O

R

TcobaEt

tame

tiippn

©3

T

pportunistic Infections in Renal Allograft Recipients

.K. Gupta

ABSTRACT

Two major factors for successful organ transplantation are better control of rejection andbetter prevention and treatment of infections. In renal allograft recipients, immunosup-pressive drug therapy is the major cause of immunocompromised status and occurrence ofinfections, which arise most commonly as a result of invasion by endogenous opportunists.It may also follow colonization by exogenous environmental organisms and via transfer ofcytomegalovirus along with the transplanted kidney. The overall incidence of opportunisticinfections varies from center to center; up to 15% of renal transplant recipients die of theseinfections. Clinical signs and symptoms of infection in immunocompromised patients maybe concealed or imitated by the underlying disease, and a high index of clinical suspicionis vital. The unusual pathogens encountered in these patients demand thorough investi-gation. A total of 84 opportunistic infections encountered in renal allograft recipientsduring histopathologic and cytopathological evaluation of various specimens during thelast 15 years is presented in this report. Invasive fungal infections were the most commonpathogens, amounting to 55% of all infections. The dramatic increase in the diversity andnumber of opportunistic infections detected in these patients is not only due to anincreasing population of susceptible individuals but also due to an improved recognition byadvanced laboratory diagnostic techniques. The success of management of opportunisticinfections depends on strong clinical suspicion, early diagnosis, and prompt treatment. Thechallenges of early diagnosis of opportunistic infections and prompt treatment are great;

the rewards are even greater.

g

u

PS

HE SUCCESS OF SOLID ORGAN transplantation,particularly renal transplantation, has markedly in-

reased over the years. The two major factors for successfulrgan transplantation are better control of rejection andetter prevention and treatment of infections. These twore closely related and are mirror images of one another.very immunosuppressive program that has been devised

o prevent rejection increases the risk of infection.In renal allograft recipients, immunosuppressive drug

herapy is the major cause of immunocompromised statusnd occurrence of infections. Defects in host defenseechanisms in a renal allograft recipient may lead to

mergence of various opportunistic infections.The term opportunistic infection is applied to an infec-

ion occurring in an immunocompromised host withmpaired defense mechanisms. In other words, it is annvasive infection by a “nonpathogen” in an immunocom-romised host or an infection by a “sometime” or “true”athogen of a type or severity rarely encountered in a

ormal host. y

2007 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 39, 731–733 (2007)

The microorganisms that invade the individuals may berouped into three major categories.1

1. True pathogens: Involve the normal and abnormalhost alike (eg, Hemophilus influenzae, Salmonellatyphi).

2. Sometimes pathogens: Commonly present as coloniz-ers of the mucocutaneous surface. They cause clinicaldisease only when introduced into normally steriletissues following a break in the integrity of a muco-cutaneous surface (eg, staphylococcal and group Astreptococcal sepsis following break in skin integrityand Gram-negative and Bacteroides fragilis sepsisfollowing bowel perforation).

From the Department of Pathology, Sanjay Gandhi Postgrad-ate Institute of Medical Sciences, Lucknow, India.Address reprint requests to Prof R.K. Gupta, Department of

athology, Sanjay Gandhi Postgraduate Institute of Medicalciences, Lucknow-226014, India. E-mail: rkgupta_1944@

ahoo.com

0041-1345/07/$–see front matterdoi:10.1016/j.transproceed.2007.01.063

731

airfapit

r

●

●

●

opit

puuTmbcn

sit

aiitbs

errstaftd

eoMcm

tihptta

sctpt

MANLLS

s; EBV

732 GUPTA

3. Nonpathogens: Usually have no impact on the nor-mal host. They are capable of invading and causingdisease only in individuals with impairment of eithernonspecific or specific host defenses or both.

Infections in transplant patients arise most commonly asresult of invasion by endogenous opportunists following

mmunosuppressive therapy with drugs such as corticoste-oids, cyclosporine, and azathioprine. Infection may alsoollow colonization by exogenous environmental organismsnd via transfer of cytomegalovirus along with the trans-lanted kidney. The overall incidence of opportunistic

nfections varies from center to center; up to 15% of renalransplant recipients die of these infections.

Factors contributing to infection in renal transplantecipients are as follows:

Pretransplant factorsUnderlying medical condition (eg, diabetes mellitus,bronchitis)Prior colonization/latent infection/medicationLack of specific immunity

Transplant factorsSurgical trauma

Posttransplant factorsImmunosuppressionInfective immunosuppression

The dramatic increase in the diversity and number ofpportunistic infections is not only due to an increasingopulation of susceptible individuals but also due to an

mproved recognition by advanced laboratory diagnosticechniques.

Clinical signs and symptoms of infection in immunocom-romised patients may be less overt than in normal individ-als and may commonly be concealed or imitated by thenderlying disease. A high index of clinical suspicion is vital.he unusual pathogens encountered in these patients de-and thorough investigation. In some patients, there may

e sufficient time for adequate investigations and specifichemotherapy. In others, the potential for rapid mortality

Table 1. Opportunistic Infections O

Bacteria Virus

ycobacterium tuberculosis HSVtypical mycobacteria Varicella zosterocardia species CMVisteria monocytogens HHV-6, 7egionella pneumophilia HHV-8almonella EBV

Papova-BK, JCPapillomaParvo virus B19

HSV, herpes simplex virus; CMV, cytomegalovirus; HHV, human herpes viru

ecessitates urgent empirical “best guess” therapy. Re- r

ponse to routine monotherapy may be suboptimal inmmunocompromised patients, and combination chemo-herapy is often required from the outset.

