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10

Post-transplant Infections

Although the rates are markedly decreased from previous

decades, infection is the most important cause of early mor-

bidity and mortality following transplantation. Infection is

closely linked to the degree of immunosuppr ession and thus to the fre-

quency and intensity of rejection and its therapy. The potential sources

of infection in the t ransplant patient are multiple, including organisms

from the allograft itself and from the environment. Patients should be

advised to be sensible to possible exposures and to wash their handsthoroughly when exposed to infected individuals or human excre-

ment, specifically, exposures in daycare and occupational settings as

well as during gardening and pet care. In those taking immunosup-

pressive agents, signs and symptoms of infections are frequently blunt-

ed until disease is far advanced. Therefore, due to the unusual nature

of the infections and the lack of t imely symptom development, the key

to patient survival is the prevention of infection. Infections may be

prevented by pretransplant vaccinations, along with prophylactic

medications, preemptive monitoring and behavior modification.

Currently, the most common infectious problems within the firstmonth following transplantation are bacterial infections of the wound,

lines, and lungs. Additionally, herpetic stomatitis is common. Beyond

1 month following transplantation, infections are related to more

intense immunosuppression and include viral, fungal, protozoal, and

unusual bacterial infections. Although hepatitis may occasionally

cause fulminate and fatal disease if acquired peritransplantation, the

manifestations of hepatitis B or hepatitis C infections occur years fol-

lowing transplantation.

Connie L. Davis

C H A P T E R

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10.2 Transplantation as Treatment of End-Stage Renal Disease

FIGURE 10-1

Timetable for the occurrence of infection in t he renal transplantpatient. Exceptions to this chronology are frequent. CMVcytomegalovirus; CNScentral nervous system; EBVEpstein-Barr virus; HSVherpes simplex virus; UTIurinary tract infec-

tion; VZVvaricella-zoster virus. (Adapted from Rubin andcoworkers. [1]; with permission.)

Hepatitis

Bacterial

Conventional Unconventional

CNS

Fungal

Viral

TB Pneumocystis

Aspergillus, nocardia, toxoplasma

WoundPneumonialine-related

Hepatit is B

UTI: bacteremia, pyelitis, relapse UTI:

Cryptococcus

EBV VZV papova adenovirus

CMV onsetHSV

CMVchorioretinitis

Listeria

Relativelybenign

Onset of non-A, non-B hepatit is

Time,mo0

Transplant

1 2 3 4 5 6

CLASSIFICATION OF INFECTIONSOCCURRING IN TRANSPLANT PATIENTS

Infections related t o t echnical complications*

Transplantation of a contaminated allograft, anastomotic leak or stenosis, woundhematoma, intravenous line contamination, iatrogenic damage to the skin,mismanagement of endotracheal tube leading to aspiration, infection relatedto biliary, urinary, and drainage catheters

Infections related t o excessive nosocomial hazard

Aspergillus species,Legionella species,Pseudomonas aeruginosa, and other gram-negative bacilli ,Nocardia asteroides

Infections related to particular exposures within t he community

Systemic mycotic infections in certain geographic areas

Histoplasma capsulatum,Coccidioides immitis,Blastomyces dermatitidis,Strongyloides stercoralis

Community-acquired opportunistic infection result ing from ubiquitous saphro-phytes in the environment

Cryptococcus neoformans,Aspergillus species, Nocardia asteroides,Pneumocystis carinii

Respiratory infections circulating in the community

Mycobacterium tuberculosis, inf luenza, adenoviruses, parainfluenza, respiratorysyncytial virus

Infections acquired by the ingestion of contaminated food/water

Salmonella species,Listeria monocytogenes

Viral infections of particular import ance in transplant patients

Herpes group viruses, hepatit is viruses, papillomavirus, HIV

*All lead to infection with gram-negative bacilli, Staphylococcusspecies, and/orCandida species.

The incidence and severity of these infections and, to a lesser extent, the otherinfections listed, are related to the net state of immunosuppression present ina particular patient.

FIGURE 10-2

Classifications of infections occurring in transplant patients.

(Adapted from Rubin [2]; with permission.)

Period of prophylaxis Timing of infectionBacterial (mean 60 days)

CMV (mean 70 days)

Non-CMV viral (mean 145 days)

Fungal (mean 163 days)

Months after transplant

Patients,n

0

10

20

30

40

50

1 2 3 46 712

FIGURE 10-3

Timing of infections following kidney/pancreas transplantationat a single transplantation center using antiviral (ganciclovir IVfollowed by acyclovir) and antibacterial (trimethoprim-sul-famethoxazole) prophylaxis. CMVcytomegalovirus. (FromStratta [3]; with permission.)

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10.3Post-transplant Infections

INFECTIOUSDISEASE HISTORY TO BE TAKEN PRIOR TO TRANSPLANTATION

1. Past immunizations.

2. Past infections or exposures to infections.

A.BacterialRheumatic fever, sinusitis, ear infections, urinary tract infections, pyelonephritis, pneumonia, diverticulitis, tuberculosis

B. ViralMeasles, mumps, varicella, rubella, hepatit is

3. Chronic or recurrent infections, such as pneumonia, sinusitis, urinary tract infection, or diverticulitis4. Surgical history, such as splenectomy

5. Transfusion or previous transplant history and dates

6. Past travel history, including military service

7. Past immunosuppressive drug treatment (eg, for asthma, renal disease, or rheumatologic disease)

8. Lifestyle

A.Smoking, drinking, ill icit drug use, marijuana smoking

B. Sexual partners, orientation, unprotected contact and date, safety practices used, sexually t ransmit ted diseases,genital warts

C.Food, consumption of raw fish or meat, consumption of unpasteurized products, such as milk, cheese, fruit juices,or tofu

D.Avocationgardening and the use of gloves, cleaning sheds, hiking, camping, water sources, bathing pets, cleaningpet litter and cages, hunting practices

E. Vocationjobs that require exposure to possible infectious agents, such as daycare, ministry, small closed offices,garbage collections or dump workers, construction workers, forestry workers, health care, veterinarians, farmers

FIGURE 10-4Infectious disease history to be taken priorto t ransplantation.

Preventive Strategies

PRETRANSPLANT VACCINATIONSOR BOOSTERSTOBE GIVEN TO ALL TRANSPLANT RECIPIENTSUNLESSRECENT ADMINISTRATION CAN BE DOCUMENTED

1. Td (Tetanus toxoid, diphtheria)

2. Pneumococcal vaccine

3. Hepatitis B

4. Influenza

PRETRANSPLANT VACCINATIONSTO BE GIVEN IFSERONEGATIVE OR PAST INFECTION BY HISTORYCANNOT BE DOCUMENTED

1. Measles-mumps-rubella vaccine

2. Polio

3. Varicella (0.5 mL subcutaneously followed by booster of 0.5 mL in 48 weeks)4. Haemophilus influenzatype B

FIGURE 10-5

Pretransplant vaccinations or boosters to be given to all transplant

recipients unless recent administrat ion can be documented.

FIGURE 10-6

Pretransplant vaccinations to be given if seronegative or pastinfection by history cannot be documented.

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FIGURE 10-7

Inactivated vaccines that are considered safe and ma y be given asneeded post-transplant for anticipated exposure.

INACTIVATED VACCINESTHAT ARE CONSIDERED SAFEAND MAY BE GIVEN ASNEEDED POST-TRANSPLANTFOR ANTICIPATED EXPOSURE

1. Anthrax

2. Cholera

3. Rabies vaccine absorbed

4. Human diploid cell rabies vaccine

5. Inactivated typhoid vaccine, capsular polysaccharide parenteral vaccine,or heat phenol-treated parenteral vaccine

6. Japanese encephalit is virus vaccine

7. Meningococcal vaccine

8. Plague vaccine

VACCINESTHAT MAY NOT BE GIVEN(LIVE ATTENUATED VACCINES)

1. Bacille Calmette-Gurin (BCG)

2. Measles

3. Mumps

4. Rubella

5. Oral polio

6. Oral t yphoid

7. Yellow fever

FIGURE 10-8

Vaccines that may not be given include live attenuated vaccines.

A. DOSAGE AND ADMINISTRATION GUIDELINESFOR VACCINESAVAILABLE IN THE UNITED STATES

Vaccine

DT

Td

DTP

DTaP (Acel-Imune)

DTP-HbOC (Tetramune)

Haemophilus B, conjugate vaccineProHIBit (PRP-D), manufactured by

Connaught Laboratories

HibTITER(HbOC), manufactured byPraxis Biologicals

PedvaxHib (PRP-OMP), manufacturedby MSD

Hepatit is B

Infants born to HBsAg-negative

mothers and children < y[ ]Recombivax HB (MSD)

Engerix-B (SKF)

Dosage

0.5 mL

0.5 mL

0.5 mL

0.5 mL

0.5 mL

0.5 mL0.5 mL

0.5 mL

0.5 mL

2.5 g (0.25 mL)

10 g (0.5 mL)

Route of administration

IM

IM

IM

IM

IM

IMIM

IM

IM

IM in the anterolateral thigh or inthe upper arm; SC in individualsat risk of hemorrhage

Type

Toxoids

Toxoids

Diphtheria and tetanustoxoidswith killedB. pertussis organisms

Diphtheria and tetanus toxoids with acellular pertussis

Diphtheria and tetanus toxoids with killedB. pertussisorganisms andHaemophilusb conjugate (diphtheriaCRM197 protein conjugate)

Polysaccharide (diphtheria toxoid conjugate)

Oligosaccharide (diphtheria CRM protein conjugate)

Polysaccharide (meningococcal protein conjugate)

Yeast recombinantderived inactivated viral antigen

(Continued on next page)

FIGURE 10-9

AD, General immunization guidelines. H BOChaemoph ilus Binfluenzaediphtheria protein conjugate vaccine, oligosaccharide;IDintrad ermal; IMintram uscularly; DTdiphtheria t etanus;DTPdiphtheria tetanus pertussis; MMRmeasles mumpsrubella; MRmeasles rubella; MSDMerck Sharpe & Dohme;

PRP-Dhaemophilus Bdiphtheria toxoid conjugate vaccine,polysaccharide; PRP-OMPhaemophilus influenzae typebmeningococcal protein conjugate vaccine; SCsubcutaneous;SKFSmithKline and French; Tdtetanus, diphtheria. (FromIsada and coworkers [4]; with permission.)

