Post-op TMP-SMZ/Nystatin/valganciclovir or famciclovir (CMV D-/R-)
6

Pancreas: Add to liver regimen, fluconazole 400 mg po daily
Lung: Vancomycin 1 gram iv q 12 h plus cefepime 1 gram iv q 8 h (or coverage designed
based on patient flora) ; post-op antifungals per protocol, ganciclovir
 Heart: Vancomycin +/- cefepime; post-op TMP-SMZ/Nystatin/ganciclovir or famciclovir
C. Anti-Pneumocystis and general prophylaxis
Background: Without trimethoprim-sulfamethoxazole prophylaxis, the incidence of
Pneumocystis carinii pneumonia in the first six months post-transplant approaches 15%. In
addition, patients who are more than six months post-transplant and who have poor allograft
function and a history of particularly intense immunosuppressive therapy, or who are infected
with cytomegalovirus, have an even higher risk for Pneumocystis and other opportunistic
infections. Low dose trimethoprim-sulfamethoxazole prophylaxis (in adults: 1 single strength per
day PO, as opposed to therapeutic doses) is well tolerated and essentially eradicates Pneumocystis
infection from this patient population. In addition, the incidence of early urinary tract infection
and respiratory infection are reduced. Such infections as nocardiosis, listeriosis, and toxoplasmosis
and a variety of gastrointestinal and pulmonary infections are reduced also.
Regimen: one single strength trimethoprim-sulfamethoxazole tablet (containing 80 mg
trimethoprim, 400 mg sulfamethoxazole) po qhs for a minimum of 6 months post- renal
transplant. Patients infected with CMV, with chronic rejection, or recurrent infections are
maintained on lifelong prophylaxis. All liver, heart, lung, and pancreas recipients are maintained
on TMP/SMX for life.
Alternative Regimen: For those patients not tolerating trimethoprim-sulfamethoxazole
(documented), then alternative regimens are required. The MGH has used a combination of
atovaquone 1500 mg PO with meals once daily plus levofloxacin (or equivalent fluoroquinolone
without anti-anaerobic spectrum) 250 mg once daily. Alternatives include: dapsone (after
confirming normal G6PD status), pentamidine (iv), or desensitization to TMP-SMX. None of these
alternative programs offer the same broad protection of TMP-SMX. Thus, the decision to
discontinue TMP-SMX must be carefully considered.
D. Herpes Group Virus Prevention
Background: The human herpes viruses (cytomegalovirus, CMV; herpes simplex virus 1
and 2, HSV-1 and HSV-2; Epstein-Barr virus, EBV; varicella-zoster virus, VZV; human herpes virus6, HHV-6; human herpes virus-7, HHV-7; and human herpes virus-8, HHV-8, the putative cause of
Kaposi's sarcoma) are the most important causes of infectious disease morbidity and mortality in
the transplant recipient. CMV is responsible for direct causation of infectious disease syndromes
(e.g., mononucleosis, pneumonia, gastrointestinal infection, hepatitis, retinitis, etc.). CMV also
causes such indirect effects as a global suppression of host defenses that predisposes to
opportunistic superinfection, a role in the pathogenesis of allograft injury, and increasing the risk
of EBV-associated post-transplant lymphoproliferative disease by 7 to 10 fold. Accordingly,
7
significant effort must be applied to limit the morbidity and mortality caused by these viruses in
general and due to CMV in particular. The different regimens employed are determined by the
clinical risk, the major determinants of which are the past experience of donor and recipient with
the virus (as defined by the presence or absence of circulating antibody prior to transplant) and
the nature of the immunosuppressive therapy that is required.
Regimens:
1. Treatment of Symptomatic CMV Disease:
The standard of care for treating symptomatic CMV disease is a minimum of 2-3 weeks of
oral valganciclovir 900mg po bid for mild to moderate disease or intravenous ganciclovir at a dose
of 5 mg/kg twice daily (with dosage adjustment for renal dysfunction). The end point of
intravenous therapy is the documented clearance of virus from the blood as demonstrated by
two negative CMV quantitative PCR assays a week apart. In seropositive individuals, the risk of
subsequent relapse is ~15-20%, which can be reduced by following intravenous therapy with oral
valganciclovir 450 mg PO qd in renal transplant recipients or 900 mg PO qd in extra renal
transplant recipients (see table below) for 1-3 months. In patients with relapsing infection, CMV
immunoglobulin (at a dose of 150 mg/kg iv once and 100 mg/kg iv q month x 3-6) may be
administered in conjunction with the intravenous ganciclovir therapy in seronegative recipients or
hypogammaglobulinemic individuals. Of great importance, use of oral valganciclovir for
intravenous ganciclovir in the face of high viral loads or severe disease carry a risk for selecting
ganciclovir resistant virus.
