medicine health rhodeisland · 2016. 9. 30. · beans to treat pd, however, requires in- ......

UNDER THE JOINTEDITORIAL SPONSORSHIP OF:

Brown Medical SchoolDonald Marsh, MD, Dean of Medicine& Biological Sciences

Rhode Island Department of HealthPatricia Nolan, MD, MPH, Director

Rhode Island Quality PartnersEdward Westrick, MD, PhD, Chief MedicalOfficer

Rhode Island Chapter, American College ofPhysicians-American Society of Internal Medicine

Fred J. Schiffman, MD, FACP, GovernorRhode Island Medical Society

Yul D. Ejnes, MD, President

EDITORIAL STAFFJoseph H. Friedman, MD

Editor-in-ChiefJoan M. Retsinas, PhD

Managing EditorHugo Taussig, MDBetty E. Aronson, MD

Book Review EditorsStanley M. Aronson, MD, MPH

Editor Emeritus

EDITORIAL BOARDBetty E. Aronson, MDStanley M. Aronson, MDEdward M. Beiser, PhD, JDJay S. Buechner, PhDJohn J. Cronan, MDJames P. Crowley, MDJohn P. Fulton, PhDPeter A. Hollmann, MDAnthony Mega, MDMarguerite A. Neill, MDFrank J. Schaberg, Jr., MDFred J. Schiffman, MDLawrence W. Vernaglia, JD, MPHNewell E. Warde, PhDWilliam J. Waters, Jr., PhD

OFFICERSYul D. Ejnes, MD

PresidentTilak K. Verma, MD, MBA

Vice PresidentDavid B. Ettensohn, MD

President-ElectFredric V. Christian, MD

SecretaryPeter A. Hollmann, MD

TreasurerMichael B. Macko, MD

Immediate Past President

DISTRICT & COUNTY PRESIDENTSPamela A. Harrop, MD

Bristol County Medical SocietyRobert A. Salk, DO

Kent County Medical SocietyJayanthi Parameswaran, MD

Newport County Medical SocietyStephen T. Conway, MD

Pawtucket Medical AssociationPatrick J. Sweeney, MD, PhD, MPH

Providence Medical AssociationR. Scott Hanson, MD

Washington County Medical SocietyNaeem M. Siddiqi, MD

Woonsocket District Medical Society

RHODEISLANDMedicine Health�

PUBLICATION OF THE RHODE ISLAND MEDICAL SOCIETY

VOLUME 85, NO. 4 APRIL, 2002

Medicine and Health\Rhode Island (USPS 464-820), a monthly publication, is owned and published by the Rhode Island Medical Society,106 Francis Street, Providence, RI 02903, Phone: 401-331-3207. Single copies $5.00, individual subscriptions $50.00 per year, and $100per year for institutional subscriptions. Published articles represent opinions of the authors and do not necessarily reflect the official policy of theRhode Island Medical Society, unless clearly specified. Advertisements do not imply sponsorship or endorsement by the Rhode Island MedicalSociety. Periodicals postage paid at Providence, Rhode Island. ISSN 1086-5462. POSTMASTER: Send address changes to Medicine andHealth\Rhode Island, 106 Francis Street, Providence, RI 02903. Classified Information: RI Medical Journal Marketing Department, 175Mathewson Street, Providence, RI 02903, phone: (401) 331-4637, fax: (401) 331-3594

Cover: “Block Island II,” oil on linen,32” x 32”. 2001, by Gretchen DowSimpson, a Rhode Island artist. “BlockIsland II” and other new paintings may beseen at Axelle Fine Arts, 148 SpringStreet, NYC, May 18 - June 19. Visit herwebsite: www.gretchendowsimpson.com

COMMENTARIES

114 An April Fool’s Day CommentaryJoseph H. Friedman, MD

115 The Arrival and Departure of a Baffling DiseaseStanley M. Aronson, MD, MPH

CONTRIBUTIONS

TRANSPLANTATIONGuest Editor: Reginald Y. Gohh, MD

116 The Evolution of Transplantation in Rhode IslandReginald Y. Gohh, MD, and Angelito F. Yango, MD

118 Blood and Marrow Stem Cell Transplantation at the Roger Williams MedicalCenter, 1999-2001

Gerald J. Elfenbein, MD, FACP

125 Infections in the Transplant RecipientStaci A. Fischer, MD

128 Live Donor Renal TransplantationPaul Morrissey, MD, and Bette Hopkins-Garcia, RN, MS, CCTC

131 An Update In Transplant Immunosuppressive TherapyMichael A. Thursby, DO, Angelito F. Yango, MD, and Reginald Y. Gohh, MD

COLUMNS

134 Images in MedicinePNEUMOCYSTIS CARINII CHOROIDITIS

King To, MD, and Marjorie A. Murphy, MD

135 Rhode Island Quality PartnersDIABETES AND HEART DISEASE

Raymond Maxim, MD

136 Advances in PharmacologyDRUG PRODUCT EXPIRATION DATES: PRACTICE IMPLICATIONS

Celia P. MacDonnell, PharmD, RPh, and Norman A. Campbell, JD, PhD, RPh

138 Health By NumbersDIABETES: AN EPIDEMIC OF A CHRONIC DISEASE

Barbara Kondilis, MSW, MPH, Joann Lindenmayer, DVM, MPH, andDona Goldman, RN, MPH

140 Public Health BriefingASTHMA, PARTICULATES, AND DIESEL EXHAUST

Leanne Chiaverini

COMMENT: Charles B. Sherman, MD

143 A Physician’s LexiconHANDS ON MEDICINE

Stanley M. Aronson, MD, MPH

143 Vital StatisticsEdited by Roberta Chevoya

144 Rhode Island Medical Journal Heritage

114Medicine and Health / Rhode Island

COMMENTARIES� �

�An April Fool’s Day Commentary

What a difference a scale makes!

It is not widely known that fava beansproduce large amounts of L-

diorthophenylalamine, L-Dopa, the per-cussor of dopamine, the neurotransmitterdeficient in Parkinson’s disease. To use favabeans to treat PD, however, requires in-gestion of about one cup three times daily.While this did cure constipation in thefew patients who completed the 1-monthprotocol, three dropped out and three suf-fered witnessed cases of spontaneous com-bustion. Improvement in motorsymptoms was statistically significant(p<.05) but minor in degree. Smokingsun-dried fava beans also reportedly im-proved symptoms but the report was con-founded by the subjects’ use of inhaledgingko and oral mink milk.

We made the obvious leap, when werealized that oral intake of fava beanswould be difficult, to using brain implants.Based on a two-decade experience of stick-ing all sorts of things into human brains,from human and pig brain cells, humanadrenal glands, electrodes, catheters, drugwafers, we reasoned that an all natural, or-ganically grown, free-range fava beanwould be more likely to be well toleratedthan any artificial material. Use of favabean is supported by the entire group ofMediterranean farming associations andis opposed by only a handful of biotechcompanies who failed in their attempts topatent the fava bean. They requested ahold on NIH funding of fava bean re-search until a patentable bean can be “in-vented.” This is under review by the Bushadministration.

The particular subspecies chosen,“favora Parkinsonian,” named by a descen-dant of the legendary physician, was, ironi-cally, found to contain the highestpercentage of L-Dopa among all speciesof the plant. It is found growing natu-rally in one of the uninhabited Greek is-lands. PD patients unable to tolerateL-Dopa or dopamine agonists by mouthwho were incapacitated by their worsen-ing motor symptoms were asked to vol-unteer for this project. The protocol had

been approved by the Culinary InstituteReview Board of Johnson & Wales Uni-versity and co-sponsored by the Agricul-ture Department of the InteriorDepartment of United States and the In-stitute of Alternative Medicine at the Na-tional Institutes of Health. Informedconsent was obtained prior to study entry.

The patients received 15 fragmentsper side of 1mm3 of the heart of the bean3 days after a sprout was identified. 5 frag-ments were implanted in the caudate and10 to the putamen (4 anterior & 6 poste-rior). The procedure was well tolerated,with no major adverse events identified.All subjects received fava bean implants.There were no sham procedures. Subjectswere evaluated at baseline, one week, fourweeks and then every four weeks post-implant using standard measures ofParkinson motor function. Subjects werecompared on the Unified Parkinson’s Dis-ease Rating Scale, motor section, at eachevaluation to their baseline score. Sub-jects were advised to avoid prolonged sun-light to prevent the implants fromexcessive growth. Surprisingly, to the au-thor, and the sponsors, no benefit wasnoted over the 25 weeks of the trial. Toavoid overlooking a potentially helpful andmuch needed intervention, a re-analysiswas undertaken by the Independent Safetyand Efficacy Monitoring Committee, un-derwritten by grants from Enron, and bythe Oversight Committee, sponsored bythe Arthur Anderson com-pany. Using a scale fre-quently employed in recentneurosurgical trials, TheUniversal Open Label Un-biased Assessment Tool.{See Figure} This simple glo-bal impression scale repre-sents a realistic evaluation ofthe subject as if he was a reallife patient in a private prac-tice. On this scale patientsare given 5 points for beingalive, 5 points if better, 10points if much better, 15

points if even better than that, 25 pointsif better than they’ve ever been but notactually mentally impaired.

Using this scale a very different out-come was documented. On this scale sub-jects improved by significant numbers(p<10-6) and the treatment was an obvi-ous success.

This brief description of a clinicalresearch project illustrates the importanceof choosing the best assessment instru-ments for a particular study. In many ar-eas, PD research is a good example; aparticular test becomes embedded as a“gold standard.” In assessing side effectsof antipsychotic drugs, for example, theSimpson Angus Scale has been the goldstandard for measuring parkinsonism, al-though no study by PD experts has everor would ever validate this scale which isquite obviously extremely poorly designed.Yet for 30 years it has been popular.

Open label studies are particularlyeasy to “under power,” that is, use too fewsubjects to attain statistical significance,so sensitive scales need to be utilized.

We thank our Oversight Commit-tee for forcing us to reassess our data. Wewould welcome readers’ suggestion ofother analyses but unfortunately when theNIH asked to review the data we discov-ered, much to our chagrin, that the recordshad been shredded.

– Joseph H. Friedman, MD

115Vol. 85 No. 4 April 2002

�The Arrival and Departure of a Baffling Disease

The world cowers as it now confronts a succession of unfamil-iar infectious diseases, new forms of environmental poison-

ing and novel ways of inflicting harm upon the human body.Many have wondered in recent years what unspeakable sins musthave been committed by people to justify the terror wrought bywave after wave of new contagions. In earlier years, people con-tend, there were no such calamities as HIV/AIDS, legionnaire’sdisease, Lyme disease, Ebola fever, toxic-shock syndrome, Hantafever and yet other microbial terrors. These newly arrived bur-dens, they conclude, must represent the microbiological preludeto a global Armageddon.

Yes, there are some 35 million humans currently afflictedwith the HIV pathogen; and other infectious ailments such asEbola fever, while perhaps not totally new, now constitute a pal-pable threat to the health of humans living beyond the Africanrain forests. Yet in terms of infectious disease, men and womenhave never been healthier. Smallpox has been made extinct andwill stay so unless man, in his infinite cleverness, uses it as a delib-erate terrorist weapon; polio and measles, by virtue of effectivevaccines, are close to global eradication; still other diseases of child-hood, including diphtheria, pertussis and rubella, are a thing ofthe past, at least in those populations wealthy enough to immu-nize their children. And still other diseases, once major scourges,through no known medical intervention have disappeared fromthe face of the earth.

In the category of spontaneously retreating diseases, con-sider a devastating neurological disease which, from 1917 to 1925,afflicted about 250,000 people in Europe, Australia, Japan andthe United States. The first cases, at least in the recent medicalliterature, were described in an article submitted by an Austrianneurologist named Constantine von Economo to the April, 1917,issue of Vienna’s weekly medical newsletter.