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B. DOSAGE AND ADMINISTRATION GUIDELINESFOR VACCINESAVAILABLE IN THE UNITED STATES

Vaccine

Recombivax HB (MSD)

Engerix-B (SKF)

Children 1119 y

Recombivax HB (MSD)

Engerix-B (SKF)

Adults > 19 y

Recombivax HB (MSD)

Engerix-B (SKF)

Dialysis patients and immunosuppressed patients

Recombivax HB (MSD)

Engerix-B (SKF)

Dosage

5 g (0.5 mL)

10 g (0.5 mL)

5 g (0.5 mL)

20 g (1 mL)

10 g (1 mL)

20 g (1 mL)

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D. DOSAGE AND ADMINISTRATION GUIDELINESFOR VACCINESAVAILABLE IN THE UNITED STATES

Vaccine

Meningococcal

MMR

MR

Mumps

Pneumococcalpolyvalent

Poliovirus (OPV)trivalent

Poliovirus (IPV)trivalent

Rabies

Rubella

Tetanus (adsorbed)

Tetanus (fluid)

Yellow fever

Dosage, mL

0.5

0.5

0.5

0.5

0.5 (2 y)

0.5

0.5

1

0.5 (12mo)

0.5

0.5

0.5

Route of administration

SC

SC

SC

SC

IM or SC (IM preferred)

Oral

SC

IM , ID

SC

IM

IM, SC

SC

Type

Polysaccharide

Live virus

Live virus

Live virus

Polysaccharide

Live virus

Inactivated virus

Inactivated virus

Live virus

Toxoid

Toxoid

Live attenuated virus

Children 615 months in epidemic situations:Dose is given at the time of first contact wit h a health care provider;children

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PRETRANSPLANT BACTERIAL SEROLOGIES

SerologyRPR(Rapid plasma reagin)

PPD

ModificationIf positive, check with a treponemal specific testFluorescent treponemal antibody

absorbed test (FTA-ABS) or microhemagglutination assay for t reponema pallidum(MHA-TP)

If positive the general recommendation without documented previous treatment afterfirst evaluating a chest radiograph is isoniazid 300 mg/d to continue for 6 months or9 to 12 months post-transplant

FIGURE 10-11

Pretransplant bacterial serologies.

EFFECT AND POSSIBLE EFFECTSOF PROPHYLACTIC ANTIVIRAL STRATEGIES

No treatment

Risk: HSV

CMV

VZV

EBV

Adenovirus HHV6

HHV8

Acyclovir orally 3M

HSV

Slight CMV

VZV

Slight EBV

No change in adenovirusSlight HHV6

Slight HHV8

Ganciclovir IV acyclovir PO 3M

HSV

Slight CMV

VZV

EBV

?AdenovirusSlight HHV6

Slight HHV8

CMVIgG 5 doses

?Effect

Slight CMV

?Effect

?Effect

?Effect?Effect

?Effect

Ganciclovir 3M PO

HSV

CMV

VZV

EBV

?Slight in adenovirus? HHV6

? HHV8

FIGURE 10-12

Effect and possible effects of prophylactic antiviral strategies. CMVcytomegalovirus; EBVEpstein-Barr virus; HHV6human herpes

virus 6; HHV8human herpes virus 8; HSVherpes simplex; VZVvaricella zoster. Q uestion markindicates question as to the effect.

PROPHYLACTIC ANTIBACTERIAL AND ANTIPROTOZOAL STRATEGIES

Type of infection

Wound

Urinary tract

Legionella

Pneumocystis

Toxoplasmosis

Nocardia

Listeria monocytogenes

Treatment perioperatively or postoperatively

Against uropathogens and staphylococci, eg, ampicill in-sulbactam, cefazolinplus aztreonam 24 to 48 hours adjusted for renal function

Risk urinary leak, hematoma, lymphocele

Common choices

Trimethoprim sulfamethoxazole

Ciprofloxacin

Cephazolin

Ampicillin

Duration of treatment varies

An important factor is the presence of the urinary catheter






FIGURE 10-13Prophylactic antibacterial/antiprotozoal strategies.

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PREVENTION OF RESPIRATORY INFECTIONSIN THE IMMUNOSUPPRESSED PATIENT

Infection

Pneumococcal pneumonia

Influenza illness

Haemophilus influenzae

Tuberculosis

Mycobacterium avium complex illness

Pneumocystis carinii pneumonia

CMV pneumonia

Legionella pneumonia

Aspergillosis

Candida illness

Cryptococcosis

Histoplasmosis

CoccidioidomycosisStrongyloidiasis

Options for prevention

Pneumococcal vaccination; oral penicillin prophylaxis; passive prophylaxis with immune globulin

Annual influenza vaccination; amantadine or rimantadine prophylaxis (for influenza A virus only)

H. influenza type B vaccination

Case finding and early treatment; infection control procedures; preventive therapy with isoniazid

Rifabutin prophylaxis

Prophylaxis with oral trimethoprim-sulfamethoxazole or aerosolized pentamidine

Use of CMV-seronegative organs and blood products for CMV-seronegative recipients; passive prophylaxis withCMV immune globulin; prophylaxis with antiviral agents (acyclovir, ganciclovir)

Identification of source; institution of control measures associated with potable water, such as hyperchlorination,maintenance of hot water t emperature above 50C (122F)

Use of HEPA filter to minimize airborne spores; avoidance of decaying leaves and vegetation

Prophylaxis with antifungal agents

Avoidance of pigeons and pigeon droppings; prophylaxis with antifungal agents

Complete travel history to identify patients at risk; avoidance of areas of high exposure toHistoplasma; formalintreatment of infected soil

Complete travel history to identify patients at risk; avoidance of areas of high exposure to Coccidioides immitisComplete travel history to identify patients at risk; ova and parasite analysis of stool specimen in patients at risk;

thiabendazole prophylaxis

FIGURE 10-14

Prevention strategies for the prevention of pulmonary infection. CMVcytomegalovirus;HEPAhigh-efficiency particulate air. (Adapted from Maguire and Wormser [5]; with permission.)

Prevention Strategies

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PASSIVE IMMUNIZATION AGENTSIMMUNE GLOBULINS

Immune globulinHepatit is B (H-BIG*)

Percutaneous inoculation

Perinatal

Sexual exposure

Immune globulin (IG)

Hepatit is A prophylaxis

Hepatit is B

Hepatit is CMeasles

Rabies

Tetanus (serious, contaminated, wounds;3 mo or continuous exposure) repeat every 46 mo

0.06 mL/kg/dose (H-BIG should be used)

0.06 mL/kg/dose (percutaneous exposure)0.25 mL/kg/dose (max 15 mL/dose) (within 6 d of exposure)

0.5 mL/kg/dose (max 15 mL/dose) (immunocompromised children)

20 IU/kg/dose (within 3 d)

250500 units/dose

Within 48 hours but not later than 96 hours after exposure

010 kg 125 units = 1 vial

10.120 kg 250 unit s = 2 vials



>40 kg 625 units = 5 vials

RouteIM

IM*

IM

IM

*Deep IM in the gluteal region for large doses only. Deltoid muscle or the anterolateral aspect of the thigh are preferred sites for injection. No greater than 5 mL/site in adult s or largechildren; 13 mL/site in small children and infants. Maximum dose: 20 mL at one time.

IG prophylaxis may not be indicated in a patient who has received IGIV within 3 weeks of exposure.1/2 of dose used to infiltrate the wound with the remaining 1/2 of dose given IM Rabies immune globulin is not

recommended in previously HDCV immunized patients.No greater than 2.5 mL of VZIG/one injection site. Doses >2.5 mL should be divided and administered at different sites.

FIGURE 10-15

Passive immunization a gents for prevention po stexposure.HBIGhepatitis B immune globulin; H DCVhuman d iploidcell rabies vaccine; IGimmune globulin; IGIVintravenous

immune globulin; IMintram uscularly; VZIGvaricellazoster immune globulin. (From Isada and coworkers [4];with p ermission.)

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FIGURE 10-16

Live virus vaccinations generally not given totransplant patients. IGimmune globulin;OPVpoliovirus vaccine live ora l. (FromIsada and coworkers [4]; with permission.)

CH3COOCH3COO

6H2O

H2N

N

N

N

N

(CH3)CH

H2N

HN

N

O

N

N

O

N

N

O

S

NH2

HOCH2

OO

OH

OCH2P(OH)22H2O

OH O

OCC

O

O

O

O

O

CP

NH3Cl+

3Na+

N

N H2N

HN

N

O

O

HO

N

N HN

HN

N

O

O

HOOH

N

N

FamciclovirPenciclovir

PhosphonoformicacidFoscarnet Cidofuvir Lamivudine

Valacyclovir Acyclovir GanciclovirAcyclovir

Oral bioavailability:Excretion:

Plasma t1/ 2:

Intracellular t1/2:

Antiviral spectrum:

77%100%* R

23 h

720 h

HSV/V2V/EBV

54%100%liver/GI

23 h

0.71 h

HSV/V2V/EBV

15%100%* R

23 h

0.71 h

HSV/V2V/EBV

2%7%91%unchanged urine

23 h

6 h3 wk

HHV8, CMV, adeno, HBV

Administration:

t1/2:

Tissue t1/ 2:

Metabolism:

IV

26 h

87.541.8 h

100%renal excretion

IV

34 h

1765 h

85%renal excretion

86%oral bioavailabili ty

57 h

1015 h

70%90%renal excretion

A

B

FIGURE 10-17

Antiviral agents.Asterisk indicates excreted unchangedin the u rine; all antivirals are subject to changes in t1/2with chan ging renal function. Adenoadenovirus;

GUIDELINESFOR SPACING THE ADMINISTRATION OFIMMUNE GLOBULIN (IG) PREPARATIONSAND VACCINES

Immunobiologic combinations

Simult aneous administr ation

IG and killed antigen

IG and live antigen

First

IGKilled antigen

IG

Live antigen

Nonsimult aneous administrati on

Second

Killed antigenIG

Live antigen

IG

Recommended minimum interval between doses

None. May be given simultaneously at different sites or at any timebetween doses.

Should generally not be given simultaneously. If unavoidable to do so,give at different sites and revaccinate or test for seroconversion in3 months. Example: MMRshould not be given to patientswho havereceived immune globulin within the previous3 months.