Prophylaxis of High Risk Patients: Prophylaxis is achieved with 50% of the therapeutic dose of
valganciclovir (corrected for renal function). The main side effects of these agents include
neutropenia.
8
Dosage Recommendations for Ganciclovir and Valganciclovir in Adult Patients with
Impaired Renal Function
CrCl
Induction Dose
Maintenance/ Prevention Dose
≥70
5.0 mg/kg IV q12 hours
5.0 mg/kg IV q24 hours
50-69
2.5 mg/kg IV q12 hours
2.5 mg/kg IV q24 hours
25-49
2.5 mg/kg IV q24 hours
1.25 mg/kg IV q24 hours
10-24
1.25 mg/kg IV q24 hours
0.625 mg/kg IV q24 hours
<10
1.25 mg/kg IV 3 times a week after
0.625 mg/kg IV 3 times a week after
hemodialysis
hemodialysis
(mL/min)
*After loading dose of 5 mg/kg.
Valganciclovir
CrCl (mL/min)
Induction Dose
Maintenance/ Prevention Dose
≥60
900 mg twice daily
900 mg once daily
40-59
450 mg twice daily
450 mg once daily
25-39
450 mg once daily
450 mg every 2 days
10-24
450 mg every 2 days
450 mg twice weekly
<10
not recommended
not recommended
9
Prophylaxis for Herpes Group Viruses*
Preventative regimens are determined by the clinical risk, the major determinants of which are the past
experience of donor and recipient with the virus (as defined by the presence or absence of circulating
antibody prior to transplant) and the nature of the immunosuppressive therapy.
CMV Universal Antiviral Prophylaxis*
CMV serologic status +/anti-lymphocyte therapy
(ALS)
Therapy
D+/R-
Intravenous ganciclovir 5mg/kg iv for first dose then
per renal function or po valganciclovir (450 mg/d renal,
900/d liver corrected for renal function) x 3 months
D+ or R+
with ALS (i.e.,
thymoglobulin)
Screening
(CMV viral load)
Intravenous ganciclovir 5mg/kg iv for first dose then po
valganciclovir (450 mg/d renal, 900/d liver corrected
for renal function) x 6 months
D-/R+ (no ALS)
Oral Valganciclovir (450 mg/d renal, 900/d liver
corrected for renal function) x 3 months
D-/R-
Oral famciclovir (Famvir) 500 mg po qd x 3-4 months
(can use valacyclovir 500 bid or acyclovir 400 tid if
preferred for insurance reasons)
Status unknown
Intravenous ganciclovir 5mg/kg iv for first dose and QD
(corrected for renal function) until status determined.
NOTE:
All new transplants require TMP-SMZ ss po qd or
alternative (levofloxacin 250/d and atovaquone
(Mepron) 1500/day) for 6 mos. “N’er do wells” - TMPSMZ for life
For higher risk
(D+/R-), consider
weekly for 8-12
weeks after end
of prophylaxis
Symptoms only
Comments:
Use of CMV-negative or leukocyte-filtered blood is recommended in seronegative recipients.
Neutropenia: The dose of antiviral therapies ARE NOT reduced for neutropenia. + ALG:
Valacyclovir (8 gm/d, renally adjusted) has been used as an alternative agent in renal transplant
recipients.
*Preemptive Therapy: Preemptive therapy requires a carefully organized monitoring program
and patient compliance. CMV viral load testing may be used for monitoring. Monitoring
should be performed once weekly after transplantation for 12 – 24 weeks. Infections
10
indicated by positive assays are treated with either oral valganciclovir (900 mg two times a
day) or intravenous ganciclovir (5 mg/kg two times a day). Full doses are used for loading
after which dosing is corrected for renal function. Therapy is continued until viremia is
undetectable.
Mixed Prophylaxis: Many centers prefer universal prophylaxis for highest risk recipients
(D+/R- or R+ with lymphocyte depletion) and preemptive therapy for other groups.
11
E. Antifungal Strategies:
1. Anti-candidal Prophylaxis: This is aimed predominantly at mucocutaneous infection and
can be accomplished by prescribing oral clotrimazole or nystatin 2-3 times per day at a time of high
steroid therapy or in the face of antibacterial therapy. Fluconazole, at a dose of 400 mg/day for 10-14
days is used in the treatment of prophylaxis failures. Routine prophylaxis with fluconazole is used for
pancreas transplants, for biliary surgery (& ERCP), and for HSCT and neutropenic prophylaxis.
Fluconazole is used for technical complications (bleeding, leaks) in advance of culture data.
2. Molds: susceptibility data are required for optimal therapy of molds. Treatment based on
galactomannan (GM) assays has not been routinely useful for solid organ patients and infections due
to non-Aspergillus fungi are common. CT scans are more sensitive than GM assays for diagnosis.
12
D:\681445190.doc