Von Economo portrayed an ailment which began innocentlyenough with moderate malaise, some fever, and a headache oftenaccompanied by pains in the muscles. But within a day or sothese symptoms were complicated by confusion, paralysis of someof the eyeball muscles and a dramatic somnolence [sleepiness].This latter finding prompted von Economo to call the diseaseencephalitis lethargica.

Close to half of his patients recovered with no further diffi-culties. But many, either immediately following the acute phaseor after a symptom-free interval of months or more, went on todevelop a progressively worsening rigidity of their limb muscles,rhythmic tremors of their hands, an expressionless face [despitethe coexistence of a high measure of anxiety], restlessness, increasedsalivation and an inversion of sleep pattern [sleeping during theday while remaining awake at night].

The mask-like face, the restless, jerky movements, the trem-ors, the rigidity of the limbs exhibited by those patients in thechronic phase of encephalitis lethargica closely resembled anotherneurological disease described by Parkinson in 1817.

Indeed, many neurologists called this new disorder post-en-cephalitic parkinsonism. But there were notable differences. Thedisease described by Parkinson appeared, most commonly, in theelderly with no preceding episode of encephalitis. The biphasic

disorder described by von Eonomo, on the other hand, arose atany age, including childhood.

The cases of this seemingly new disease, described in 1917,may not have been the first to be encountered by the medicalprofession. In 1675, Sydenham described something he called febriscomatosa [sleeping fever]; in 1712, in the German city of Tubingen,there was a cluster of cases with brain involvement calledSchlafkrankheit [sleeping sickness]; and in Italy in the 1890s therewas an ill-defined disease, called nona, distinguished by excessivesleepiness and other nervous system symptoms. But the numbersof people involved in each of these instances was small. And be-cause the clinical descriptions were so meager, it is difficult to de-termine whether these prior cases were of the same nature as the1917 cases. But one thing is certain: they never reached the mag-nitude or gravity which characterized the 1917-1925 outbreak ofencephalitis lethargica.

Before the epidemic had run its course, an estimated 40,000cases had been identified in the United States, many dying duringthe acute phase; a moderate number recovering completely andabout half going on to the protracted parkinsonian phase. Largenumbers of these patients populated the nursing homes, particu-larly on the East coast. A motion picture, The Awakening, has de-scribed their plight.

The epidemic in the United States coincided with the greatinfluenza pandemic of 1918-19; and while some at first thoughtthat one caused the other, this view has not been accepted by pa-thologists [who demonstrated very different microscopic changesin each of the two diseases], by epidemoiologists [who showedthat each disease had its own trajectory] or by neurologists [whodistinguished the two diseases solely by clinical examination].

In England there were an estimated 10,000 cases and in west-ern Europe an additional 120,000 cases. The pathologic findingswere consistent with an infection of viral origin although no virushad ever been convincingly recovered; admittedly, the technics forviral isolation in those days were primitive.

Two curious epidemiologic features bear noting. First, mostcases arose in the late winter months, thus suggesting that insectswere not involved in its dissemination. Second, this epidemic wasvirtually confined to Europe, the United States, Canada, Australiaand Japan.

Encephalitis lethargica remains a two-fold mystery. First, whatcaused it? And second, what factors, either ecological or man-made, accounted for its essential disappearance?

Answers to these questions are of more than academic inter-est. Medicine still has no inkling of the causative agent of thisdisease; therefore it has no way of preventing the disease or identi-fying its pathogen. And since the profession doesn’t know whatfactor or factors caused it to wane in the 1920s, it has no interven-tion to employ as a preventive weapon should it reappear.

When virologists somberly reflect on diseases which may ariseunbidden in the foreseeable future, encephalitis lethargica is alwaysincluded in their list of possible candidates.

– Stanley M. Aronson, MD, MPH


�The Evolution of Transplantation in Rhode Island

Reginald Y. Gohh, MD, and Angelito F. Yango, MD

Organ transplantation has estab-lished itself as effective therapy for

end-stage renal, hepatic, cardiac and pul-monary disease, with more than 20,000grafts performed annually in NorthAmerica.1 Similarly, successes of hemato-poietic cell transplantation have resultedin a large number of patients becominglong-term survivors of diseases that pre-viously were fatal. Before 1994, suchprograms did not exist in Rhode Island.Area residents who required transplan-tation travelled to Massachusetts, Con-necticut or farther to obtain treatment.Such inconveniences not only added tothe total cost of the transplant procedure,but also heightened the already consid-erable stress and anxiety of patients, whohad to undergo the procedure away fromhome, removed from family and friends.

This issue of Medicine & Health/RhodeIsland focuses on the transplant servicesthat have become available in Rhode Is-land within the last decade, with particu-lar emphasis on kidney transplantation.Dr. Gerald Elfenbein, the director of theRoger Williams Medical Center’s(RWMC) Stem Cell Transplant Pro-gram, will also provide information re-garding the innovative therapies nowavailable at his center.

To evaluate Rhode Islanders’ needfor a kidney transplant program, ananalysis was undertaken to estimate thenumber of local residents who mightbenefit. Although the actual number ofkidney transplants performed on RI resi-dents in transplant centers within NewEngland increased from 12 in 1983 to28 in 1991, this value was not an accu-

rate representation ofneed, since it did notinclude the numberof Rhode Islanderswho would have un-dergone transplanta-tion if there hadexisted a transplantcenter within thestate. National utili-zation rates for renaltransplantation ex-pressed in relation-ship to the totalnumber of U.S. resi-dents maintained ondialysis yielded amore accurate mea-sure of need. (Figure1) Using this for-mula, it was esti-mated that 43patients should havereceived a renal al-lograft in 1991,yielding an unmetneed of 15 trans-plants in that year.This striking differ-ence persisted evenafter adjusting for pa-tient age (since an

older patient population may not be assuitable for transplantation). Thus, al-though Rhode Island had one of the larg-est dialysis populations per capita in thecountry, Rhode Islanders received fewerkidney transplant procedures annuallythan U.S. citizens on average. In short,a substantial number of Rhode Islandersdid not have adequate access to trans-plantation and would have benefitedfrom the creation of a local site.

Although the lack of a local programwas clearly a factor in limiting access totransplantation, such procedures are impos-sible without the availability of healthydonor grafts. The supply of donor grafts isthe major factor affecting access to trans-plantation. However, these limitations canbe greatest for residents of regions lackingtransplantation programs, in large part dueto the policies that govern regional alloca-tion of donor grafts to specific institutions.These policies give regional priority for theuse of grafts to those centers that also re-trieve them. Although hospitals in RhodeIsland could harvest cadaver kidneys, theycould not take advantage of their regionalpriority for utilizing them because no areahospitals performed transplant procedures.This meant that organs harvested in RhodeIsland were not, as a matter of priority, as-signed to local residents, even when localresidents may have been in need.

Given the demonstration of localneed, the Kidney Transplant Program atRhode Island Hospital was establishedin 1996. Since performing its first ca-daver kidney transplant in March 1997,the program has grown, with more than250 kidney transplants performed to date(Table 1). More importantly, the cre-ation of a local program has resulted in asteady increase in the number of RhodeIsland residents receiving kidney trans-plants (Table 2). Over the last three years,the average annual transplant rate locallynow exceeds the national rate (6.2 vs. 5.1transplants/100 dialysis patients), repre-senting a diametrical change from previ-ous results. This is a clear indicator thataccessibility to transplant services hastruly improved in Rhode Island.

Figure 1. Estimate Need of KidneyTransplantation in Rhode Island2,3

Step 1: U.S Rate of Transplantation per DialysisPopulation (1991): (# Kidney transplants)/U.S. Dialysis Prevalent Population = 10,026/142,488 =

7 Kidney Transplants per 100 DialysisPatients

Step 2: Applying U.S. Rate of Transplantation to RIDialysis Population (1991) 7/100 x 612 =

43 RI Residents Needed Kidney Trans-plants in 1991

Table 1. Rhode Island Transplant Rate4

ActualExpected Number of

US Transplant Number of RI TransplantRate (per 100 RI Transplant Recipients

Year dialysis pt.) Recipients (Tx Rate)

1993 6.3 43 30 (4.3)

1994 5.8 41 42 (5.5)

1995 5.6 42 37 (4.8)

1996 5.5 43 53 (6.6)

1997 5.2 41 59 (7.0)

1998 5.2 46 56 (5.7)

1999 4.9 44 48 (5.8)

117Vol. 85 No. 4 April 2002

Despite these encouraging results, amore somber observation is the stagnantrate of organ donation both nationally andlocally. Simply put, the number of kidneytransplants performed each year cannotkeep pace with the number of candidateson the waiting list. Despite a 25% increasein the number of kidneys recovered nation-ally from cadaver donors between 1990 to1999, the kidney waiting list has more thandoubled in the same period.1 When thetransplant program was established atRhode Island Hospital, it was hoped thatorgan donation would be spurred by in-creased public awareness and acceptance ofthe issue and, ultimately, more willingnessto donate organs. Furthermore, clinicianswould be more motivated to improve com-munity education regarding organ dona-tion. Unfortunately, efforts to increase thecadaver donor pool have been generallyunsuccessful. Data from the New EnglandOrgan Bank, the local organ procurementorganization, show that the potential or-gan donor pool has remained unchangedwithin the last decade, resulting in longerwaiting times for those individuals seekinga cadaver kidney. The increasing demandfor organs has increased the pressure toidentify new sources of donor organs.These include the use of “marginal do-nors” (as determined by age, cause of death,or hemodynamic instability) and in par-ticular, increased reliance on living relatedand living unrelated donors. As experiencewith the latter has accumulated, the resultshave been surprisingly superior to thoseafter cadaver transplantation.4 Thus for thefirst time, relative volume of living donortransplantation now exceeds 50% of totaltransplant activity at our center. Dr. PaulMorrissey and Bette Hopkins-Garcia dis-cuss the efficacy and difficult ethics behindthe use of living donors, both locally and

worldwide. Nevertheless, the shortage ofcadaver organs continues to pose the mostsevere limitation to the number of patientswho could potentially benefit from trans-plantation.

The unprecedented success of pa-tients undergoing organ replacementtherapy is strongly correlated to the de-velopment and introduction of new im-munosuppressive agents to the clinicalarmamentarium. Depending on the or-gan transplanted and the donor source,graft survival in the 85-95% range at 1year has become commonplace,1 withacute rejection rates reported at less than10%. Because many of these recipientsare living longer and ultimately return-ing to the care of their referring physi-cians, we have provided a review of thenewer immunosuppressive drugs. Par-ticular emphasis is placed on issues rel-evant to the primary care physician, suchas drug interactions and side effect pro-files. As the incidence of acute allograftrejection has decreased dramatically inthe past several years, increasing atten-tion has focused on the management oflong-term complications in transplant re-cipients. Among these, infectious com-plications remain a major cause ofmorbidity and mortality for transplantrecipients. Dr. Staci Fischer briefly re-

views the epidemiology andclinical behavior of infection inthe post-transplant recipient.

The participation of Dr.Fischer, an infectious diseasespecialist, in this forum high-lights a generally unappreciatedaspect of the transplant process:any transplant procedure ishighly complex, requiring theactive involvement of a widerange of health care specialistsin a multidisciplinary ap-

proach. Furthermore, transplant recipi-ents often have complex medical andsocial histories and complications arisingfrom their primary illnesses. It is impera-tive, therefore, that the patient’s primaryphysician be available nearby to take anactive role in clinical decisions that ariseduring the patient’s hospitalization for thetransplant. Thus, the creation of localtransplant centers has not only directlyprovided vitally needed services to a num-ber of Rhode Island residents, but hasalso provided indirect benefits for theentire state. By enhancing the develop-ment of a local system of health servicescatered to these individuals, the “cultureof transplantation” has become firmly en-trenched in Rhode Island.

REFERENCES1. Excerpts from the 2000 Annual Report

of the U.S. Scientific Registry of Trans-plant Recipients and the Organ Procure-ment and Transplant Network.

2. Excerpts from 1991 End Stage RenalDisease Network of New England An-nual Report.

3. Excerpts from the 1991 Annual Reportof the U.S. Scientific Registry of Trans-plant Recipients and the Organ Procure-ment and Transplant Network.