NoneNone

6 wk, and preferably 3 mo

2 wk

*The live virus vaccines, OPV, and yellow fever are exceptions to these recommendations. Either vaccine may beadministered simultaneously or any time before or after IG without significantly decreasing antibody response.

CMVcytomegalovirus; EBVEpstein-Barr virus;HH V8human herpesvirus 8; HSVherpes simplex virus;VZVvaricella-zoster virus.

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Drug-P1

GP1

R1

R1

R2

R2

Famciclovir

viral

thymidinekinase

Drug P2cell

kinase

cell

(no viral enzymes needed)

kinase

cellularenzymes

GP2

CP2

cell

kinaseGP3

cell

kinase

Drug P3 viralDNAPolymerase

viralDNAPolymerase

cell

kinase

Cidofovir

Valacyclovir

car v UL97

gene productautophosphorylatingprotein kinase

Ganciclovir

Acyclovir

FIGURE 10-18

Antiviral activation and action (acyclovir, vala-

cyclovir, famciclovir, ganciclovir). Resistance

(R) to ant ivirals has been found at the level

of viral thymidine kinase (R1) and DNA po ly-

merase (R2). Ganciclovir is monophosphory-

lated in cytomegalovirus (CMV)-infected cells

by the CMV UL97 gene product. Acyclovir,

valacyclovir, and famciclovir are not easily

phosphorylated in CMV-infected cells.

Cidofovir does not require viral enzymes to be

phosphorylated to the active diphosphonate.

DRUG INTERACTIONSBETWEEN ANTIVIRALS, ANTIFUNGALS,ANTIBACTERIALS, ANTIMYCOBACTERIALS, AND ANTIPROTOZOALSWITH CYCLOSPORINE AND FK506

Drug

Antifungals

Amphotericin B

Clotrimazole troches (more in FK506)

Ketoconazole (keto>itra>fluconazole)

GriseofulvinAntibacterial

Clarithromycin

Doxycycline

Erythromycin

Gentamicin

Nafcillin

Rifampin

Rifabutin

Sulfamethoxazole/trimethoprim

Ticarcillin

AntimycobacterialIsoniazid

Pyrazinamide

Antiparasitic

Chloroquine

Effect on CSA/ FK506

Nephrotoxicity of combination

FIGURE 10-19

Drug interactions between antivirals,antifungals, antibacterials, antimycobacte-rials, and antiprotozoals with cyclosporineand FK506. (From Lake [6] and Yee [7];with permission.)

INFECTIONSTRANSMITTED TO TRANSPLANT RECIPIENTSVIA THE DONOR ORGAN

Virus

HIV, cytomegalovirus,herpes simplex virus,Epstein-Barr virus,hepatitis B virus,hepatitis C virus,hepatitis D virus, ?

hepatitis G virus,adenovirus (?), parvovirus (?),papillomavirus, rabies,Creutzfeldt-Jakob

Bacteria

Aerobe (gram posit ive),aerobe (gram negative),anaerobes,Mycobacteriumtuberculosis, atypicalmycobacteria

Fungi

Candida albicans, Histoplasma capsulatum,Cryptococcus neoformans,

Marosporium apiospermum

Parasitic

Malaria toxoplasmosis,trypanosomiasis,strongyloidiasis

FIGURE 10-20

Infections transmitted to transplant recipientsvia the donor organ.

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FIGURE 10-21

The lifecycle of cytomegalovirus (CMV). The envelope binds withthe cell membrane, and the DNA is uncoated and transferred intothe nu cleus, where cell protein synthesis machinery is used to man -ufacture new DNA and capsid. The DNA is packaged into the cap-sid and returns to the cytoplasm, where the tegument and envelopeare assembled around the capsid and the whole virus transportedto the cellular surface and released.

Envelope

Tegument

Capsid

Attachment andpenetration

Release ofviral DNA

Egress

UncoatingCytoplasm

Nucleus

TranscriptionProtein synthesis

Replication

IEE

LDNA

Scaffold Assembly Packaging

Cytomegalovirus

CMV is a double-stranded DNA virus that causes disease fol-lowing transplantation after primary infection, reinfection, or reac-tivation o f latent infections. CMV disease is seen most frequent lywithin the first 4 to 6 months of transplantation if no antiviralprophylaxis is used; however, in th e presence of ant iviral pro phy-laxis and new immunosuppressive agents, the onset of CMV dis-ease may be shifted to longer intervals from transplantation. Therealso may be a slight increase in the occurrence of CMV enteritiswith the use of some of the newer combinations of immunosup-pressive agents. When the recipient is CMV positive and receivesan organ from a CMV-positive donor, reactivation of the latent

infection in the recipient is responsible for 15% to 30% of theinfections seen, and reinfection with the virus from the donor isresponsible for 70%.

CMV d isease prevention may be accomplished by administeringproph ylactic antiviral agents or by the use of rout ine surveillancetesting. Variables to be considered in an individuals risk of CMVdisease development are the use of a ntilymphocyte medications,and the donor and recipient, CMV serostatus. The highest riskgroup for CMV disease is the group at risk for primary CMVexposure and those given antilymphocyte preparations. Specifically,increased CM V disease is seen during situations that trigger viralreplication. H igh levels of tumor necrosis factor alpha, such aslevels occurring during infections or after O KT3 administrat ion,activate the CMV promoter, thus stimulating the conversion fromthe latent to the reactivated state.

All of the prophylactic strategies for the pr evention of CM Vdisease have shown some benefit in different studies; currently,however, the most effective approach is oral ganciclovir. A morebioavailable oral ganciclovir may even increase the effectivenessand is now under investigation. Oral ganciclovir is started whenthe patient is able to take oral medications within the first week

following transplantation and is administered at a dose of 1 g 3times a day for 3 months following transplantation adjusted forrenal function. The pro tective effect is also seen in those who havereceived a ntilymphocyte preparations. The most desirable solutionwould be a vaccine that induced natural immunity mechanisms.Vaccines targeted against th e structural glycoproteins of CM V arecurrently continuing under development but are not yet available;their ultimate effectiveness is not known at this time. As patientswho already have had natural infections are not immune to reinfec-tion or reactivation, a vaccine solution may not be possible.

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MANIFESTATIONSOF CMV DISEASE IN RENALTRANSPLANT RECIPIENTS

CMV disease

A. Syndrome: fever, leukopenia, malaise, lack of anot her cause

B. Organ specific: hepatitis, enterit isduodenum, colon; pancreati tis; pneumonit is;interstitial nephritis, retinitis

C. Risk of CMV disease by donor

D/R

D+R-

D+R+

D-R+

D-R-

Infection*

70%100%

50%80%

Disease

56%80%

27%39%

0%27%

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RANDOMIZED TRIALSEVALUATING CMV PROPHYLACTIC STRATEGIESADMINISTERED DURING THE TIME OF GREATEST RISK FOR CMV DISEASE

Author

Metsellar

Steinmuller

Teuschert

Snydman*

Boland

Drug

IgG

Induction or RejectionAntilymphocyte

ATG-rej

ALG/OKT3

None

Some

None

Serostatus

All patients

R+

D+R-

D+R-

D+R-

n

20

18

18

35

11

CMV Disease

30%

39%

100%

60%

18%

n

19

16

18

24

11

CMV Disease

37%

13%

20%

21%

27%

Dosing

Cytotec, 6 doses

Sandoglobulin, 5 doses

Cytotec, 11 doses

Cytotec

Cytotec, 5 doses

*Antilymphocyte serum was given to two globulin and eight control patients as induction therapy and four globulin and seven control patients as antirejection therapy.

BalfourAcyclovirPO ALG All patients

Subgroups

D+R-

D+R+

51

7

8

29%

100%

38%

53

6

9

8%

17%

11%

Acyclovir800 mg po qid x 3 months

Rondeau

Conti

Hibberd

Brennan

Ganciclovir ATG/OKT3

Antilymphocyte

OKT3

ATG

D+R-

R+

R+

D+or R+

15

18

49

23

73%

56%

33%

61%

17

22

64

19

47%

9%

14%

21%

Ganciclovir 5 mg/kg bidIV d1428

Ganciclovir with antilymphocytedrug 2.5 mg/kg/IV bid

Ganciclovir 2.5 mg/kg/dduring ALG

Oral ganciclovir 1 g tid

SquilletValacyclovir NA R+ 204 10.8% 204 0% 2 g qid

TreatedControl

FIGURE 10-25

Randomized t rials evaluating cytomegalovirus (CMV) prophylactic strategiesadministered during the time of greatest risk for CMV d isease.

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FIGURE 10-26

The prevention of cytomegalovirus (CMV)disease. This figure shows the different strate-gies for the management of CMV-positivetransplant recipients or recipients of CM V-

positive organs.

Preemptive treatment

The "prevention" of CMV disease

* Different laboratories have different thresholds for clinically significant posit ive tests.The most costly approach.The most convenient and effective. Both ganciclovir and acyclovir are adjusted for

renal function.

a.

No testing orantiviral therapyWait for infection

b.

c.

d.

Antiviral prophylaxis

CMV antigenemiatesting or PCRtesting weekly startingthe third or fourthpostoperative week

For all CMV D+ R,D+ R+, DR+ the followinghave been employed

CMV D+

CMV R+

po ganciclovir1 g tid 3 months

Oral high dose acyclovir800 mg po qid 3 months

Pooled IV IgG or CMVhyperimmune globulin

IV ganciclovir posttransplant only or followed

by oral acyclovir for 3months

()*or low titer

positive-dependingon the laboratory

threshold

Continuesurveillance

(+)Treat with

IV ganciclovir5 mg/kg bid adjusted

for renal function 1014 d

DETECTION OF CMV DISEASE AND INFECTION

Antibodies: the development of IGM anti-CMV antibodies, a four fold or greater increase in IgG titers

Culture:

A. Standard culture in a f ibroblast monolayerResults may require up to 6 wk

B. Shell vial culturesthe buffy coat is centrifuged onto fibroblasts increasing fibroblast infection. Viral infectionis detected by applying a monoclonal antibody directed against the 72-Kd major immediate early protein ofCMV. RBCs in the buffy coat may be toxic to the monolayer result ing in a false-negative test. Urine and BALspecimens may be positive without predict ing disease. Result s are available in 16 to 36 h.