The common opportunistic infections occurring in renalllograft recipients are summarized in Table 1. The major-ty of bacterial infections do not show specific morpholog-cal changes in the involved organs; the gold standard forhe diagnosis of bacterial infections therefore continues toe bacterial culture. The specimen for bacterial culturehould be obtained prior to antibiotic therapy.

Viral infections are a major complication of the postop-rative course in renal transplant recipients. Cytomegalovi-us infections occur in up to 65% of kidney transplantecipients, and 14% to 46% of infections are reportedlyymptomatic.2 BK polyoma virus causes allograft dysfunc-ion as a result of tubulointerstitial nephritis in 2% to 5% ofll transplant recipients.3 Epstein-Barr virus is responsibleor a number of disorders, but the major concern in renalransplant recipients is posttransplant lymphoproliferativeisorder.4

Opportunistic fungal infections are being increasinglyncountered in organ transplant recipients. The most seri-us fungal infections are those caused by Cryptococcus,ucor, and Aspergillus species.5 Organisms once considered

ontaminant are proven pathogens in immunocompro-ised patients.Immunocompromised patients present with altered pat-

ern, progression, and clinical manifestations of parasiticnfections. Parasites that can complete their life cycle in theuman host are observed more commonly in immunocom-romised individuals. The intensity of inflammatory reac-ion is dictated by the intensity of host response. Coinfec-ion with viruses like cytomegalovirus has been known toccentuate the severity of opportunistic parasitic infections.

The immunosuppressive programs used in all forms ofolid organ transplantation are quite similar, with eitheryclosporine or tacrolimus being the cornerstone of main-enance antirejection therapy. As a result, there are similaratterns of infection in all form of solid organ transplanta-ion, which follow almost a consistent timetable of occur-

ring in Renal Allograft Recipients

Fungi Parasites

Candida GiardiaCryptococcus EntamoebaPneumocystis carinii CoccidiaTorulopsis CryptosporidiumAspergillus CyclosporaZygomycosis IsosporaPhaeohyphomycosis SarcocystisHistoplasma MicrosporaBlastomyces ToxoplasmaCoccidiodes Leishmania

Strongyloides

, Epstein-Barr virus; JC, JC polyoma virus.

ccur

ence after transplantation.6 The posttransplant period is

tf

bcfacla

et

dptrslp

R

(H2

cp

pT

2

rN

WUSEP

OPPORTUNISTIC INFECTIONS 733

hus divided into three phases when evaluating the patientsor possible infections (Table 2).

A total of 251 opportunistic infections were encounteredy us during the last 15 years on histopathologic andytopathological evaluation of various specimens obtainedrom immunocompromised patients (Table 3). The renalllograft recipients had predominantly fungal infections asompared to patients with AIDS, who had mainly tubercu-ar lesions, heavily positive for acid-fast bacilli. Aspergillusnd Candida were the most common fungal infection

Table 2. Time of Occurrence of Various Infections AfterRenal Transplantation

Surgical Complications(�6 wk)

Opportunistic Infections(6 wk to 6 mo)

Acquired Infections(�6 mo)

ound infectionTItaphylococcus aureusscherichia colineumonia

Atypical mycobacteriaCryptococcusPneumocystis cariniiCMVCandidaAspergillusToxoplasma

TuberculosisPneumococcal

pneumoniaInfluenzaUTI

UTI, urinary tract infection; CMV, cytomegalovirus.

Table 3. The Causes of Immunosuppression (n � 251)

Posttransplant 84AIDS 48Malignancy 37Diabetes mellitus 31Prolonged steroid use 25CRF/chronic liver disease 3Cause unknown 23

iCRF, chronic renal failure.

ncountered. Some patients had mixed infection with morehan one pathogenic agent (Table 4).

The success of management of opportunistic infectionsepends upon strong clinical suspicion, early diagnosis, andrompt treatment. The therapeutic prescription for theransplant patients should consist of an immunosuppressiveegimen to prevent and treat rejection and an antimicrobialtrategy to make it safe and prevent infection. The chal-enges of early diagnosis of opportunistic infections andrompt treatment are great; the rewards are even greater.

EFERENCES

1. Rubin RH, Young LS: Introduction. In Rubin RH, Young LSeds): Clinical Approach to Infection in the Immunocompromisedost. 4th ed. New York: Kluwer Academic/Plenum Publishers;

002, 12. Kashyap R, Shapiro R, Jordan M, et al: The clinical signifi-

ance of cytomegaloviral inclusions in the allograft kidney. Trans-lantation 67:98, 19993. Sachdeva MS, Nada R, Jha V, et al: The high incidence of BK

olyoma virus infection among renal transplant recipients in India.ransplantation 77:429, 20044. Cohen JI: Epstein-Barr virus infection. N Engl J Med 343:481,

0005. Braun WE: The medical management of the renal transplant

ecipient. In Johnson RJ, Feehally J (eds): Comprehensive Clinicalephrology. London: Mosby; 2000; 89.1

Table 4. Infections Encountered in Renal TransplantRecipients (n � 84)

Bacterial 15Viral 19Fungal 46Parasitic 3Mixed 3

6. Fishman JA, Rubin RH: Infection in organ-transplant recip-ents. N Engl J Med 338:1741, 1998