4. UNOS Data Reports, 1993-1999.5. Terasaki PI, Cecka JM, Gjertson DW,

Takemoto S. High survival rates of kid-ney transplants from spousal and livingunrelated donors. NEJM 1995;333:333-6.

Reginald Y. Gohh, MD, is MedicalDirector, Division of Organ Transplanta-tion, Rhode Island Hospital, and AssistantProfessor of Medicine, Brown MedicalSchool.

Angelito F. Yango, MD, is AssociateMedical Director, Division of Organ Trans-plantation, Rhode Island Hospital, andAssistant Professor of Medicine, BrownMedical School.

CORRESPONDENCE:Reginald Y. Gohh, MDRhode Island HospitalDivisions of Organ Transplantationand Renal Diseases593 Eddy Street, APC-921Providence, RI 02903phone: (401) 444-8345fax: (401) 444-3283e-mail: [email protected]

Table 2. Kidney Transplants atRhode Island Hospital

Year Cadaver Donor Living DonorTransplants Transplants

1997 26 9

1998 27 25

1999 29 24

2000 31 32

2001* 29 33

*As of October 8, 2001

�

....the number of kidneytransplants performed

each year simply cannotkeep pace with the

number of candidatesplaced on the waiting list.


�Blood and Marrow Stem Cell Transplantation at the

Roger Williams Medical Center, 1999-2001

Gerald J. Elfenbein, MD, FACP

Exactly three years to the day of thesubmission date of this manu-

script, I became Director of the RogerWilliams Medical Center’s (RWMC’s)Cancer Center and Director of theRWMC’s Blood and Marrow Trans-plant Program. These three years havebeen invigorated with the acquisitionof talented colleagues by recruitmentand the performance and communica-tion of groundbreaking clinical re-search. I will describe some of thatwork. For the next three years, ourprogram has two major thrusts: anexciting and novel form of immuno-therapy in the setting of minimal re-sidual disease and our version of thenon-myeloablative allogeneic stem celltransplant that has recently becomepopular. Finally, I will close with a ba-sic research concept, tying everythingtogether in a nice, even if futuristic,package.

FIVE PILOT STUDIES:Following are five of the studies

that we completed by what may be anovel method.

1. Conventional chemotherapyhas little to offer in terms of long-termdisease-free survival for patients withhigh-risk lymphomas. High-dose che-motherapy and autologous (self-do-nated) stem cell transplantation offerthese patients an opportunity forlong-term disease free survival.At RWMC1, we explored thetherapeutic value of a well-tol-erated, high-dose chemo-therapy regimen, used formany years in patients withbreast cancer, the so-calledCTC regimen, consisting of 6g/m2 of cyclophosphamide,500 mg/mz of thio-TEPA and900 mg/m2 of carboplatin, in17 patients. Patient character-istics included: age - range 21to 63 (median 50) years; gen-der - 11 males and 6 females;

disease - 7 with Hodgkin’s disease(HD; 6 nodular sclerosis and 1 lym-phocyte depleted) and 10 withnon-Hodgkin’s lymphoma (NHL; 4large cell, 3 follicular mixed, 1 mantlecell, 1 immunoblastic, and 1 follicularsmall cell); disease status - 9 (3 HD and6 NHL) in first relapse, 3 (1 HD and2 NHL) in second relapse, 2 (HD) inthird relapse, 1 (NHL) in first com-plete remission, and 2 (NHL) in firstpartial remission. All patients were in-duced with 4 cycles of quite aggressivechemotherapy, which consisted ofcourses of continuous infusion of cy-clophosphamide and etoposide (CE;developed by Elfenbein’s team inGainesville, FL2, alternating withcourses of dexamethasone, cytosinearabinoside, and cisplatin (DHAP).Peripheral blood stem cell (PBSC) col-lection (to be reinfused after CTC) wasperformed by leukapheresis (in collabo-ration with the Rhode Island BloodCenter)- during recovery from the lastcycle of DHAP. With a maximum fol-low up of 46 months and a minimumfollow up of 11 months (median of 24months) for survivors, theKaplan-Meier estimate for overall sur-vival at 25 months is 52% and for dis-ease-free survival at 25 months is 47%.Of the subset of 4 “better” but stillhigh-risk patient (3 with HD in firstrelapse and 1 with NHL in first com-

plete remission), 2 are alive and freeof disease and 2 have died (1 of sepsisand 1 from recurrent disease). For the7 patients who progressed, the mediantime was 3 months (range 1 to 7months). CTC offers cyclophospha-mide at a very high dose and two newalkylating drugs, thio-TEPA andcarboplatin, for lymphomas. CTC ap-pears to be quite active in a broad rangeof lymphomas, is deliverable in theoutpatient setting, and should be ofuse in consolidating first complete re-missions in high-risk NHL and sec-ond complete remission of high-riskHD. Finally, CTC is sufficiently welltolerated (there were two only toxicdeaths [12%] in this group of high-riskpatients) and has a quick enough re-covery of granulocyte count (mediantime to reach an absolute granulocytecount (AGC) of 500/uL was day 12)and platelet count (median time torecovery of platelet (PLT) count of20,000/uL was day 15) after PBSCinfusion to permit relatively early in-troduction of a post-transplant treat-ment strategy to reduce the probabilityof relapse after high dose chemo-therapy followed by autologous stemcell transplantation for high-risk lym-phomas. Comment: This Phase IIstudy establishes the well-toleratedCTC regimen as a safe and effectiveregimen for lymphomas making it a

119Vol. 85 No. 4 April 2002

platform onto which post-transplantconsolidation therapy can be built (seebelow).

2. Many experts have preferredperipheral blood stem cells as a sourceof stem cells for autologous transplan-tation (see below). Failure to collectsufficient numbers of CD34 (the sur-face marker identifying hematopoieticstem cells) positive (+) PBSC aftermobilization with chemotherapy andgrowth factors (chemogrowth factormobilization) has, however, been seenin patients who are heavily pretreatedor are older aged and/or have had priorfludarabine therapy. Failed attempts atremobilization often disqualify thesepatients as candidates for autologoustransplantation. At RWMC and in col-laboration with the Hackensack Uni-versity Medical Center (HUMC) andProgenitor Cell Therapy (PCT) inNew Jersey,3 we studied four heavilypretreated patients with NHL and onepatient with primary refractory HD forwhom we could not collect at least 2 x106 /kg CD34+ PBSC (the standardminimum collection required to ensureengraftment after high dose chemo-therapy) after the first course of mobi-lization. Four were mobilized first withcyclophosphamide, prednisone andG-CSF (our best chemogrowth factormobilization regimen for hematologicmalignancies). One was mobilized firstwith high doses of the growth factorG-CSF alone (10ug/kg/day for 3+days). Second mobilization attemptswere made in three patients withG-CSF. Only in one patient did wecollect more than 2 x 106/kg CD34+PBSC in a single mobilization attemptlet alone cumulatively. Subsequently,all 5 patients were primed with G-CSFat 10ug/kg/day for 2 days.On the day of a full bonemarrow harvest as aback-up collection, the

first 80ml of marrow aspirated (2 to2.5 ml/site) were cultured in theAastromReplicell™ by PCT for 12days. Expanded marrow cells were in-fused 48-96 hours after the completionof high dose chemotherapy with theCTC regimen (see above) for the 4patients at RWMC and after BVAC (adifferent high dose chemotherapy regi-men) for the patient at HUMC. Theday of infusion of expanded marrow iscalled day 0 of transplant. On day +lafter transplant, all cryopreserved,stored PBSC were thawed andreinfused. Expanded marrow cells werewell tolerated. Patient characteristics,CD34+ PBSC numbers, and expandedmarrow cell numbers plus AGC andPLT count recovery times after autolo-gous transplant following high dosechemotherapy are shown in Table 1.

With the expectation of delayedengraftment as a result of poor firstPBSC collection, these patients wouldnot have been considered autologoustransplant candidates. With the addi-tion of expanded marrow cells toPBSC, autologous transplantation wasmade possible for these five patientswhose first collections were inadequate.AGC recovery was prompt (medianday to AGC >500/uL was day 13). PLTrecovery was prompt (median day toPLT count >20,000/uL was day 20),as well, except in the two patients whohad received prior fludaribine therapy.We concluded that ex vivo marrowexpansion is effective in providing asuboptimal PBSC collection withenough of the right cells to producerapid granulocyte and platelet recov-ery. At this point in time, we don’tknow exactly what the “right” cells are- stem cells or accessory cells. All 4NHL patients responded to high dose

chemotherapy and have toleratedrituximab (antiCD20 antibody)to reduce the probability of re-lapse. The HD patient refusedinterferon after completing hispost-transplant irradiationtherapy. Comment: This smallstudy demonstrated clearly that

bone marrow may be a valuable sourceof expandable stem (or other) cells (seebelow). The biggest problem is howlong will it take Aastrom to bring theReplicell™ to market?

3. L-phenylalanine mustard(L-PAM) is one of the most activeagents for multiple myeloma (MM)available. The maximum tolerable doseof L-PAM is 240 mg/m2 in high-dosechemotherapy and less is used in com-binations with busulfan or total bodyirradiation. The usual “transplant” doseof L-PAM is 200 mg/m2 followed byan autologous PBSC infusion. Thisusually produces a lengthy hospitaliza-tion with significant enteritis and mu-cositis. At RWMC,4 we performed afeasibility study to determine if 3 cyclesof L-PAM (followed by autologousPBSC infusion each time on the dayafter L-PAM) could be delivered at 100mg/m2 at 3-week intervals for a totalof 300 mg/m2 and on an outpatientbasis. Four patients withchemoresponsive, stage III MM hadPBSC mobilized with cyclophospha-mide, prednisone and G-CSF. AfterCD34+ cell selection, PBSC were fro-zen in 3 aliquots. A back-up,unselected, PBSC collection was alsocryopreserved. G-CSF was started day+1 and trovafloxacin and fluconazolewere started day +5 after PBSC infu-sion. Of the 12 cycles, 1 cycle was de-layed 1 week because of a centralvenous access line infection and 1 cyclewas delayed because of a death in thepatient’s family. There were 7 admis-sions: 5 for neutropenic fever (42%)and 1 each for mild enteritis and dis-seminated Herpes zoster. The datafrom the study are shown in Table 2.

For patient #3, delayed AGC re-


coveries were seen despite acceptablenumbers of CD34+ cells infused; forcourse #3, back-up PBSC were givenwhen AGC recovery appeared to be lateagain and prompt engraftment ensued.When patient #4 experienced lateAGC recovery during cycle #1 withselected cells, we immediately infusedback-up PBSC for that and both sub-sequent cycles; prompt engraftmentwas observed from then on. All 4 pa-tients showed reduction in theirM-proteins. After recovery from thethird transplant, patients #l, #3, and#4 received alpha-interferon and pa-tient #2 received thalidomide becauseof prior exposure to interferon. These4 patients demonstrate that 300 mg/m2 L-PAM can be delivered within a

space of 9 weeks with acceptablenon-marrow toxicities and with rapidrecovery of AGC and PLT counts af-ter each cycle especially after the thirdcycle which is the cycle that is the pre-lude to post-transplant therapy. Com-ment: This feasibility study delivered50% more L-PAM in the same periodof time as a standard autologous trans-plant and recovery from transplant (63days or 2 months) with much less tox-icity. Moreover the patients were ingood enough hematologic shape andgeneral health to start post-transplantimmune based therapy.