Other:

A. AntigenemiaGranulocytes and monocytes are isolated and stained with a monoclonal antibody against amatrix, tegument protein pp65 (structural late protein). Culture is not required, granulocytes and mono-cytes from the buffy coat are stained, testing results are available in 4 to 6 h. It may be argued that thepositivity may not be due to replicating virus in the WBCs but due to exogenous acquisition from infectedendothelial cells. The number of antigen positive cells per unit number of WBC counted that determinesthe onset of symptomatic diseases depends upon the individual laboratory; however, usually over 10 posi-

tive cells per 105 WBC precede the onset of symptoms by approximately 1 week.B. Polymerase chain reactionFor the detection of CMV DNA in whole blood or serum. CMV DNA is amplif ied

from whole blood or serum. The sensitivity and predictive value depend on the laboratory.

FIGURE 10-27

Detection of cytomegalovirus (CMV) diseaseand infection. BALbronchoalveolarlavage; RBCred blood cell;WBCwhite blood cell.

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SOME ANTITUBERCULOSISDRUGS

Drug

Primary antituberculous therapy

Isoniazid* (I.N.H., and others)

Rifampin*(Rifadin, Rimactane)

Pyrazinamide

Ethambutol(Myambutol)

Other Drugs

Capreomycin (Capastat)

Kanamycin (Kantrex, and others)

Streptomycin**

Cycloserine (Seromycin, and others)

Ethionamide (Trecator-SC)

Ciprofloxacin (Cipro)

Ofloxacin (Floxin)

Adult dosage (daily)

300 mg

600 mg

1530 mg/kg

15 mg/kg (about 1 g)

15 mg/kg IM or IV

15 mg/kg IM

250500 mg bid

250500 mg bid

500750 mg bid

200400 mg q12h or

400800 mg/day

Pediatric dosage (daily)

1020 mg/kg (max. 300 mg)

1020 mg/kg (max. 600 mg)

same as adult

same as adult

1530 mg/kg

1530 mg/kg

2040 mg/kg IM

1520 mg/kg

1520 mg/kg

Not recommended

Not recommended

Main adverse effects

Hepatic toxicity

Hepatic t oxicity, flu-like syndrome

Hepatic toxicity, hyperuricemia

Optic neuritis

Auditory and vestibular toxicity, renal damage

Auditory toxicity, renal damage

Vestibular toxicity, renal damage

Psychiatric symptoms, seizures

Gastrointestinal and hepatic toxicity

Nausea

Nausea

*Rifamate (containing rifampin 300 mg plus isoniazid 150 mg) is also availableCan be given orally or parenterally. Pyridoxine should be given to prevent neuropathy in malnourished or pregnant patients and those with alcoholism or diabetes. For intermittent use

after a few weeks to months of daily dosage, the dosage is 15 mg/kg twice/wk (max. 900 mg).Available orally or int ravenously. For intermittent use after a few weeks to months of daily dosage, the dosage is 600 mg twice/wk.For intermit tent use after a few weeks to months of daily dosage, the dosage is 4050 mg/kg twice/wk (max. 3 g).Daily dosage should be 25 mg/kg/d if organism isoniazid-resistant or during first 1 to 2 months; decrease dosage if renal function diminished. For intermittent use after a few weeks to

months of daily dosage, the dosage is 50 mg/kg twice/wk.

**Temporarily not available in the United States.For patients > 40 years old, 500 to 750 mg/d or 20 mg/kg twice/wk; decrease dosage if renal funct ion is diminished. Some clinicians change to lower dosage at 60 rather than

40 years of age.Some authorit ies recommend pyridoxine 50 mg for every 250 mg of cycloserine to decrease the incidence of adverse

psychiatr ic effects.

FIGURE 10-28

The treatment of tuberculosis (TB) depends on the clinical presen-tation. Pretransplant prophylaxis for a positive purified proteinderivative, if given, is with isoniazid 300 mg/d up to, or following,transplantation. Post-transplant treatment is more accepted, butdue to the possible high rate of hepatotoxicity, many centers havechosen not to administer prophylaxis. Treatment of pulmonarydisease should include at least two to three drugs (depending onresistance patterns in the area) for 6 to 9 months. Treatment of

Tuberculosis

disseminated disease or extrapulmonary disease should includethree or four drugs for 12 t o 18 months. When starting treatmentwith isoniazid and rifampicin, care should be taken to increase theglucocorticoid dose twofold and the cyclosporine by threefold tofivefold. This is because rifampicin (and somewhat isoniazid)induces the metabolism of steroids and cyclosporine and FK506through the P450 cytochrome system. (Adapted from Med Lett

Drugs Ther[8]; with permission.)

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DIAGNOSTIC TECHNIQUESFOR PNEUMOCYSTISCARINII INFECTION

Technique

Routine sputum

Induced sputum

Transtracheal aspiration

Gallium scan

Bronchoalveolar lavage (BAL)

BAL/brushing

BAL/t ransbronchial biopsy

Open lung biopsy

Needle aspirate

Yield

Poor

30%75%

Fair (with experience)

Nonspecific

>50%(>95%in AIDS)

As for BAL alone

Over 90%(all patients)

Over 95%(all patients)

Up to 60%

Complications

Rare

Rare

Common: bleeding; subcutaneous air

Injection site

Bleeding, aspiration fever, bronchospasm

As for BAL

See BAL; pneumot horax

Anesthesia, air leakage, altered respiration,wound infection

Pneumothorax, bleeding

Comments*

Cultures needed

First choice; excellent in AIDS

Rarely worthwhile

Posit ive in >95%of infected patients

Wedged terminal BAL with immunofluorescence

Not useful for P. carinii

Impression smears; cultures/pathology

Gold standard noninfectious/infectious processes;large sample

Best in localized disease

*All samples should be cultured and stained for bacteria (including mycobacteria), fungi, viruses, and examined for protozoa. Opt imal procedures depend on the locally available expert ise.

FIGURE 10-29

Diagnostic techniques for Pneumocystis carinii infection.(Adapted from Fishman [9]; with permission.)

Protozoal/Parasitic Infections

THE TREATMENT OF PNEUMOCYSTISCARINII

Agent(s) (route)

Trimethoprim

and sulfamethoxazole(TMP-SMZ) (IV/po)

Pentamidineisethionate (IV)

Dapsone (po) withTMP (po/IV)

Clindamycin (IV/po)and primaquine

Trimetrexate (IV) wit hfolinic acid (po)(leucovorin)

Pyrimethamine (po)

with sulfadiazine

Atovaquone (po)

Dose

15 mg/kg/d TMP (to 20)

75 mg/kg/d SMZ (t o 100)

4 mg/kg/d300 mg/d maximum

100 mg/d1520 mg/kg/d (900 mg)

600900 mg q 6 h1530 mg base po qd

3045 mg/m2/d80100 mg/m2/d

Load 50 mg bid x 2 d,then 2550 mg qd

Load 75 mg/kg, t hen100 mg/kg/qd

750 mg po tid

Options

Treat through rash: reduce TMP or SMZ by

one half; desensit ize

Lower dose (23 mg/kg); IM not advised

Methemoglobinemia; G6PD;maybe tolerated in sulfadiazine allergy

Methemoglobinemia; diarrhea(pyrimethamine for primaquine)

Leukopenia, anemia;thrombocytopenia; relapse common

Not studied fully

Maximum 4 g in t wo doses; up to 8 g

Variable absorbance, improvedwith fatty food; rash

* Adjunctive therapies(see text); corticosteroids (high dose with rapid taper); possibly interferon gamma;granulocyte-macrophage colony-stimulating factor.

Based on clinical judgment of physicians; some agents are not approved by t he Food and Drug Administrationfor this indication.

FIGURE 10-30

The treatment ofPneumocystis cariniiinfection. (Adapted from Fishman [9];with permission.)

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ANTIBIOTIC THERAPY FOR TOXOPLASMAGONDII INFECTION

Drug

Pyrimethamine

Sulfonamide

Clindamycin

Spiramycin

Dose100 mg po x 2

(then) 25 mg50 mgpo, qd, or qod

Sulfadiazine 4 g po(then 11.5 g po qidor tri-sulfapyridine;(75100 mg/kg/d)

6001200 mg IV or600 mg po q6h

1 g po tid or qid

DurationLoad36 wk

36 wk

36 wk

36 wk

CommentsBone marrow suppression;

may give folinic acid 5 mg po/imqod except leukemia

Decrease dose for neutropenia;sulfa allergy common

Slower resolution thanwith sulfa;C. difficile colitis

In pregnancy or sulfa allergy with

pyrimethamine; CNSdata limited

*Active infection: twice weekly blood counts are necessary to detect bone marrow suppression resulting from therapy.Lifelong prophylaxis after acute infection is recommended in transplant and AIDSpatients.

Investigational: trimetrexate, atovaquone, macrolides, gamma interferon.

FIGURE 10-31

Antibiotic therapy for Toxoplasma gondiiinfection. (Adapted from Fishman [9];with p ermission.)

FIGURE 10-32(see Color Plate)

Candida esophagitisseen on esopha-gogastroduo-denoscopy.

Yeast and Fungal Infections

FIGURE 10-33(see Color Plate)

Endoscopic view ofsevere esophagitis.

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FIGURE 10-34 (see Color Plate)

Displayed ar eAspergillus as fungus balls, which ar e proliferatingmasses of fungal hyphae. The hyphae are septute, 5 t o 10 mthick, and branch at acute 40 angles. Aspergillus frequentlyinvades blood vessels, causing hemorrhage and necrotizing

inflammation with do wnstream infarction. This image showsthree fungus balls in the lung (Gomori-Ammon stain for fungi).