4. In 1998, we initiated a strategyto improve clinical disease-free survivalfor patients with hematologic malig-

nancies. The strategy has five steps:a. Increased intensity of disease

specific, induction therapy (maximalcytoreduction; CE/DHAC[carboplatin switched for cisplatin tominimize nephrotoxicity developed byElfenbein’s team in Tampa] for NHLand HD and DCIE [dexamethasone,cyclophosphamide, idarubicin, andetoposide developed by Elfenbein’steam in Tampa5] for MM).

b. Mobilization of blood stem cellswith chemotherapy and growth factorfor fastest recovery of granulocytes andplatelets (cyclophosphamide, pred-nisone and G-CSF) instead of justG-CSF alone and to provide an anti-tumor effect as well.

c. Positive selection of CD34+cells, i.e., stem cells (which, also, purgesthe PBSC collection of tumor cells, i.e.,negative selection of tumor cells).

d. High dose chemotherapy withknown effective regimens (disease spe-cific but with lowest known toxicity;CTC for NHL and HD and L-PAM x3 for MM).

e. Consolidation with disease-spe-cific immunotherapy (treating minimalresidual disease [see below]). AtRWMC,6 we evaluated the first 18 con-secutive patients who were transplanteligible and are in or have already com-pleted the 5th step. Among the patientswere 10 with NHL, 1 with HD, and 7with MM. Only 5 (28%) would beconsidered to be good prognosis pa-tients (first complete remission of NHLor first partial remission of MM). Only7 (39%) had sufficient CD34+ cellscollected to allow positive selection.The 11 lymphoma patients (63%) re-ceived CTC (see above) and the 7 MM(37%) received 3 cycles of L-PAM (seeabove). AGC recovery to > 500/uL (seebelow) was prompt in 16 pts (89%).Lymphoma patients received involvedfield irradiation for residual masses orhistory of bulky disease. One patient(5.5%) refused immunoconsolidationtherapy after completing irradiation forHD (see above). The 12 patients (67%)whose disease was CD20 positive (asurface marker for B cells, 2 with MMand 10 with NHL) received all fourplanned weekly doses of antiCD20monoclonal antibody (rituximab). Five

Figure 1.

Figure 2.

121Vol. 85 No. 4 April 2002

of the 7 MM patients (71 %) werestarted on alpha-interferon but only 2(40%) tolerated chronic administra-tion of interferon. With a medianfollow-up of 15 months, there haveonly been 4 patients (22%) who de-veloped disease progression. There havebeen 6 deaths (33%), 4 from progres-sive disease (22%) and 2from late,trimethaprim-sulfamethoxazoleresistant Pneumocystiscarinii pneumonia(11%). We found it fea-sible to incorporateimmunoconsolidationinto the treatment afterautologous transplant butit is too early to commentupon disease-free sur-vival.6 Comment: Nowyou can see where wewere going all along withour strategy to improvedisease-free and overallsurvival by betterc y t o r e d u c t i o npre-transplant, less toxictransplant regimens, andimmune based therapypost-transplant. We havecompared the NHL pa-tients in this study (#4)to the NHL patients instudy #1. They (#4) areabout as similar as youcan get to historical con-trols (#1). They (#1) weretreated nearly identicallyexcept for thep o s t - t r a n s p l a n timmunoconsolidationtherapy (#4). With all thereservations intrinsic tocomparing one smallphase II study (#4) to an-other small phase II study(#1) performed at an ear-lier point in time, we didsee a significant differencein freedom from relapseand disease-free survivalfor the patients who re-ceived the post-transplanta n t i - C D 2 0immunoconsolidationtherapy (Figures 1 and 2).

5. There have been many debateswhether blood and marrow derivedstem cells engraft at significantly dif-ferent rates after transplantation.Bensinger for the Seattle group (NEJM2001;344:175-81) stated that theirrandomized clinical trial (RCT)

“confirm(ed) that engraftment occursmore rapidly with peripheral-bloodcells than with bone marrow” in allo-geneic transplants. In 1995, Elfenbein’sTampa team published preliminarydata7 and, in 1999, they published thefinal report8 “of the first prospective,stratified, randomized trial (also an

Figure 3.

Figure 4.


RCT) comparing G-CSF primed bonemarrow cells with G-CSF mobilizedperipheral blood cells for pace of he-matopoietic engraftment” demonstrat-ing identical granulocyte and plateletrecovery times for the two types of stemcells after autologous transplants. Howcould these two RCTs be in such starkcontrast? The difference between thetwo RCTs is not whether the trans-plants were autologous or allogeneic,nor whether post-grafting therapy in-volved methotrexate or not. The dif-ference is how the donor was treatedprior to collection of the stem cells. InBensinger, to collect PBSC the donorwas pretreated with G-CSF at 16 ug/kg/day for 5 days whereas to collectstem cells from the bone marrow(BMSC) NO pretreatment was given.In Bensinger, cyclosporine and meth-otrexate were given as acute graft ver-sus host disease (GVHD) prophylaxis.Myeloid engraftment was defined asthe first of three consecutive days thatthe AGC was more than 500/uL. AtRWMC,9 we evaluated the results ofour recent experience of 7 consecutivepatients who had been transplantedwith BMSC from healthy donors, allof whom had been pretreated withG-CSF at a dose of 10 ug/kg/day for 3days. Only cyclosporine was utilized asGVHD prophylaxis. Prior to the re-turn to BMSC, albeit G-CSF primed,we had performed a consecutive seriesof 15 G-CSF mobilized PBSCallotransplants that was rather novel inits time (starting June 1994). Table 3summarizes the comparative study factsand presents engraftment results as themedian day (range) for the AGC toexceed 500/uL.

We believe that large RCTs willconfirm that G-CSF pretreated mar-row will engraft just as rapidly asG-CSF mobilized peripheral blood andmay, potentially, produce less GVHD.RCTs, no matter how large, may onlybe relied upon for interpretation withinthe bounds of their experimental de-sign. Apparently, Bensinger et al. neveranticipated that the confounding vari-able G-CSF was responsible for the ef-fect they observed (difference inengraftment times) and not the ana-tomical site from which the stem cells

were collected. Finally, these data dem-onstrate that post-grafting methotrex-ate delays the pace of granulocyterecovery considerably. Comment: Thedebate will rage on about bone mar-row stem cells and blood-derived stemcells but I am convinced that the twoare equivalent from the point of viewof early engraftment. Bone marrowcertainly offers advantages from thepoint of view of long-term engraftmentwhile blood derived stem cells offeradvantages from the point of view ofantitumor activity. Both scenarios aredependent on the cells that contami-nate the stem cell collections.

TWO NEW THRUSTS

I have been a “card carrying mem-ber” of two “brotherhoods”, immunol-ogy and experimental hematology,since 1967 when I came under the tu-torial wing of George Santos at JohnsHopkins. Therefore, I recruited LarryLum from Wisconsin to develop a pro-gram in cellular immunotherapy butwith an intriguing twist. Immuno-therapy certainly has not been as suc-cessful as originally hoped. Why? Whatinterested me so much in Larry’s workis how low the effector-to-target ratioswere in his in vitro cytotoxicity assaysand that effectors could kill a secondtarget cell in sequence. Potentially, thiswould help with the problem in vivowhere the tumor vastly outnumbers theimmune cell population. He does thisby expanding and activating patient Tcells ex vivo (call them activated T cellsor ATC). But there is the problem oftrafficking. How does he get the ATCto the tumor sites and, if they get there,why would they stay there? The answerto the first question is the cells arriveat the tumor sites in the blood at ran-dom unless they are directly injectedinto the tumor or are chemoattracted.Not easy to do, control, or ensure. Thesecond question is more easily an-swered: “arm” the ATC with abispecific antibody that, on the onehand, binds to the T cell and, on theother hand, binds to the tumor cell.Larry makes these “bi” antibodies inhis own lab. His project is not onlyIRB-approved but also FDA-approvedand looks at arming ATC with an an-

tibody to HER2/neu found on somebreast cancer cells and most prostatecancer cells. Patients with minimal re-sidual disease are being treated now.There is also a project for metastaticbreast cancer. In the not-too-distant fu-ture, we hope to have an antibody toEpCAM, which binds to a diversenumber of carcinomas. Armed ATCmay be considered the autologous ul-timate in immunoconsolidationtherapy.

Back to experimental hematology,I recruited Pete Quesenberry fromMassachusetts, a world-class experi-mental hematologist whose successwith low-dose total body irradiationand cellular immune therapy withHLA identical sibling donor cells inpatients with hematologic malignan-cies made me take notice as this wasthe least toxic of all the “mini”-transplant regimens in the world. Hisgoal was mixed chimerism (a state ofco-existence of donor and host cells sothat there would be no graft versus hostdisease and, because there was mixedchimerism, obviously there wasn’t anyrejection). But, even with mixed chi-merism, there was an antitumor effect,the graft versus tumor effect (GVT),else the diseases would not have got-ten better. All this without major sideeffects. Simply marvelous pilot data.We activated this protocol at RWMC.Further, I have been struggling formany years with the problem of find-ing donors for patients when they don’thave HLA-identical sibling donors,which happens more than 65% of thetime. I have spent many years pursu-ing autologous transplants and study#4 is the ultimate expression of thisresearch direction but it is limited bythe number of antibodies that are cur-rently available like rituximab forNHL. None yet for MM, for instance.HLA matched, unrelated donor(MUD) stem cells may now be ob-tained (about 65% of the time) fromadults and from cord blood but theformer transplants are very difficult toperform (read very toxic) and the lat-ter are still rare in adults (because oflow numbers of stored cord bloods andexpansion problems). See Figures 3 and

123Vol. 85 No. 4 April 2002

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ith important purchases, the lowest price isn’t always the best buy. Quality is more critical in the purchase of a home,

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4 for 5 year overall survival data after HLA-identical trans-plants, MUD transplants and autologous transplants for avariety of diseases. HLA-haplomatched (halfmatched) re-lated donor allogeneic stem cell transplants have been per-formed in the new world as well as in the old world but inlimited numbers. They are of the same difficulty as MUDtransplants (read toxicity). The question, then, that Pete andI posed to each other was could mini-HLA-haplomatchedallogeneic transplants be done using the same methodologyas in his HLA identical sibling mini-transplants? If success-ful, there would be mixed chimerism, bi-directional toler-ance, and dynamite GVT. At the time of this writing wehave performed 13 of these HLA-haplomatched transplants.We are using a fixed number of CD34+ cells/kg and slowlyescalating the number of T cells/kg in the graft after only100 cGy of total body irradiation. Patients have toleratedthe regimen very well so far. Patients with solid tumors andpatients with hematologic diseases are both eligible. In thefuture, we will test donor ATC as opposed to quiescent do-nor T cells. GVT with quiescent donor T cells or donorATC may be considered the allogeneic ultimate in the strat-egy of immunoconsolidation therapy.

THE CLOSER

Now the closer, the ultimate in bringing the bench tothe bedside, in combining immunology with experimen-tal hematology, and in using adult stem cells to treat dis-eases other than those of the hematopoietic system or toattack cancer. We are working on a project in which adultstem cells will be targeted to ischemic myocardium withbispecific antibodies. If this troika of cardiology, stem cellbiology, and immunobiology is successful, we’ll be in thebrave new world of treating ischemic heart disease and,potentially, congestive cardiomyopathies, in the future.

REFERENCES1. Malik S, Oblon D, Falvey M, Elfenbein G. High dose cyclo-

phosphamide, thio-TEPA, and carboplatin, the CTC regimen,for high-risk lymphoma. Blood 1998;2:368b.

2. Cassano W, Graham-Pole J, Elfenbein G, et al. Phase I/II trialof escalating doses of etoposide (VP) and cyclophosphamide(CY) followed by autologous marrow transplantation (ABMT)in patients with relapsed malignancies Proc ASCO 1989;8:13.

3. Elfenbein G, Malik S, Pecora A, et al. Engraftment after highdose therapy for lymphoma with low doses of CD34+ periph-eral blood stem cells and ex vivo expanded bone marrow cells.In: Autologous Blood and Marrow Transplantation, Proceedingsof the 10th International Symposium. (Dicke KA, Keating A,Eds.). Carden Jennings, Charlottesville, VA, 2001:590-6.

4. Malik S, Lum L, Sharon A, et al. Feasibility of dose densetherapy of multiple myeloma with 1-phenylalanine mustard.In: Autologous Blood and Marrow Transplantation, Proceedingsof the 10th International Symposium. (Dicke KA, Keating A,Eds.). Carden Jennings, Charlottesville, Virginia, 2001:487-92.

5. Ballester OF, Moscinski LC, Fields KK, et al. Dexamethasone,cyclophosphamide, idarubicin and etoposide (DC-EE): Anovel, intensive induction chemotherapy regimen for patientswith high-risk multiple myeloma. Brit J Hematol1997;96:746-8.

6. Elfenbein G, Malik S, Falvey M, et al. Feasibility of a five-stepstrategy to improve out-comes for autologous stem cell trans-plants for hematologic malignancies. Experimental Hematol-ogy, 2001;29:93.

7. Janssen WE, Smilee RC, Elfenbein GH. A prospective random-ized trial comparing blood vs. marrow derived stem cells formeatopoietic replacement following high dose chemotherapy. JHematotherapy 1995;4:139-40.

8. Janssen WE, Elfenbein GH, Perkins JB, et al. Final Report ofthe first prospective, stratified randomized trial comparing G-CSF primed bone marrow cells with G-CSF mobilized pe-ripheral blood cells for pace of hematopoietic engraftment anddisease free survival after high dose therapy and autotrans-plant. In: Autologous Blood and Marrow Transplantation, Pro-ceedings of the 9th International Symposium. Dicke KA, KeatingA, eds. Carden Jennings, Charlottesville, VA 1999:580-98.

9. Elfenbein G, Oblon D, Malik S, et al. Bone marrow stemcells do engraft rapidly if collected after G-CSF priming ofhealth donors: Counterpoint. Blood 2001;86:413a.

Gerald J. Elfenbein, MD, FACP, is Director, Cancer Cen-ter, Director, Blood and Marrow Transplant Program, RogerWilliams Medical Center, and Professor of Medicine, BostonUniversity.

CORRESPONDENCE:Gerald J. Elfenbein, MD, FACPBlood and Marrow Transplant ProgramRoger Williams Medical Center825 Chalkstone AvenueProvidence, RI 20908phone: (401) 456-6565fax: (401) 456-6793e-mail: [email protected]

125Vol. 85 No. 4 April 2002

�Staci A. Fischer, MD

Infections in the Transplant Recipient

Despite advances in allograft match-ing, transplant surgical techniques,

and immunosuppressive agents, infec-tion remains a significant complicationof renal transplantation. As recipientssurvive longer following transplantation,primary care physicians andnephrologists in the community must beaware of the epidemiology and clinicalbehavior of infection in the post-trans-plant patient.

Fever, considered a cardinal sign ofinfection in the immunocompetant host,is often absent in the transplant recipi-ent, in whom corticosteroids attenuatethe febrile response.1,2 Leukocytosis maybe absent as the result of azathioprine ormycophenolate mofetil therapy.3 As aresult, familiarity with the clinical pre-sentation and timing of infections aftertransplantation are critical in reorganiz-ing the presence of infection in thesecomplex patients.

PRESENTATION OF INFECTION INTHE POST-TRANSPLANT PATIENT

The clinical presentation of infec-tions in renal transplant recipients maydiffer significantly from that inimmunocompetant hosts.4,5 Patientsmay present with vague symptoms suchas fatigue, dyspnea, headache, malaiseand/or chills, often without fever or leu-kocytosis. Notably, these symptoms areconsistent with rejection as well as infec-tion, so that aggressive diagnosis is war-ranted in evaluating these patients.

One of the most common focalcomplaints is that of nasal congestion.Azathioprine commonly causes this, andmay increase the risk of upper respira-tory infections such as sinusitis and oti-tis media in post-transplant patients. Inaddition to adenovirus, rhinovirus, Strep-tococcus pneumoniae, nontypableHaemophilus influenzae and other patho-gens associated with such processes innormal hosts, more complex infectionsdue to Pseudomonas species and fungisuch as Aspergillus or the agents of mu-cormycosis may also be seen in the trans-plant patient. While empiric therapy forthese and other infections may be neces-sary, antibiotics must be chosen carefully

and patients followed closely for re-sponses. If no response is seen in two tothree days, or if symptoms progress,prompt referral to the transplant centershould be obtained.

Diarrhea and other gastrointestinalsymptoms (including nausea) pose an-other diagnostic dilemma in post-trans-plant patients. While taking numerousmedications capable of producing gas-trointestinal toxicity, these patients com-monly present with cytomegalovirus andother infections with nausea or vague gas-trointestinal complaints, often withoutsignificant fever. Early performance ofstool studies (including examinations forwhite blood cells, enteric bacterial patho-gens, ova and parasites, Clostridium difficileand Cryptosporidium) is indicated in theevaluation of diarrhea, with prompt en-doscopic evaluation including biopsies inany patient with persistent gastrointesti-nal complaints.

TIMING OF INFECTIONS FOLLOW-ING TRANSPLANTATION

Because immunosuppressivetherapy is most aggressive in the first yearfollowing transplantation, most patientsare at greatest risk for opportunistic in-fection in the first twelve postoperativemonths.5 Such pathogens include virusessuch as cytomegalovirus (CMV), herpessimplex virus (HSV) and Epstein-Barrvirus (EBV); fungi such as Cryptococcusneoformans and Pneumocystis carinii;higher-order bacteria such as Nocardiaasteroides; and mycobacteria includingMycobacterium tuberculosis. Patients re-quiring additional immunosuppressivetherapy or infected with certainimmunomodulating pathogens such asCMV or hepatitis B or C are at greaterand more prolonged risk for infectionfrom these opportunists.

The time following transplantationhas been divided into three periods: theearly period (the first month post-trans-plant), when infections complicating thesurgery itself, such as wound infections,urinary tract infection and pneumonia,occur; the middle period (1-6 months post-transplant), when more typical opportun-ists like CMV cause infection; and the late

period (>6 months post-transplant), whenopportunists such as Pneumocystis cariniiand Cryptococcus neoformans typically causedisease.5 (Table 1).

Renal transplant recipients are at par-ticular risk for urinary tract infection, in-cluding pyelonephritis of the allograft.6 Inthe immediate post-transplant period, in-fection may be the result of transmissionof bacteria or fungi with the allograft itself.The presence of ureteral stents and bladdercatheterization increases the risk of noso-comial urinary tract infections. Recipientsof cadaver allografts with prolonged is-chemic times are at particular risk for pyelo-nephritis as well as surgical wound infection.

PATHOGENS OF PARTICULARCONCERN IN THE TRANSPLANTRECIPIENT

Legionella pneumophila is a fas-tidious gram-negative bacillus that iswidely distributed in environmental wa-ters and potable water systems and maycause sporadic or epidemic disease.7 Pa-tients typically present with fever, mal-aise and myalgias, followed by a drycough which may be associated withpleuritic chest pain, abdominal pain, di-arrhea and/or headache. Chest radio-graphs most commonly reveal unilobaralveolar infiltrates, although multilobarinfiltrates and small pleural effusions maybe seen. Hyponatremia may be a clue tothe presence of Legionella pneumonia.Diagnosis requires growth on selectivemedia. Direct fluorescent antibody stain-ing of sputum or bronchoalveolar lavagespecimens may be useful while culturesare pending. Treatment consists of 21days of azithromycin or quinolonetherapy. Due to significant interactionswith erythromycin, this antibacterialdrug should generally be avoided in thetransplant setting.

Listeria monocytogenes colonizesthe gastrointestinal tract and may pro-duce bacteremia, meningitis or menin-goencephalitis, typically in the middle orlate periods.8 Patients usually presentwith fever, headache and/or altered men-tal status. Cerebrospinal fluid (CSF) ex-amination typically reveals a neutrophilicpleocytosis and hypoglycorrhachia; gram


staining generally fails to demonstrate thecharacteristic gram-positive organisms.Culture of blood and/or CSF remains thecornerstone of diagnosis. Penicillin orampicillin (or trimethoprim-sulfamethoxazole in the penicillin-aller-gic patient) is recommended for 21 days.9

Third generation cephalosporins, com-monly employed as the empiric therapyof acute bacterial meningitis, are ineffec-tive against Listeria.

Nocardia asteroides may causepneumonia and/or brain abscess, usuallyin the middle period.10,11 Fever andcough are common with nodular or cavi-tary infiltrates on chest roentgenogram.Metastatic abscesses may develop in thebrain, skin, bone, liver, kidney or joints.Modified acid-fast staining of tissue speci-mens may reveal the characteristicbeaded, branching filaments; culture isdiagnostic. Trimethoprim-sulfamethoxazole is the antimicrobial ofchoice for Nocardia infection, typicallyadministered for 12 months.

Cytomegalovirus (CMV) is themost common infection following trans-plantation, and usually develops in themiddle period.12,13,14 Disease is mostcommon and severe in patients serone-gative for CMV pretransplant who re-ceive a CMV seropositive kidney.Patients may present with flu-like symp-toms (CMV syndrome), nonproductivecough associated with bilateral intersti-tial and alveolar infiltrates (pneumoni-tis), nausea and bloating (gastritis),diarrhea or gastrointestinal bleeding (coli-tis), visual acuity changes (chorioretini-tis), or more uncommonly, withhepatitis, pancreatitis, myocarditis orencephalitis. Prolonged fever or malaisemay be symptoms of CMV infection ofthe transplanted kidney itself. Diagno-sis generally requires histologic evidenceof CMV, with the presence of character-istic intranuclear inclusions in tissuespecimens; culture may be helpful. Treat-ment consists of intravenous gancicloviradministered for 14 to 21 days.

Epstein-Barr Virus (EBV) maycause a febrile mononucleosis-like syn-drome, although splenomegaly and phar-yngitis are uncommon and theheterophile antibody test is often nega-tive.15 Diagnosis requires culture of EBVfrom normally sterile body sites and/orpositive immunofluorescence studies ontissue samples. Although acyclovir is

commonly prescribed, its clinical utilityhas not been demonstrated in this set-ting. The most feared complication ofEBV infection is post-transplantlymphoproliferative disorder (PTLD),a proliferation of previously infected,transformed B lymphocytes that may bemalignant. Most PTLD patients presentwith fever and lymphadenopathy, some-times with pulmonary or hepatic involve-ment. As this entity often requireswithdrawal of immunosuppression, pa-tients with suspicion of PTLD shouldbe referred to the transplant center fordefinitive diagnosis and therapy.

Pneumocystis carinii, now clas-sified as a fungus, may present with fe-ver, dyspnea and nonproductive coughof subacute onset, most commonly inthe first year post-transplant.16 Chestradiographs typically reveal diffuse in-terstitial infiltrates, and hypoxemiamay be present. Bronchoalveolar lav-age fluid or tissue specimens reveal thecharacteristic cysts upon silver staining.As fewer organisms are generallypresent in transplant patients than inthose with HIV infection, examinationof expectorated sputum is insensitive.Treatment consists of high dosetrimethoprim-sulfamethoxazole for atleast 14 days.

Aspergillus species may cause pneu-monia in the early or middle periods.17,18

Patients typically present with fever anda dry cough, although with vascular in-vasion, hemoptysis and pleuritic chestdiscomfort may develop. Hematogenousspread to the brain may result in confu-sion and/or focal neurological deficits.Computed tomography scans reveal low-density lesions with minimal contrast en-hancement, and cerebrospinal fluidcultures are generally negative. Ampho-tericin B should be instituted immedi-ately in these patients, as the mortality

rate remains high (>90%).Candida albicans and other candidal

species, common gastrointestinal tract andskin colonizers in post-transplant patients,may cause wound infection, pyelonephri-tis, fungemia, esophagitis, or other seriousinfections. Amphotericin B should be usedin acutely ill patients, or fluconazole in thepatient with non-life threatening diseaseinvolving susceptible species.

PROPHYLACTIC ANTIBIOTICSSome of the opportunistic infections

discussed above are preventable. Patientsare generally placed on daily or thriceweekly trimethoprim-sulfamethoxazole(TMP-SMX) for prophylaxis of P. cariniiand Toxoplasma gondii in the first yearfollowing renal transplantation.