TREATMENT OF FUNGAL INFECTIONSIN THE SOLID-ORGANTRANSPLANT RECIPIENT BY CATEGORY OF INFECTION

Category of infection

Mucocutaneous candidiasis

Candiduria

Invasive candidiasis

Life-threatening

Catheter-associated

Less-ill, sensitive organism

Aspergillosis

Mucormycosis,Phaeohyphomycosis,

HyalohyphomycosisCryptococcosis

Histoplasmosis,Coccidioidomycosis,Blastomycosis

Pneumocystis carinii

Prophylactic

Nystatin (oral)

?Itraconazole

TMP/SMX

Preemptive

Fluconazole*

Itraconazole

Fluconazole

Itraconazole

Definitive

Fluconazole

Amphotericin B bladder irrigation;Fluconazole

Amphotericin B (0.51.0 mg/kg)+/ flucytosine

Amphotericin B

Fluconazole in selected cases

Fluconazole

Amphotericin B (1.01.5 mg/kg)**

Amphotericin B (1.0-1.5 mg/kg)**

Amphotericin B + flucytosine x 2 wk,then Fluconazole x 410 wk ifclinical and microbiologic response

Amphotericin B;it raconazole may be useful asprimary therapy

TMP/SMX

*Asymptomatic candiduria in renal transplant recipientsNot T. glabrata or other resistant species

Removal of catheterLess ill, sensitive organism, nephrotoxicit y owing to amphotericin B and proven microbiologic and clinical responsePulmonary colonization immediately before or after transplantation

**Surgical dbridement where possibleExcision of focal pulmonary nodule due to C. neoformans orH. capsulatumFor coccidioidomycosis in endemic areas

FIGURE 10-35

Treatment of fungal infections in the solid-organ transplant recipient by category ofinfection. TMP/SMXtrimetho prim-sulfamethoxazole. (Adapted from Hadleyand Karchmer [10]; with permission.)

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FIGURE 10-36

Survival of hepatitis B virus (HBV)infected patients with end-stagerenal disease treated with either dialysis or transplantation. Patientsinfected with HBV (hepatitis B surface antigen [HBsAg] positive)on h emodialysis were matched for age with 22 previously trans-planted H BsAg-positive patients. This study shows the reason forconcern an d investigation as to the safety of transplantation inHBV-infected patients. Although there are o ther studies showing asignificantly decreased survival in patients tran splanted with HBV

infection, most currently show equivalent survival of over 10 years.The cause of death in the HBV-infected group, however, may moreoften be from infection and liver failure tha n from cardiac disease.

Dialysis

Transplant

31

22

1918

15

13 13

11

9 9

6

2420

1712 9 7

6 5

1

Years following detection of HBsAg

Cumula

tivesurvival,%

0

10

20

30

40

50

60

70

80

90

100

20 4 6 8 10

Hepatitis B

The safety of transplantation in HBsAg-positive patients hasbeen debated for over 25 years. Increased mortality, if seen, is usuallyseen beyond 10 years following transplantation and is often sec-ondary to liver failure or sepsis. The acquisition of hepatitis B infec-tions post-transplant, however, does carry a worse prognosis.Virtually all patients with severe chronic active hepatitis, and 50%to 60% of those with mild chronic active hepatitis on liver biopsyprior to transplantation, will progress to cirrhosis. Patients withchronic persistent hepatitis usually do not show histologic progres-sion over 4 to 5 years of follow-up, although mild lesions do notguarantee preservation of hepatic function over longer periods. The

complete natu ral history of hepatitis B following transplantation isnot known, as biopsies have been performed largely in those whohave abnormal liver function tests; however, one recent study, thatincluded analyses of all individuals who were HBsAg positivearound the time of transplantation, has shown histologic progres-sion in 85.3% of those who were rebiopsied with t he developmentof hepatocellular carcinoma in eight of 35 patients who developedcirrhosis. A key to management of patients who were HBsAg posi-tive following transplantation is to periodically monitor the liver byultrasound and to perform a serum alpha-fetoprot ein level to detecthepatocellular carcinoma at the earliest possible stage. The key tominimizing the effects of hepatitis B infections following transplan-tation, however, is to administer the hepatitis B vaccine as early aspossible in the treatment for end-stage renal disease. It is noted that60% will develop ant ihepatit is B titers when vaccinated while ondialysis compared with only 40% of those who have already beentransplanted. Co-infection with hepatitis C ma y result in moreaggressive liver disease but so far has not led to a marked decreasein patient survival. Because of the high risk of acute renal failure orrejection with the use of interferon post-transplant, t reatment ofhepatitis B with interferon following renal transplantation is no t

advised. Lamivudine or other experimental antihepatitis agents maybe used pretransplant for patients with hepatitis B infection. (Figureadapted from Har nett and coworkers. [11]; with permission.)

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POST-TRANSPLANT SURVIVAL IN HEPATITISBINFECTED PATIENTS

Author

Pirson

Hillis

Touraine

Dhar

Roy

Pfaff

HBsAg +

61

16

140

51

85

781

Year

1977

1979

1989

1991

1994

1997

HBsAg +

94

55

94

92

100

88.8

+HBsAg posit ive; HBsAg negative.

Later studies have usually shown comparable patient and graft survival in HBsAg-positive patients compared with HBsAg-negative patients. There may only be a slight 3%to 4%differenceoverall in long-term graft and patient survival in favor of HBsAg-negative patients.

HBsAg +

28

HBsAg +

60

91

88

75

77.6

FIGURE 10-37

Post-transplant survival in hepatitis Binfected patients. Later stud-ies have shown comparable patient and graft survival in hepatitis Bsurface antigen (HBsAg)positive patients compared with HBsAg-negative patients. There may only be a slight 3% to 4% difference

overall (in favor of HBsAg-negative patients) in long-term graft andpatient survival. (Data from Pirson a nd cowor kers [12], Hillis andcoworkers [13], Touraine and coworkers [14], Dhar and coworkers[15], Roy and coworkers [16], and Pfaff and Blanton [17].)

CHRONIC HEPATITISB INFECTION IN HBsAg-POSITIVE RENALTRANSPLANT RECIPIENTS: RESULTSOF LIVER BIOPSIESPERFORMEDPERITRANSPLANT AND A MEDIAN OF 66 MONTHSLATER

Histology

Normal

Chronic persistent

Chronic active

Cirrhosis

Miscellaneous

First Biopsyn = 131

%

39%

25%

25%

0%

11%

66 months

Second biopsyn = 101

%

6%

18%

42%

28%

6%

Histologic deterioration was seen in 85.3%of t hose rebiopsied wit h hepatocellular carcinoma seen in 8/35 withcirrhosis. Patients had not been treated with anti-HBV agents. 151 patients were HBsAg posit ive, median age 46,35 females, 116 males. Immunosuppression in 124 was prednisone and azathioprine and in 27 cyclosporine,azathioprine, and prednisone. The median follow-up was 125 months (range 1 to 320). Median time of HBsAgpositively was 176 months with 20%acquiring HBV infection post-t ransplant.

FIGURE 10-38Chronic hepatitis B infection in hepatitis Bsurface an tigen (H BsAg)positive renaltransplant recipients. Results of liver biop-sies performed peritransplant and a medianof 66 mont hs later in 131 of 151 HBsAg+

patients. Histologic determination was seenin 85.3% of patients rebiopsied, with hepa-tocellular carcinoma seen in eight of 35patients with cirrhosis. Patients had notbeen treated with anti-hepatitis B virusagents. With a median age of 46, 151patients were HBsAg positive (35 female,116 male). Immunosuppression in 124patients was with prednisone and azathio-prine, and in 27 p atients was withcyclosporine, azathioprine, and prednisone.(From Fornairon and coworkers [18];with permission.)

1 y, %HBsAg

95

90

93

98

100

91.8

3 y, % 5 y, %HBsAg +

87

66

61.6

10 y, %HBsAg

80

HBsAg

80

88

93

75

80.6

HBsAg

82

68 (8 y)

65.8

Patients evaluated, nHBsAg

60

149

869

541

172

13,287

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FIGURE 10-41

Patient survival in 235 hepatitis C virus (H CV)-positive patients.Patients coinfected with HC V and hepatitis B virus (HBV) hadcomparable survival 12 years after transplant as t hose infectedwith HCV alone although fibrosis was more common in duallyinfected pat ients. Results were based on 27 b iopsies in pat ientswho were both HCV positive and HBV positive and 81 biopsiesin patients who were both HCV positive and HBV negative. Overtime, liver failure occurred more frequently in patients who wereboth HCV and HBV positive (17%) than in patients who wereboth HCV positive and HBV negative (7%). (From Pouteil-Nobleand coworkers [19]; with permission.)

HCV+HBV (n=189)

HCV+HBV+ (n=46)

Months

Cum

ulativesurvival,%

0.5

0.6

0.7

0.8

0.9

1.0

2412 360 48 60 72 84 96 108 120


CHRONIC HEPATITISB INFECTION: CAUSESOF DEATHIN 151 HBSAG-POSITIVE PATIENTSOVER 125 MONTHS

Liver related (n = 15)

Spontaneous bacterial peritonitis 6

Hepatocellular carcinoma 4

Liver failure 5

Fibrosing cholestatic hepatitis 2

Not liver related (n= 26)

Cancer 6

Sepsis 8

Cardiovascular 5

Stroke 3

Other 4

FIGURE 10-39

Chronic hepatitis B infection. Causes of death in 151 hepatitis Bsurface antigen (HBsAg)positive patients over 125 months. Deathfollowing transplantation is more frequently due to sepsis and liverfailure in patients with hepatitis than in patients without chronic

hepatitis. (From Fornairon and coworkers [18]; with permission.)

Death following transplantation in patients with hepatitis is more frequently causedby sepsis and liver failure than in patients with chronic hepatitis.

Hepatitis B virus screening in renal transplant candidates

()No further testing

except by routinedialysis schedule

No renal t ransplant aloneReferral to Liver transplantcenter (if appropriate)

that transplantsHBV DNA(+) candidates

Hepatitis B virusScreen by HBsAg

(+) DNA/eAg (+)

Biopsy

In trials

Cirrhosis

() DNAindicates lack ofviral replication

Mild tosevere hepatitis

(CPH, CAH)

?Biopsy?Use antiviral

Consult hepatology

LamividineFamacyclovir

LabucovirAdefovir

(+) eAg

HBV DNA

Considertreatment

FDA approvedinterferon

FIGURE 10-40

Hepatitis screening in renal transplant candidates. CAHchronic active hepatitis; CPHchronic persistent hepatitis;HBsAghepatitis B surface antigen; HBVhepatitis B virus.