As mucocutaneous fungal infec-tions, most notably oral candidiasis, arecommon in the early period, topical an-tifungal therapy with nystatin solutionor clotrimazole troches is commonplace.

Patients may also receive prophylaxisagainst CMV and/or HSV infection. Thereare dozens of published trials of a variety ofagents, often used sequentially or in com-bination, to prevent CMV disease. In gen-eral, recipients without prior evidence ofCMV infection who receive a kidney froma similarly CMV-naïve donor do not re-quire specific CMV prophylaxis, althoughany blood products administered to themshould be CMV seronegative, irradiated orfiltered to remove the white blood cellswhich latently carry the virus. Other kid-ney transplant recipients should beprophylaxed against CMV using antiviralagents such as ganciclovir, valganciclovir orvalacyclovir for 3 to 6 months after trans-plantation.19 Because the prevention andearly diagnosis of CMV infection and dis-ease is of utmost importance in the care ofthe transplant patient and represents an areaof constantly changing diagnostic andtherapeutic modalities, these aspects of thepatient’s care should be dictated by thetransplant center.

Immunizations, important elementsof infection prevention in all patients, areless effective and sometimes contraindicatedin the transplant recipient.20,21 While theinfluenza vaccine is typically administeredto transplant recipients annually, theirseroconversion rate is substantially lowerthan that of the healthy adult population.Live virus vaccines (i.e., the measles-mumps-rubella, yellow fever, Bacille-

�

Patients may presentwith vague symptoms

such as fatigue, dyspnea,headache, malaise and/orchills, often without fever

or leukocytosis.

127Vol. 85 No. 4 April 2002

Calmette-Guerin or BCG, and oral poliovirus vaccines) are contraindicated in allimmunosuppressed patients, as they havebeen associated with the development ofdisseminated infection in these settings.Studies of the Varicella vaccine are under-way to evaluate its use in susceptible trans-plant recipients; many transplant centersare administering this vaccine to seronega-tive patients pretransplant.

GUIDELINES FOR THE CARE OFTHE POST-TRANSPLANT PATIENT

Care of the renal transplant recipi-ent inevitably involves monitoring his orher household contacts — looking forsigns of potentially transmissible infec-tions from humans and pets alike. Ingeneral, frequent hand washing by allhousehold members (especially children)is the most important intervention to bemade. A veterinarian should evaluatepets regularly, and the transplant recipi-ent should avoid direct contact with ani-mal excrement, the source of manypet-transmitted opportunistic infections.Significant animal scratches and bites,including those from healthy-appearingcats or dogs, should be evaluated quicklyin the post-transplant patient, as a num-ber of serious infections (most notablythose from Capnocytophaga species andPasturella multocida) may result.

Children living with or in frequentcontact with the renal transplant recipientshould not receive the oral polio vaccine,which is associated with fecal shedding oflive viral particles for weeks to months fol-lowing administration. In these children,the parenteral, inactivated polio vaccineshould be administered instead.

Transplant recipients should avoidingestion of undercooked meats, unpas-teurized milk products and raw seafood,and should seek infectious disease con-sultation prior to any trips outside thecontinental United States for specific in-fection prevention instructions.

ANTIBIOTIC SELECTION IN THEPOST-TRANSPLANT PATIENT

While antimicrobial spectrum is theprimary consideration in choosing em-piric therapy in this patient population,it is critical to recognize the potential druginteractions that may occur when somecommon antibiotics are used.22

Some macrolides, including eryth-romycin and clarithromycin, are metabo-

lized via the cytochrome p450 system andmay dramatically increase cyclosporineand FK-506 serum levels, resulting innephrotoxicity. Azithromycin andclindamycin, which utilize alternateroutes of metabolism, are considered safeto use. The use of itraconazole andketoconazole may have similar effects.

The use of doxycycline, isoniazidand rifampin may accelerate cyclosporineand FK-506 metabolism, resulting insubtherapeutic serum concentrations.The use of nephrotoxic agents such asthe aminoglycosides and amphotericin Bshould be approached with great cautionin patients on cyclosporine or FK-506.With the increasing number of cepha-losporins, quinolones and liposomal am-photericin B products available, avoidingmore toxic antimicrobial drugs is becom-ing easier with time.

CONCLUSIONThe care of the renal transplant re-

cipient requires a team approach, withthorough patient education, aggressivesurveillance and effective prophylaxis andtreatment of the inevitable infectionswhich develop. The primary care physi-cian serves as a critical link between thepatient and the transplant center. Armedwith a general background in post-trans-plant opportunistic infections and a com-mitment to detailed evaluation,nephrologists and general internists maycontribute more effectively to the life andcare of these complicated patients.

REFERENCES1. Barry JM. Immunosuppressive drugs in renal

transplantation: A review of the regimens.Drugs 1992;44:554-66.

2. Thompson AE. New immunosuppressiveagents and infection in solid organ transplanta-tion. Crit Care Med 1993;21:S351-3.

3. Suthanthiran M, Strom TB. Renal transplan-tation. NEJM 1994;331:365-76.

4. Fischer SA, Trenholme GM, Levin S. Fever inthe solid organ transplant patient. Infect DisClin North Am 1996;10:167-84.

5. Rubin RH. Infection in the organ transplant re-cipient. In Rubin RH, Young LS (eds): ClinicalApproach to Infection in the Compromised Host, ed3. New York, Plenum, 1994: 629-705.

6. Rubin RH, Wolfson JS, Cosimi AB, et al. In-fection in the renal transplant recipient. Am JMed 1981;70:405-11.

7. Yu VL, Kroboth FJ, Shonnard J, et al. Legion-naires’ disease: New clinical perspective from aprospective pneumonia study. Am J Med1982;73:357-61.

8. Stamm AM, Dismukes WE, Cobbs CG, et al.Listeriosis in renal transplant recipients: Report

of an outbreak and review of 102 cases. RevInfect Dis 1982;4:665-82.

9. Spitzer PG, Hammer SM, Karchmer AW.Treatment of Listeria monocytogenes infectionwith trimethoprim-sulfamethoxazole: Case re-port and review of literature. Rev Infect Dis1986;8:427-30.

10. Hooper DC, Pruitt AA, Rubin RH. Centralnervous system infection in the chronically im-munosuppressed. Med Care 1982;61:166-88.

11. Wilson JP, Turner HR, Kirchner KA, et al.Nocardial infections in renal transplant recipi-ents. Med Care 1989;68:38-57.

12. Mustafa MM. Cytomegalovirus infection anddisease in the immunocompromised host.Pediatr Infect Dis J 1994;13:249-59.

13. Glenn J. Cytomegalovirus infections follow-ing renal transplantation. Rev Infect Dis1981;3(6):1151-78.

14. Ljungman P. Herpes virus infections inimmunocompromised patients: Problems andtherapeutic interventions. Ann Med1993;25:329-33.

15. Straus SE, Cohen JI, Tosato G, et al. Epstein-Barrvirus infections: Biology, pathogenesis, and man-agement. Ann Intern Med 1993;118:45-58.

16. Kramer MR, Stoehr C, Lewiston NJ, et al.Trimethoprim-sulfamethoxazole prophylaxis forPneumocystis carinii infections in heart-lungtransplantation — How effective and for howlong? Transplantation 1992;3:586-9.

17. Hibberd PL, Rubin RH. Clinical aspects offungal infection in organ transplant recipients.Clin Infect Dis 1994;19 (Suppl):S33-40.

18. Rubin RH, Hooper DC. Central nervous sys-tem infection in the compromised host. MedClin North Am 1985;69:281-96.

19. Patel R, Snydman DR, Rubin RH, et al. Cy-tomegalovirus prophylaxis in solid organ trans-plant recipients. Transplantation1996;61:1279-89.

20. Avery RK. Infections and immunizations inorgan transplant recipients: A preventive ap-proach. Cleve Clin J Med 1994;61:386-92.

21. Ambrosino DM, Molrine DC. Critical appraisalof immunization strategies for prevention of in-fection in the compromised host. Hematol OncolClin North Am 1993;7:1027-49.

22. Lake KD. Management of drug interactionswith cyclosporine. Pharmacotherapy1991;11:110S-8S.

Staci A. Fischer, MD, is Assistant Pro-fessor of Medicine, Division of InfectiousDiseases, Brown Medical School.

CORRESPONDENCE:Staci A. Fischer, MDRhode Island HospitalDivision of Infectious Diseases593 Eddy StreetProvidence, RI 02903phone: (401)444-8130fax: (401)444-8154e-mail: [email protected]


�Paul Morrissey, MD, and Bette Hopkins-Garcia, RN, MS, CCTC

Live Donor Renal Transplantation

Kidneys can be purchased for livedonor renal transplantation in

Turkey, India, Iraq and other nations.1

These “donations” are legal in somecountries, overlooked in others and un-fortunately often managed in a “blackmarket” where the middleman (facili-tator) takes a cut of the procurementfee. While this practice can be viewedfrom many sides (ethical, medical, so-cial justice, utilitarian) it highlights thefact that most patients are not thrivingon dialysis, the majority favor trans-plantation as an alternative, that thereis a worldwide shortage of cadaver or-gans and that live donor transplanta-tion is the best therapy for end-stagerenal disease (ESRD). I will explorethese issues with reference to the stateof renal transplantation in Rhode Is-land.

HISTORICAL PERSPECTIVE

Prior to 1954 nobody survivedESRD. The successful identical twinkidney transplant performed at thePeter Bent Brigham Hospital on De-cember 24, 1954, offered hope to thosein need of renal replacement. Identi-cal twin transplantation remained theonly viable option for treating ESRDuntil 1960 when the first immunosup-pressive therapies were added. Hemo-dialysis was introduced in the 1960s;by the end of that decade centers wereestablished in many major medical cen-ters throughout the United States.

Dialysis did not become widelyavailable until Congress amended theSocial Security Act in 1972 to provideMedicare coverage to people withESRD. A patient was dialyzed on thefloor of Congress to demonstrate thisnew therapy. Joseph Chazan, MD,established the first public hemodialy-sis unit in Rhode Island at the RhodeIsland Hospital in 1970. Less thanthree years later the first “free-stand-ing” unit opened in East Providence.Continuous ambulatory peritonealdialysis (CAPD) was introducedshortly thereafter. Since that time pa-

tients with ESRD have had three treat-ment options: hemodialysis, CAPDand renal transplantation.

Steady progress has been made inthe safety and efficacy of all renal re-placement therapies. With the adventof new immunosuppressive agents, re-nal transplantation has become saferand more successful. One-year allograftsurvival rates of 50%, common in the1970s, improved to 80% in the 1980sand are now >85% for cadaver renaltransplants and >94% for live donorrenal transplantation. In 1999, 12,485renal transplants were performed ofwhich 8011 were from cadaver donorsand 4474 from living sources.1

ESRD affects persons of all ages.The average age of persons starting di-alysis is 61 years old. The incidence ofESRD is increasing most rapidly in theolder age groups with 35% of all newpatients older than age 65. An increas-ingly difficult task is choosing the ap-propriate ESRD modality for olderpersons with hypertensive nephroscle-rosis, type II diabetes mellitus and ad-vanced arteriosclerosis. The prevalenceof ESRD (1997) according to Medi-care records was 1,105 per million. InRhode Island, a state of 1,053,000 per-sons, approximately 900 persons are ondialysis and 400 have functioning re-nal transplants.

LIVING DONORS

Live donor renal transplantation(LDRT) is the optimal therapy formost patients with ESRD.3 Some pa-tients are excluded due to comorbidillness, advanced age with limited life

expectancy and social instability (non-compliance). Over 50,000 patients areon the national waiting list for a renaltransplant, including 2000 patients inNew England where we typically re-cover organs from 170 brain-dead or-gan donors per year. The typical waitfor cadaver renal transplantation inNew England is 2 years for ABO=A orAB and 3 - 4 years for ABO=O or B.Recent data suggest that the less timespent on dialysis the better the patient’soutcome.3 Given the long waits inNew England, this can only beachieved by securing a live donor.

Nationally, living donors provide36% of all kidneys transplanted andthe number is steadily increasing.(Table 1) However, this pattern is notseen worldwide with the number ofLDRT per million population re-ported in 1997 as: USA (14.1), Canada(9.5), UK (2.8), France (1.2) and Spain(0.5). At RIH, 119/256 (46 %) trans-plants have come from a living donorand LDRT comprised more than halfof the transplants in the past two years.

Kidneys from live donors providesuperior results to cadaver sources.(Table 2) Both one-year and long-termsuccess rates are excellent. Immediatefunction of the kidney occurs in 19/20 cases and 98% of transplanted pa-tients have a functioning allograft atone month. Initial immunosuppres-sive requirements are less than for ca-daver renal transplants, as is the riskof early acute rejection. As a result, theattendant infectious complications andthe predictable side effects of chronicimmunosuppression are decreased. In

Table 1. Growth in Live Donor Renal Transplants (LDRT)in the U.S. and Outcomes

Number of Transplants One-Year Graft SurvivalYEAR LDRT CRT LDRT CRT1991 2393 7281 90 811993 2851 7510 91 831995 3359 7689 93 851997 3907 7767 94 871999 4474 8011 95 89

129Vol. 85 No. 4 April 2002

�

Kidneys from live donorsprovide superior results to

cadaver sources.

contrast to cadaver renal transplanta-tion, a live donor transplant can bescheduled electively, typically within 2-3 months of initiating evaluation, andis more likely to be an early or eventhe initial (“preemptive”) treatment forESRD.

THE LIVING DONOR

The benefits of LDRT must be bal-anced with the risk of major surgery inan entirely healthy person. The donor’sbenefit is slightly less tangible - derivedfrom the satisfaction of helping a lovedone. Potential living kidney donors mustmeet five basic requirements: (1) goodto excellent health, (2) ABO-compatiblewith the recipient, (3) two kidneys withnormal function, (4) crossmatch nega-tive (nonreactive) - no lysis of donor lym-phocytes by recipient’s serum and (5)properly motivated without evidence offinancial remuneration or coercion. Inshort, a potential donor for anunsensitized (lacking preformed antibod-ies) recipient must be a healthy, willing,and ABO-compatible individual withnormal renal function.

In our experience, the donor sourcehas been sibling (46), child (25), parent(15), spouse (9), distant relative or in-law (9), friend (11) and stranger (4).Thirty-three of the donors were unrelatedto the recipient. The four “stranger”donors included a Buddhist priestessfrom Vermont who contacted our pro-gram in 1998 wishing to donate a kid-ney to anybody on our list.5 Afterproceeding with a psychological evalua-tion and the routine medical work-up theNew England Organ Bank was contactedto assist in selecting the appropriate re-cipient. On May 22, 1998 the live do-nor transplant occurred from an“anonymous” donor who never crossed

paths with the fortunate recipient of hergood will. Two other “strangers” werepart of a two-way swap agreed upon tomatch ABO incompatibilities. Two chil-dren, each unable to donate to hismother, donated a kidney to the otherfamily in a series of simultaneous surger-ies. A fourth stranger donation tookplace under a novel program, “HopeThrough Sharing”, which allows personswaiting for a kidney transplant to moveto the top of the list when a relative, withan incompatible kidney, donates to astranger on the list. On August 27, 2001,a woman donated her kidney to the topABO-compatible patient at Rhode IslandHospital and her ABO-incompatiblehusband became the top listed person inhis blood group for all of New England.This gentleman, listed for only fourmonths, received a cadaver kidney 11days later. As a result of this living do-nor, two persons were transplanted - thedonor’s husband anda fortunate secondpatient who receiveda living donor al-lograft.

MORBIDITY AND

MORTALITY OF

LDRTA l t h o u g h

widely accepted asstandard practice inthe U.S., some cen-ters continue to bereluctant about the

use of live donors for transplantation.This is a truly unique circumstance inmedical practice - placing an individual“at risk” for the benefit of another. Whileour society accepts individuals takingrisks and occasionally losing their livesfor an overall good (fire fighters, soldiersand police officers), some believe that themedical profession should operate undera different standard. Major concerns forthe donor include the potential morbid-ity and mortality of the donor nephrec-tomy, long-term function of theremaining kidney and the psychologicalwell being of the donor. Donor mortal-ity, typically from pulmonary embolismor a peri-operative cardiac event, is about0.03 - 0.05%.6 Previous studies havereported morbidity rates of 8 - 24%.Long-term follow-up (20 - 30 years)demonstrates that renal function remainsstable. Occasionally the donor will de-velop insignificant microscopic pro-teinuria years after nephrectomy. Qualityof life studies and psychological assess-ments after kidney donation reveal thatmost (> 93%) were happy to have do-nated and > 95% would or probablywould donate again given the same cir-cumstances. Quality of life studies showthat kidney donors surpass the nationalnorms even years after donation. Onerecent study also reveals that the life ex-pectancy for kidney donors is greater thanaverage.

EXPERIENCE WITH LDRT AT

RIHOur overall experience at RIH

with LDRT has been excellent. Thedonor and recipient operations are per-formed simultaneously in adjoining

Table 2. Live Donor (LDRT) versus Cadaveric (CRT)Renal Transplantation.

Item LDRT CRTAllograft half-life 16-19 years 10-12 yearsWaiting time 2 - 4 months 24 - 48 monthsDonor Age 18 - 60 4 - 80Quality of kidney Excellent Good to excellentImmediate function 95 % 50 %Average hospital stay 5 - 7 days 7 - 14 daysImmunosuppression Lower doses StandardRisk of acute rejection 5 - 10 % 15 - 20%

P E D I A T R I C I A N

Board-certified and with 15 years in private practice,I am planning to return to R.I. to be near family.

Am seeking to join existing group practice.Have R.I. license, but no long-term

contractual agreements.

Please contact:Janet V. Marsella-Wildman, D.O.

P.O. box #3051, St. Charles, Illinois 60174TEL: 630-584-4860

EMAIL: [email protected]


operating rooms. The kidney is recov-ered from a flank incision between the11th and 12th ribs. Immediate func-tion occurred in 113/119 transplantswith two cases each of slow graft func-tion, delayed graft function (one dialy-sis session required after surgery), andprimary graft nonfunction. The over-all initial success rate was 98% andgraft survival at one year was 93%. Theprimary reason for graft failure was re-cipient death with a functioning renaltransplant (6 cases). Two grafts neverfunctioned and two were lost to recur-rent acute rejection.

Of primary concern in this ven-ture is the wellbeing of the healthydonor. Operative complications fol-lowing 119 donor nephrectomies werelimited to one wound infection, oneUTI, two cases of pneumothorax andone blood transfusion. Five cases wereperformed laparoscopically with thekidney removed intact through a 3-inch incision in the pubic hairline. Thisprocedure provides a quicker postop-erative recovery, better cosmesis andhas encouraged some people to donatewho would not have agreed to an openprocedure. In our hands, laparoscopicdonor nephrectomy has been per-formed with a level of safety that mir-rors the open procedure. Followingdonor nephrectomy the average patientuses parenteral narcotics for 2 - 3 daysand oral narcotics for one week. Do-nors have been discharged home in3.85 ± 0.67 days and typically returnto work in 2 - 6 weeks. In Rhode Is-land most donors qualify for Tempo-rary Disability Insurance (TDI).Although the entire cost of kidney do-nation is covered by the recipient’s in-surance, many donors lose vacationtime and wages.

EFFORTS TO INCREASE THE RATE

OF TRANSPLANTATION

For most persons with ESRD kid-ney transplantation and in particularkidney transplantation from a live do-nor represents the best option for long-term survival, a high quality of life andreduced complications. We are limitedby the availability of kidneys to trans-plant. Cadaver donors are increasingin age and many kidneys considered

unacceptable five years ago are beingtransplanted into appropriately matchedrecipients as “marginal” organs or evenas dual renal transplants (two marginalkidneys transplanted into a single recipi-ent). Efforts continue to increase theavailability of live donor kidneys as weextend the social acceptability of unre-lated and stranger organ donation. In-terestingly, in a Gallup poll this year80% of respondents supported strangerkidney donation. Furthermore, respon-dents answered that they would (24%)or probably would (21%) donate a kid-ney to a stranger in need for free. Thisremarkable response has not been real-ized in practice (only a few hundred al-truistic donations have occurred), butit implies an untapped resource. AtRIH, we have formed a committee ofhospital staff and social workers to re-view potential altruistic donors. Moreinformation is available at our websitewww.lifespan.org/transplant/donor/al-truistic.

FUTURE CONSIDERATION

Despite the generosity of the pub-lic and their good intentions expressedin the Gallup poll, we have a criticalshortage of organs for transplantation.Innovative practices have led to in-creased rates of donation, but the sup-ply does not match the need. We maybe entering a time where economic re-imbursement for the donor is a practi-cal, safe and fair means to solve thisproblem. In the current system thedonor often pays travel expenses andthen loses wages and vacation timewhile recovering from the surgery.Even paying $20 for analgesics uponhospital discharge is a burden for somedonors. Such disincentives need to beremoved to encourage this act of hero-ism (donating an organ). Regulatingpayments to donors or their familiesoffers the best opportunity to eliminatecurrent injustices and abuses in the sys-tem. The suggestion that rewardingtheir gift reduces these persons to com-modities supposes that the transplantteam can be removed from their obli-gation to “care about the patient”. Ithas been suggested that all organ do-nors (cadaver and living) be awarded aGold Medal from the government.

The worth of this medal may be $3000(less than 1/6 of the current kidney ac-quisition fee). This money could beused to defray funeral costs for cadaverdonor families or used by the living do-nor to supplement lost wages. The re-ward may encourage some to donatewho would not. For others, not desir-ing financial compensation, the medalcould be saved and cherished as a re-minder of their heroism. Careful over-sight of this program would protectdonors from exploitation and increasethe availability of living donors - theoptimal therapy for ESRD.

REFERENCES1. This Little Kidney Went to Market.

New York Times Magazine, May 27,2001.

2. UNOS Annual Report 2000. Depart-ment of Health and Human Services,Health Resources and Services Admin-istration. www.hrsa.gov/osp/dot.

3. Terasaki PI, et al. High survival ratesof kidney transplants from spousal andliving unrelated donors. NEJM 1995;333: 333-6.

4. Mange KC, et al. Effect of the use ornonuse of long-term dialysis on thesubsequent survival of renal trans-plants from living donors. NEJM2001; 344: 726-31.

5. Gohh RY, et al. Controversies in or-gan donation: the altruistic living do-nor. Nephrol Dial Transplant 2001; 16:619-21.

6. Bia MJ, et al. Evaluation of living re-nal donors. The current practice ofUS transplant centers. Transplantation1995; 60: 322-7.

Paul Morrissey, MD, is TransplantSurgeon in the Division of Organ Trans-plantation, Rhode Island Hospital, andAssistant Professor of Surgery, BrownMedical School.

Bette Hopkins-Garcia, RN, MS,CCTC, is Transplant Coordinator, Di-vision of Organ Transplantation, RhodeIsland Hospital.