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FIGURE 10-42Risk factors associated with reported cases of acute hepatitis C in the United States (1991 to1995). Hepatitis C transplant infection prior to transplantation has not been definitivelyshown in most studies to markedly affect survival for at least 5 years following renal trans-plantation. Furthermore, hepatitis Cpositive individuals who are otherwise good transplantcandidates appear to have increased survival when transplanted, compared with staying ondialysis. Liver biopsies performed prior to t ransplanta tion have usually shown mild histologi-cal changes or chronic persistent hepatitis, but sequential biopsies have not been performedfor a long enough period of time and compared with survival to outline the natural history.Transaminase levels do no t help to predict histology or outcome. Death in hepat itis Cpositiveindividuals is more often related to infection than in hepatitis Cnegative transplant recipients.

Post-transplant treatment with interferon alpha has led to an unacceptably high rate of bothrejection and acute renal failure secondary to severe interstitial edema without tubulitis.Additionally, except for a few individuals, interferon has not resulted in long-term viral clear-ance. Most studies show the return of hepatitis C viremia within 1 month following cessationof interferon. At this point it appears that hepatitis G infections (also caused by an RNAvirus) in renal t ransplant recipients, although occasionally associated with slight increases inchronic hepatitis, are not associated with decreased survival.

Hepatitis C

Injectiondrug use 43%

Unknown 1%

Household 3%Occupation/hemodialysis 4%

Transfusions 4%

Sexual 15%

Other high risk 30%

16%Drug-related4%STD history1%Prison9%Low SES

Lipoproteinenvelope

E2/NS1 glycoprotein

E1 glycoprotein

33 nm core55 nm RNA

Hepatitis C virus screening in renal transplant candidates

HCV Ab ()no further testing

unless high-risk behavior

Hepatitis C virus

Screen for HCV by EIA-2 or 3

Liver biopsy

Transplant

PCR

Cirrhosis

Cleared infectionRepeat PCRin high-riskgroup in 6 months

Mild changesCPH (mild hepatitis)CAH (moderate tosevere hepatitis)

Monitor clinicallyfor the onset ofcirrhosis

Monitor carefullyfor infection

Referral for liver

and kidneytransplant

Transplant

HCV (Ab) (+)

+

Interferon treatment

Currently unknownsustained response

Referral for

FIGURE 10-43

Proposed structure of the hepatitis C virus.

FIGURE 10-44

Hepatitis screening in renal transplant candidates. CAHchronicactive hepatitis; CPHchronic persistent hepatitis; HC V(ab)hepatitis C virus antibody; PCRpolymerase chain reaction.

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FIGURE 10-45

The survival of hepatitis C virus (HCV)infected p atients aftertransplant group 1 or while awaiting transplantation group 2.Patients who a re transplant ed have an increased survival. A smallbiopsy study of dialysis (n = 14) and transplant (n = 14) patients

showed no difference in h istologic progression in t ransplant recipi-ents. The amount of fibrosis, however, was slightly increased.(Adapted from Knoll and coworkers. [20]; with permission.)

Group I

Group II

Time,mo

Fractionofpatientssurviving

0.5

0.6

0.7

0.8

0.9

1.0

120 24 36 48

HCV +

HCV

Survival,%

0

20

40

60

80

100

MCW Miami UCSF

LRD

UCSF

CAD

NEOB UW

3 yr

HCV +

HCV

Survival,%

0

20

40

60

80

100

MCW Miami UCSFLRD

UCSFCAD

NEOB UW3 yr

FIGURE 10-46

Five-year patient (panel A) and graft (panel B) survival in hepatitis Cvirus (HCV)positive and HCV-negative patients from recent reportsfrom United States centers. There is no significant difference over5 years in patient or kidney graft survival. MCWMedical Collegeof Wisconsin; MiamiUniversity of Miami; NEOBNew EnglandOrgan Bank; UCSF CAD University of California, San Franciscowith cadaveric donors; UCSF LRDUniversity of California, SanFrancisco, with living related donors; UWUniversity of Washington.

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FIGURE 10-47

Renal and hepatic outcome in patientstreated with interferon alpha post-renaltransplant for hepatitis C virus (HCV)infection. Interferon t reatment results in a

high rate of transplant acute renal failure orrejection. Transplant biopsies in those withacute renal failure show severe diffuseedema. Acute renal failure is not veryresponsive to steroids. Virologic clearing israre, as H CV-RNA is detectable, on a ver-age, 1 month after discontinuing interferonif the polymerase chain reaction (PCR)became negative during t reatment. ALTalanine a minotransferase; SCsubcuta-neously; TIWthree times a week. (Data

from Thervet and coworkers [21],Magnone and coworkers [22], Rostaingand coworkers [23,24], and Yasumura andcoworkers [25].)

RENAL AND HEPATIC OUTCOME IN PATIENTSTREATED WITH INTERFERONALPHA FOLLOWING RENAL TRANSPLANT FOR HCV INFECTION

Author

Year

Number treated

HCV + HBV +

Dose mU, SC, TIW

Normalization of ALT

Discontinued treatment

Number wit h cirrhosis

PCR+PCR

RelapsePCR+

Acute renal failure

Rejection

Lost transplant

New proteinuria

Thervet

1994

13

4

35

1

7

8

NA

NA

2

0

0

NA

Magnone

1995

11

1

1.55

NA

7

NA

NA

NA

0

7

6

NA

Rostaing

1995

14

0

3

10

7

1

4

4

5

0

1

2

Rostaing*

1996

16

NA

3

NA

9

NA

NA

NA

6

0

3

NA

Yasumura

1997

6

0

6

6

0

0

2

0

0

1

0

1

*Most are overlapping patients with the 1995 study.

Hepatitis G

FIGURE 10-48

Hepatitis G virus (HGV) in renal transplantation: prevalence ofinfection and associated findings. Hepatitis G virus is an RNAvirus of the flaviviridae family. Hepatitis G virus was isolated inde-pendently by two different group s of investigators and calledhepatitis GB viruses by Simmons and colleagues, and hepatitis Gvirus by Lenin and colleagues. It now appears that GB virus-A andGB virus-B are tamarin viruses and GBV-C is a human virus with

sequence homology of more than 95% with the hepatitis GVsequence. The virus has been shown to be transmitted by transfu-sions, including plasma products, by frequent parenteral exposure,including intravenous (IV) drug abuse, by sexual exposure, and bymother to child tr ansmission. In t he United States, the pr evalenceof hepatitis G virus is 1.7% among healthy volunteer blooddonors, 8.3% among cadaveric organ donors, and 33% among IV

drug a busers. Among chronic hemodialysis patients, the pr evalenceof hepatitis G virus RNA has been variable, ranging from 3.1% inJapan to 55% in Indonesia and some areas in France. Likewise, thereported incidence of co-infection with hepatitis B virus (HBV) andhepatitis C virus (HCV) is extremely variable.

Hepat itis G virus RNA is detected by reverse transcriptase poly-merase chain reaction (PCR). The development of reliable serologicassays for hepatitis G has been difficult due to the lack of linearepitopes expressed by hepatitis G virus. The risk for pretra nsplanthepatitis G infection is associated with increasing numbers o fblood transfusions and with longer duration of dialysis. Post-trans-

plantation, most patients with hepatitis G virus remain viremic;however, patients ha ve been shown to clear the virus post-tra ns-plant. At this time, hepatitis G virus does not appear to invoke apoor outcome after transplantation, either in the form of severeliver disease or increased mortality; however, the long-term studiesneeded to provide a firm conclusion about this have not been per-formed. The question of transmission of hepatitis G virus via trans-plantat ion is still under investigation. N Anot available; NEOBNew England Organ Bank. (Data from Dussol and coworkers [26],Murthy and coworkers [27], and Fabrizi and coworkers [28].)

HEPATITISG VIRUSIN RENAL TRANSPLANTATION:PREVALENCE OF INFECTION AND ASSOCIATED FINDINGS

Author

Year

Location

%infection

%with HCV infection

%with chronic ALT elevation

Rejection rate

%with HBsAg

Survival versus HGV negative

Dussol

1997

Marseille

28%

12.5%

12.5%

Unchanged

8%

NA

Murthy*

1997

NEOB

18%

28%

35%

Unchanged

NA

Unchanged

Fabrizi

1997

Milan

36%

91%

18%

NA

18%

NA

*One patient may have acquired HGV through the donor organ. Five of 10 pretransplantpositive patients became HGV RNA negative post-transplant.

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FIGURE 10-52

The occurrence of AIDS in HIV-infected transplant recipientsaccording to immunosuppressive treatment. Immunosuppressionincluded cyclosporine in 40 ind ividuals and no cyclosporine in13 individuals.

The precise natural history o f HIV infection following renaltransplantation is still not well delineated. The largest single seriesfrom Pittsburgh analyzed 11 patients who were HIV positive priorto transplantation and 14 patients who developed HIV infectionsfollowing transplantation. Of the 11 patients infected before trans-plantat ion, six were alive an average of 3.3 years following trans-plantat ion. Five patients had died, however; three of AIDS-relatedcomplications. Of the 14 patients infected peritransplantation,seven patients were alive at follow-up an average of 4.8 years later.There had been seven deaths, thr ee due to AIDS. Complicationsseemed to correlate with increased immunosuppression for rejec-

P=0.001

No cyclosporine treatment (n=13)

Cyclosporine treatment (n=40)

Pr

oportionofpatientswithAIDS

0.00 6 12 18 36 4830

Months since transplantation-related HIV-1 infection

60544224 66

0.1

0.3

0.5

0.6

0.2

0.4

0.7

0.8

0.9

1.0

FIGURE 10-51Viruses that cause interstitial nephritis in renal t ransplant recipi-ents. Consider this condition when nonspecific inflammation isseen on b iopsy or unexplained rejection occurs. Viruses may causerenal disease by direct infection o f the glomerular and /or tub ularcells or by the immune response directed against virally infectedcells. Most commonly nonspecific interstitial inflammation is seenbut severe tubular injury by mononuclear cells, peritubular inflam-mation, a nd int erstitial fibrosis may also be seen. The presentationof virally mediated interstitial nephritis may be acute o r subacute.In addition to r outine light microscopy, occasionally evaluation by

immunofluorescence, electron microscopy, or special stains for lightmicroscopy ar e necessary to m ake the diagnosis.

Viral Interstitial Nephritis

VIRAL INTERSTITIAL NEPHRITIS

Adenovirus

BK virus

Cytomegalovirus

Epstein-Barr virus

Herpes simplex virus 1, 2, 6

Varicella-zoster virus

HantavirusHepatitis C viruspossible

HIV

HIV

tion. Another report evaluating 53 patients infected with HIVaround the time of transplantation found that patients treated withcyclosporine appeared to have a better long-term prognosis thanthose who were treated with prednisone and azathioprine.

In summary, although there are no firm conclusions, it appearsthat there is not much difference between pre- or post-transplantacquisition of HIV infection, although some authors, based onsmall numbers of patients, have concluded that the age of thepatient and the duration of the infection are both prognostic fac-tors. It also appears that approximately 25% of HIV-infected indi-viduals do poorly within the first 6 months of transplantation,especially following an tirejection t reatment (Rubin, unpublisheddata). Another 25% of individuals appear to do very well 6 yearsand beyond following transplantation. The remainder of the indi-viduals seem to develop AIDS within 3 to 3 .5 years after transplan-tation, with an average survival of about 3 months after the onsetof AIDS. It has a lso been noted that cytomegalovirus or otherinfections t hat may increase HIV proliferation may influence thisoutcome, and that prophylactic antimicrobial strategies may alterthe natural history.

Currently, it is advised th at all tra nsplant candidates bescreened for the presence of HIV antibody and counseled aboutthe possible consequences of further immunosuppression, butnot be categorically denied t ransplantation if they are otherwiseasymptomatic. Patient management following transplantationshould be focused on the avoidance of large increases in immuno-suppression a nd opport unistic infections, with special attention tothe viral, pneumocystic, and mycobacterial infections that theseindividuals may develop. Antiretroviral strategies in transplanta-tion require study. (Adapted from Schwarz and coworkers [30];with permission.)

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FIGURE 10-53 (see Color Plate)Linear esophageal ulcers caused by herpes simplex virus (HSV) andCandida. Infection with HSV-1 and -2 leads to stom atitis andesophagitis post-transplantation without acyclovir prophylaxis.Additionally, paronychia, corneal ulcers, encephalitis, genitallesions, disseminated involvement of the gastrointestinal tract, pan-creas, and liver, and interstitial nephritis has been seen. HSV-6causes exanthem subitum in children, mononucleosis, and hepati-tis. There has been some evidence that reactivation infections maybe associated with rejection in t ransplant recipients. Both reactiva-tion and reinfection may occur. HSV-8 is associated with Kaposis

sarcoma. Prevention of these infections has been achieved usingproph ylactic acyclovir following transplantation. If clinical symp-toms occur from H SV, they usually are t reated with acycloviradjusted for renal function.

Herpes Simplex Virus


Varicella-zoster virus (VZV) infection. Primary VZV infections usu-ally result in t ypical vesicular erup tions o f generalized onset w ith-out dermatomal localization. Reactivation infection of the virusfrom the dorsal root ganglion usually causes a dermatomally local-ized vesicular erupt ion. By the time of renal transplant ation, over

94% of adults have evidence of a prior VZV infection. In thosepatients p reviously infected, an tibody titers increase followingtransplantation. Pretransplant screening is recommended to advisethe patient on treatment of post-transplant exposures. Post-trans-plant exposures to zoster or chickenpox in the nonimmune individ-

ual should be treated with acyclovir, famcyclovir, or varicella-zosterimmune globulin. Immune globulin is rarely required at t his time.Patients with t he new onset of varicella infection following trans-plantation or with diffuse zoster should be treated with intra-venous acyclovir, 10 mg/kg, three times per day, or famcyclorirdepending on renal function. Infection in the transplant recipient,particularly in those who ar e primarily infected, can result inencephalitis, disseminated int ravascular coagulation, pneumonia,bowel involvement, pancreatitis, dermatitis, and hepatitis.

The attack rate in nonimmune individuals of household contactswith varicella infections is 80% to 90%. Therefore, if individualshave not previously had varicella infections at the time of transplantevaluation, vaccination with a live attenuated strain could be consid-ered. Recently this strategy has been used in children prior to renaltransplantation. Attack rates in vaccinated individuals may be up to31%, but the disease that develops is much milder compared withthose susceptible individuals not previously vaccinated. Should resis-tant strains of varicella develop, foscarnet ha s been effective.Foscarnet is associated with a renal decline in renal function.(Adapted from Friedman-Kien [31]; with permission.)

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FIGURE 10-55

Adenovirus infection of the colon. Adenovirus infections normallycause asymptomatic infections, coryza, or pharyngitis. Infection in thefirst decade of life usually protects individuals from future infection aslong as the immune system is intact; however, in t ransplant recipients,adenovirus types 11, 34, and 35 have been shown to cause interstitialpneumonia, conjunctivitis, hemorrhagic cystitis, hepatitic necrosis,interstitial nephritis and gastroenteritis, and disseminated d isease.

Adenovirus infection may be latent prior to transplant and reac-tivate post-transplant, or a primary infection may be acquired.

Adenovirus has been shown to infect the bladder, uroepithelialcells, renal tubular cells (distal greater than proximal), theendothelium of the glomeruli and peritubular capillaries, and,occasionally, mesangial cells. The outcome of a denovirus infectionis related to the type of immunosuppression and the recipient age.

The death rate during active infection in renal transplantation maybe as high as 18% but ma y be even higher in younger pat ients.The onset of disease after transplantation is usually within 6months of the transplant.

Clinically, the most frequent symptoms of an adenovirus infec-tion involve difficult micturition, including gross hematu ria, fever,and, occasionally, renal d ysfunction. The diagnosis is suspectedwhen bacterial cultures are negative but there is gross hematuria.The urinary symptoms usually last 2 to 4 weeks. The diagnosis ismade by urine culture or by electron microscopy or lightmicroscopy, where ad enoviruses are seen as intranuclear

basophilic viral inclusions with a narrow halo between the inclu-sions and the nuclear membrane. Treatment has been somewhatsuccessful using ganciclovir. Interferon therapy is difficult becauseof the risk of acute renal failure or rejection in transplant recipi-ents. Furthermore, efficacy is questionable because of th e virusability to inhibit the mode of action of interferon. Ribavirin hassuccessfully cleared the virus in several immu nosupp ressedpatients. The use of IVIG has not been associated with reliableresults. In the future, cidofovir may also be used for the treatmentof adenovirus infections, but renal insufficiency and proteinuriamay limit use.

CENTRAL NERVOUSSYSTEM INFECTION IN THE TRANSPLANT RECIPIENT

Incidence 5%; mortality up to 85%for CNSinfections

Acute to subacuteL. monocytogenes

Subacute to chronic

Cryptococcus neoformansMycobacterium tuberculosis

Coccidiodes immitis

Focal brain infectionAspergillus

L. monocytogenes

T. gondii

N. asteroides

Candida albicans

Cryptococcus

Progressive dementiaPolyomavirus, HSV, CMV, HIV

SymptomsHeadachemay be mild, may have little meningismusFevermay be mildaltered consciousnessCerebrospinal fluid

Lymphocytic pleocytosis(viral/fungal/MTB)

HypoglycorrhaiaNeutrophilic pleocytosis (bacterial)

Over three-fourths of central nervous system infectionis accounted for byL. monocytogenes

C. neoformans

A. fumigatus

TimingEarlyListeria

Nocardia

Toxoplasma

Aspergillus

Lateas above and due to chronic enhanced immuno-suppression plusCryptococcus and tuberculosis

DiagnosisPhysical examinationCT scan identif ies hypodense ring-enhancing lesions

CSFexaminationDirected lesional aspirates

FIGURE 10-56

Central nervous system infection in th etransplant recipient. CNScentral nervoussystem; CSFcerebrospinal fluid; MTBmycobacterium tuberculosis.

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FIGURE 10-57

Causes of headache in the tr ansplant recipient. ACEangiotensin-converting enzyme; CNScentral nervous system; ATGantithy-mocyte globulin.

CAUSESOF HEADACHEIN THETRANSPLANT RECIPIENT

Medications

OKT3 (aseptic meningitis)

ATG

IVIgG

Cyclosporine

Tacrolimus

AntihypertensivesCalcium channel blockersACEinhibitors

Nitrates

Hydralozine

MinoxidilHypertension

Neck tension, muscle pulls, ligamental irritation

Sinusitis

Ocular abnormalit ies

Excessive vomiting

Migraine headaches exacerbated by cyclosporine, tacrolimus, andcalcium channel blockers

Stroke

Infection of the central nervous system

FIGURE 10-58

Work-up of an unexplained headache.

WORK-UP OF AN UNEXPLAINED HEADACHE

HistoryCharacter, pattern, positional relationshipsFever, duration of headache and feverLocation of headacheVisual, movement, sensory impairmentBowel or bladder incontinenceTraumaMedications old and newTime of medications and relationships to headache

Physical examinationEyeNeurologicalComplete the rest of the examination

If no papilledema or focal neurological deficitlumbar puncture

If papilledema or focal deficitCT first if no mass lesionlumbar puncture

Cerebrospinal fluid is sent forCell count and differentialProteinGlucoseGrams stainFungal stainsAcid fast stainFungal cultureMycobacterial cultures

Bacterial culturesCryptococcal antigenSave cerebrospinal fluid in addition for ot her tests includingHistoplasma capsulatum or Coccidiodes immitis antibody titers

FIGURE 10-59Epstein-Barr virus (EBV). EBV is associated with asymptomatic infection, mononucleosis,hepatitis, and, r arely, interstitial nephritis. In transplant recipients, posttransplant lympho-proliferative d isorder (PTLD) is a lso associated with EBV. EBV promotes B-cell pro lifera-tion, if left unchecked by immunosuppressive agents targeting the T-cell system. This chestradiograph shows multiple pulmonary nodules of PTLD. Symptoms vary from no symp-toms to diffuse organ involvement causing dysfunction. Any area of the body may beinvolved, with frequent sites being the gums, chest, abdomen, and central nervous system.

PTLD occurs during the first posttransplant year in approximately 50% of those devel-oping PTLD. It is seen in 1 % to 2 % of renal tra nsplant r ecipients. Primary EBV infectionfollowing transplantation and antilymphocyte agent use is associated with an increased

risk. Increasing qua ntitative blood EBV DN A levels may predict the onset of PTLD.

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VIRAL MENINGITIS

Causal agents

Enterovirus

Coxsackie*

ECHO*

Poliovirus

Adenovirus

MumpsArbovirus

Herpes group

Cytomegalovirus*

Herpes simplex virus 1 and 2*

HHV-6*

HHV-8*

Varicella-zoster virus*

Epstein-Barr virus*

Coronavirus

HIV

Influenza A, B

Lymphocytic choriomeningitis virus

Parainfluenza virus

Rabies virus

RhinovirusesRotavirus

Japanese encephali tis virus*

Tick borne encephalitis virus

PML (JC) virus (in development)*

BK virus (in development)*

FIGURE 10-60Viruses causing meningitis in tr ansplantrecipients. The pr esentat ion is usually withfever and headache alone or in conjunctionwith headache may be the initial symptom.Nuchal rigidity is rare in the transplantpatient. Cerebrospinal fluid samples shouldbe saved for viral ana lysis and analysisshould be r equested if the diagnosis is notrapidly available from standard studies.

Viral Meningitis


Black hairy tongue is the result of hypertrophy of filiform papillaeof the tongue, often seen in transplant patients after antibiotictreatment. The origin is unknown but is associated with topical orsystemic antibiotics, poor oral hygiene, smoking, alcohol, and theuse of mouthwashes. Most often there are no symptoms; however,nausea, gagging, taste alteration, or halitosis are reported by somepatients. Treatment includes brushing with a soft brush and, occa-sionally, t opical vitamin B, salicylic acid, gentian violet, or surgicalremoval. This entity is not to be confused with hairy leukoplakia,which is composed of white corrugated plaques on the lateral sur-face of the tongue. These lesions may be small and flat or exten-

sive and hairy. Microscopic evaluation shows epithelial cells withherpetic viral inclusions, specifically Epstein-Barr virus. Treatmentis oral acyclovir.

Black Hairy Tongue

* Cerebrospinal fluid polymerase chain reaction available to make the diagnosis but locations vary Increased in transplant patients

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FIGURE 10-62 (see Color Plate)Tinea versicolor (pityriasis versicolor) is a chronic superficial fungaldisease caused byMalassezia furfur, a yeast normally found on theskin. It is in yeast form in the unaffected skin areas and in themycelial phase on affected skin. The disease usually is located onthe upper trunk, neck, or upper a rms. Symptoms may include scal-ing, erythema, and pruritis. It may appear as slightly scaly brownmacules or whitish macules. Treatment options include oral or t opi-cal terbinafine (1% cream or gel), oral or t opical ketoconazole, oralfluconazole, or topical treatments, such as ciclopiroxolamine, piroc-toneolamine, zinc pyrithione, or sulfur-containing substances, such

as selenium sulfide; the most common treatment is selenium.Patients are asked to wet themselves in the shower, turn off thewater, apply the selenium and let it sit for 10 minutes, and thenrinse. Also, oral fluconazole, 200 mg, once or repeated once a weeklater is a simple and effective treatment. Of note, oral terbinafine,250 mg, daily for 12 weeks is associated with slightly decreasedcyclosporine levels. Terbinafine is an allylamine that binds to asmall subfraction of hepatic cytochrome P450 in a type I fashion.Side effects seen during terbinafine use include gastrointestinal dis-tress in up to 5% of patients and skin rashes in 2% of patients.

Tinea Versicolor

Kaposis Sarcoma


Kaposis sarcoma of the lower leg in a male transplant recipient.Kaposis sarcoma is a tumor, perhaps of lymphatic endothelial origin,that presents as purple papules or plaques that advance to nodules ofthe extremities, oral mucosa, or viscera. In transplant recipients it pre-sents on average by 21 months post-transplant, with the largest num-ber (46% ) within the first post-transplant year. It is seen most often inmen (3:1) and in those of Arabic, black, Italian, Jewish, and Greekancestry. It accounts for 5.7% of the malignancies reported to theCincinnati Transplant Tumor Registry (nonmelanoma skin cancersand in situ carcinomas of t he uterine cervix excluded). Transplantprograms in Italy and Saudi Arabia have reported higher rates ofpost-transplant Kaposis sarcoma. Visceral involvement is less com-mon in the transplant recipient than in the AIDS patient, but it mustbe remembered that it may be seen in the liver, lungs, gastrointestinal

tract, and nodes. Mortality is increased with visceral involvement(57% versus 23%). HHV-8 has been proposed as the causal agentof this tumor; however, not all investigators feel the evidence is con-clusive. Of note, the occurrence in AIDS patients is decreased in thosewho receive foscarnet, cidofovir, and ganciclovir, but not acyclovir.Treatment includes decreasing immunosuppression, local radiation,excision, interferon, or chemotherapy.

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FIGURE 10-64

Mucormycosis is caused by fungi of the order Mucorales, includingRhizopus,Absidia, and Mucor. Mucorales are ubiquitous sapro-phytes found in the soil and on decaying organic material, includingbread and fruit. Human infection is believed to be caused by theinhalation of spores that initially land on the oral and nasal

mucosa. Direct inoculation into tissues, however, has been reported.

Mucormycosis

Most of the spores, once in the tissue, are contained by the phago-cytic response. If this fails, as it often does in patients with diabetesmellitus and those otherwise immunosuppressed, germinationbegins and hyphae develop. The hyphae, as shown in the micro-graph, are large, nonseptate, rectangular, and branch at right angles.Infection begins with the invasion of blood vessels, which causesnecrosis and dissemination of the infection. The most common siteof involvement is the rhino-orbital-cerebral area, accounting forapproximately 70% of cases; however, pulmonary, cutaneous, gas-trointestinal, and disseminated infection may be seen. The chestradiograph during pulmonary infections may show a n infiltrate,

nodule, cavitary lesion, or pleural effusion. Gastric involvement mayrange from colonization of peptic ulcers to infiltrative disease withvascular invasion causing perforation. Although classic formucormycosis, a black eschar of the skin, nasal mucosa, or palate ispresent in on ly about 20% of patients early in the course of the dis-ease and cannot be relied on for assistance in early diagnosis.Survival is dependent on early diagnosis. Diagnosis is by biopsywith classic histologic findings and by culture of tissue. Treatmentincludes amphotericin B, surgical removal of the lesion, packing ofthe sinus areas with amphotericin Bsoaked packs, and perhapshyperbaric oxygen. Liposomal amphotericin B has also been effec-

tive. Treatment must include both surgery and amphotericin B.

A B

FIGURE 10-65

Condyloma a cuminata (anogenital/venereal warts) are caused byinfection with human papillomavirus 6 or 11. In transplant recipi-ents they may become extremely extensive. Treatment has includedfluorouracil, podophyllin, podophyllotoxin, intralesional interfer-on, t opical interferon, systemic interferon, and, mo re recently,imiquimod, wh ich causes the induction of cytokines, especially

interferon alpha. Lesions have responded in 50% of nontransplantpatients receiving the 5% cream. Invasive treatments have includedsurgical excision, cryotherapy, electrocautery, and carbon dioxidelaser. Recurrences are common. A, Condyloma acuminata in amale transplant recipient. B, Condyloma acuminata in a femaletransplant recipient.

Condyloma Acuminata

10 34

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FIGURE 10-66

Verruca vulgaris (common warts) are caused by hu man papillo-maviruses 1, 2, 3, 4, 5, 8, 11, 16, and 18, as well as others, with

the highest percentage by type 4. Warts are found most often onthe fingers, arms, elbows, and knees and are much more numerousin the immunosuppressed patient. Treatment modalities have beenthe same as for condyloma acuminata, with the addition of topicalcidofovir and hyperthermia. Therapy should be planned based onthe location, extent, and size of the lesions. N ot a ll lesions needtreatment. Early dermatologic referral is needed for those lesionsthat appear to be advancing rapidly as certain papilloma viruses(16, 18, 31, 51, 52, 56) have been associated with squamous cellcarcinomas of the skin and cervix. A and B, Verruca vulgaris of thefinger and knee. Not e the large size and mu ltiple warts. C, Verrucaplanae, flat warts at multiple locations of the hand, also often seenon t he face.

Verruca Vulgaris

A

C

B

10 35P l I f i

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FIGURE 10-67Molluscum contagiosum is an infection ofthe skin caused by the molluscum contagio-sum virus, a member of the pox virus family.Molluscum does not grow in culture orinfected laboratory animals. Manifestationsare pearly, pink, dome-shaped, glistening,firm lesions; in immunosuppressed patients,however, they may be over 1 cm in diameterand multiple lesions may occur together. Theinfection usually lasts up to 2 months in

immunocompetent pat ients, but a chronic,recalcitrant, and disfiguring infection mayoccur in immunosuppressed patients. Thevirus is contracted and spreads via close con-tact with an infected person, fomites, or viaautoinoculation. The incubation period is 2weeks to 6 months. The diagnosis is madevisually or by direct examination of curet-tings from the center of the lesion showingmolluscum intracytoplasmic inclusion bod-ies. Treatment is started for the prevention ofspreading, to relieve symptoms, and for cos-metic reasons. Treatment includes cryothera-py, curettage, podophyllin, cantharidin,trichloroacetic acid, phenol, salicylic acid,strong iodine solutions, lactic acid, tretinoin,silver nitrate, and interferon alpha topical orintralesional, and possibly oral cimetidine,with adhesive tape occlusion. None of theavailable treatments result in a rapid or defi-nite clearance in the immunosuppressed

patient. Treatment of the underlying retro-virus infection has been shown to help inAIDS patients, and perhaps reviewing thedegree of immunosuppression in the trans-plant patient will help. A, Molluscum conta-giosum papule. Note pearly umbilicaledappearance. B, H istologic slide of molluscumshowing a cross section of the papule.C, Close-up view of the molluscum bodies.

Molluscum Contagiosum

A

B

C

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Intestinal Protozoa

SIMILARITIESAMONG THE INTESTINAL SPORE-FORMING PROTOZOA

History

Identified as human pathogens in recent decades

Once considered rare pathogens; now known to commonly cause infections

The AIDSepidemic increased awareness and recognition

Biology

Protozoa

Intracellular location in epithelial cells of the intestineSpore or oocyst form is shed in stool

Pathogenesis of diarrhea

Unknown; possible abnormalities of absorption, secretion, and motility

Intense infection of small bowel associated with dense inflammatory infiltrate

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