CORRESPONDENCE:Paul Morrissey, MDRhode Island Hospital593 Eddy Street, APC 921Providence, RI 02903phone: (401) 444-8562fax: (401) 444-3283e-mail: [email protected]

131Vol. 85 No. 4 April 2002

�Michael A. Thursby, DO, Angelito F. Yango, MD, Reginald Y. Gohh, MD

An Update In Transplant Immunosuppressive Therapy

As we enter the millennium, the mostwidely acknowledged advancement

in transplantation has been the developmentof more selective and potent immunosup-pressive agents. In the early period of trans-plantation, the selection of maintenanceimmunosuppression was limited to the com-bination of azathioprine and corticosteroids.Unfortunately, these agents were relativelynon-specific and ineffective and carried therisk of a multitude of side effects. The majorclinical concerns at that time were the pre-vention of acute rejection and improvementin patient and graft outcomes, since expectedpatient survival post-transplant was low. Thedevelopment of cyclosporine in the 1970smarked the first application of T-cell selec-tive immunosuppressive therapy. The wide-spread clinical application of this agent inthe 1980s significantly improved transplantoutcomes and, depending on the specificorgan and donor source, graft survival in theorder of 85-90% at one year became com-monplace.1

The last decade has built on the foun-dations of T-cell targeted immunosuppres-sion with the introduction of tacrolimus,mycophenolate mofetil, rapamycin andnew polyclonal and monoclonal antibod-ies directed at specific receptors (IL-2 re-ceptor) on activated lymphocytes. (Table1) These agents have been used in variouscombinations with the goal of achievingmaximal immunosuppressive potency withminimal side effects. It is now common-place to have rates of acute rejection lessthan 10% (Table 2), verifying the synergis-tic interactions of these agents. The out-standing results that are achievable withthese newer medications makes it difficultto select a protocol based solely on efficacydata. The goals that define immunosup-pressive therapy have shifted toward reduc-ing maintenance immunosuppression andminimizing side effects. Furthermore, moreemphasis is now placed on choosing im-munosuppressive regimens tailored to fitthe unique characteristics of the individualtransplant recipient. The purpose of thisarticle is to review these newer agents, theirmechanisms of action and side effects, ex-amine the choices that currently exist forimmunosuppression, and finally discuss thepotential hazards of their long-term use.

TACROLIMUSTacrolimus (FK506) is a macrolide

compound that possesses similar but morepotent (approximately 100 times more)immunosuppressive properties comparedto cyclosporine. Initially, the Food andDrug Administration (FDA) approvedthis agent for use in liver transplantationbecause of its superiority in preventingacute rejection, but it has since gained in-creasing popularity in renal transplanta-tion as well. Despite having radicallydifferent chemical structures, tacrolimusshares a similar mechanism of action tocyclosporine; therefore both agents havebeen placed in the same category of im-munosuppressive agents known as

calcineurin inhibitors. Both drugs forma complex with a specific cytoplasmic re-ceptor protein (cyclophilin or FK-bind-ing protein respectively), which then targetspecific signal transduction pathwaysdownstream. The net effect is the down-stream inhibition of IL-2 signaling and IL-2 receptor elaboration, thereby inhibitingclonal expansion of cytotoxic T-cells andother cell lines involved with the acute re-jection process.2 In randomized clinicaltrials, tacrolimus produced similar patientand graft survival in renal transplantationcompared to modern versions ofcyclosporine (microemulsified form).3 Be-

TABLE 1CLASSES OF IMMUNOSUPPRESSION

CLASS OF AGENT OPTIONS SIDE EFFECTS

CALCINEURIN INHIBITOR CYCLOSPORINE NephrotoxicityHypertensionHirsutismHypercholesterolemia

TACROLIMUS NephrotoxicityIslet cell toxicityNeurotoxicityMild hypertension

ANTI-METABOLITE AZATHIOPRINE LeukopeniaThrombocytopeniaHepatitsCholestasis

MYCOPHENOLATE GI upsetMOFETIL Leukopenia

ThrombocytopeniaAnemia

OTHERS CORTICOSTEROIDS HypertensionGlucose intoleranceObesityAvasculer necrosisOseteoporosisCataracts

RAPAMYCIN HypercholesterolemiaThrombocytopeniaLeukopeniaAnemia

ANTIBODY INDUCTION THYMOGLOBULIN Fever/chillsATGAM Thrombocytopenia

LeukopeniaSerum sicknessIncreased CMV risk

ANTI-CD25 MONOCLONAL BASILIXIMAB Virtually noneANTIBODY DACLIZUMAB


cause their mechanisms of action are simi-lar, cyclosporine and tacrolimus cannot beused synergistically or additively; rather,immunosuppressive protocols must em-ploy either one or the other, not both.

Since both cyclosporine andtacrolimus are useful in maintenance im-munosuppression, the choice between thetwo medications must be based primarilyon the side effect profile of these agents.However, the toxicities are relatively simi-lar, except that tacrolimus produces morehyperglycemia and neurotoxicity.Tacrolimus is associated with less hirsut-ism, gingival hypertrophy and gynecomas-tia. In addition, there are improved lipidprofiles. Hence, the development of oneor more of these toxicities is reason enoughto convert from one agent to another.

Both cyclosporine and tacrolimus arehepatically metabolized by cytochromeP4503A4, and therefore have similar druginteractions with agents that affect this meta-bolic pathway. (Table 3) Many of these in-teractions involve commonly usedmedications and consequently, any newagents must be introduced with the recog-nition of potential interactions. Patientsshould be warned to consult physicians ex-perienced with the use of either cyclosporineor tacrolimus before considering the intro-duction of new pharmacologic therapy. Evenover-the counter preparations such as St.John’s wart may induce P450 metabolism,resulting in acute rejection because ofsubtherapeutic cyclosporine levels.4

Clinically, the most important draw-back of either of the calcineurin inhibi-tors is the development of nephrotoxicity.Both agents enhance the production ofTGF-beta, which has been implicated inthe development of interstitial fibrosis andultimately graft failure. Thus, althoughthe calcineurin inhibitors have resulted indramatic reduction in acute rejection ratesand improvement in short-term out-comes, they have not been as successful in

increasing long-term survival. The impactof calcineurin-inhibitors on the renal al-lograft is clearly demonstrated in the re-cent histologic study of protocol kidneybiopsies obtained at 2 years in the phaseIII tacrolimus versus cyclosporine trial. Analarming 66% of biopsy specimens in bothgroups have evidence of chronic transplantnephropathy.5 Multivariate analysisshowed that acute cyclosporine ortacrolimus nephrotoxicity in the first yearhad a strong correlation with the devel-opment of chronic transplant nephropa-thy. This is the genesis of a number ofclinical studies designed to either com-pletely eliminate or spare the use ofcalcineurin inhibitors to minimize neph-rotoxicity. Although early results are en-couraging, there is still no compelling datato support the notion that these agentscan be safely removed from the immuno-suppressive armamentarium without ad-versely affecting graft outcomes.

MYCOPHENOLATE MOFETILMycophenolate mofetil (MMF) was

introduced into clinical transplantation in1995 following a series of large clinical tri-als in cadaver renal transplantation show-ing improved efficacy over azathioprine forthe prevention of acute rejection whenused in combination with cyclosporineand prednisone.6,7 Similar to azathio-prine, it has an effect on purine biosyn-thesis, but acts differently in that it does

not act as a false substrate for enzymes.Rather, MMF noncompetitively inhibitsinosine monophosphate dehydrogenase,thereby inhibiting the synthesis of gua-nosine nucleotides and disrupting nucleicacid synthesis. The mechanism of actionof MMF is more selective in that it inhib-its the “de novo” pathway of purine syn-thesis while allowing the “salvage pathway”to continue its function unabated. T- andB-lymphocytes have an obligate need forpurine biosynthesis via the de novo path-way, while other mammalian cells (par-ticularly the brain) are more dependenton the salvage pathway. Because of itsimproved efficacy and specificity, MMFhas largely replaced azathioprine either asinitial immunosuppression or after an epi-sode of acute rejection. Although the costdifferential between the two agents is sub-stantial, shorter hospitalizations for rejec-tion offset the initial cost differential.

The most common adverse events re-ported with MMF are related to the GItract and appear to be dose-related. Diar-rhea has been reported to occur in up toone third of patients with varying degreesof nausea, bloating and vomiting occurringin up to 20% of patients. Although MMFtargets lymphocytes relatively specifically,leukopenia, anemia, and thrombocytope-nia occur with a similar frequency to thatof azathioprine, but generally respond todose reduction. Most importantly, MMFhas not been shown to have any nephro-toxicity, making it a useful adjunctivetherapy to the calcineurin-inhibitors.

SIROLIMUSSirolimus, also known as rapamycin,

is a macrolide antibiotic compound thatwas introduced into clinical transplantationin 1999. It is structurally similar totacrolimus and binds intracellularly to thesame cytoplasmic-binding protein (FKbinding protein). However, its immuno-suppressive activity is distinct from that ofthe calcineurin inhibitors. Likecyclosporine and tacrolimus, sirolimus in-terferes with the antigen-driven transduc-tion of signals from the cell membrane tothe nucleus. However, this agent also in-terrupts the signaling machinery whichcommits T cells to divide, leading to cellcycle arrest in the G1 phase.9 Additionally,sirolimus inhibits B-cell production of im-munoglobulins much more effectively thaneither cyclosporine or tacrolimus.

The clinical efficacy of sirolimus hasbeen verified in a number of clinical trials.These have demonstrated a significant re-duction in the incidence of acute rejection

�

The goals that now defineimmunosuppressive therapy

have shifted towardreducing maintenance

immunosuppression andminimizing side effects.

TABLE 2IMMUNOSUPPRESSIVE REGIMEN EFFICACY

RESULTS AT 1 YEAR

REGIMEN ACUTE REJECTION (%) GRAFT SURVIVAL (%)

CsA/pred (AZA) 40-50% 85-90%CsA/MMF/pred 15-20% 90-95%Tacrolimus/MMF/pred 10-15% 90-95%CsA/Sirolimus/pred 10-20% 90-95%

Abbreviations are: CsA, cyclosporine: AZA, azathioprine: MMF, mycophenolatemofetil; pred, prednisoneAdopted from reference 2.

133Vol. 85 No. 4 April 2002

when combined with cyclosporine andprednisone, compared with either azathio-prine or placebo.2 Since then, it has beenused in a number of different drug combi-nations, including calcineurin-inhibitor freeregimens where patients were randomizedto receive either rapamycin or cyclosporine,with all individuals receiving corticosteroidsor azathioprine.

The major side effects of rapamycinare myelosuppression and hyperlipidemia.The dyslipidemia is characterized by severehypertriglyceridemia, suggesting a possiblerole in the inhibition of lipoprotein lipaseactivity. However, treatment with HMGCoA reductase inhibitors is effective in im-proving lipid profiles. Rapamycin is notnephrotoxic when used alone. However,the combination of rapamycin andcyclosporine has been suggested to causesynergistic nephrotoxicity in animal stud-ies.10 Rapamycin is also metabolizedhepatically through the cytochrome p450pathway and therefore is subject to the samedrug interactions that complicate the useof cyclosporine and tacrolimus.

TRENDS IN IMMUNOSUPPRESSIVETHERAPY

The new millennium has brought agradual shift in immunosuppression in re-nal transplantation from consistent depen-dence on calcineurin inhibitors andcorticosteroids to increasingly bold experi-mentation with the sparing or eliminationof immunosuppressive drugs. With the

TABLE 3DRUG INTERACTIONS WITH CALCINEURIN INHIBITORS

DRUGS THAT DECREASE CALCINEURIN INHIBITOR CONCENTRATION

Phenytoin Carbamazepime Barbiturates Intravenous Bactrim Nafcillin Isoniazid Rifampin and Rifabutin St. John’s Wart (Hypercum Perforatum) Omeprazole

DRUGS THAT INCREASE CALCINEURIN INHIBITOR CONCENTRATION

Calcium channel blockers (verapamil, diltiazem, nicardipine) Macrolide antibiotics Doxycycline Ticarcillin Antifungal agents (ketoconazole, fluconazole) Amiodarone Carvedilol Metoclopramide Colchicines Sex hormones Alcohol

range of agents available today, immuno-suppression that is based on relative patientrisk is an achievable goal. Although opti-mal approaches have not yet been estab-lished, a number of risk factors relative toacute rejection and long-term outcomeshave been established. Cadaver donorsource, African-American race, history ofprevious poor transplant outcomes and, tosome extent, the etiology of underlying re-nal failure, might all be considered risks fa-voring the occurrence of acute rejection andmay warrant enhanced immunosuppres-sion. On the other hand, older recipients,recipients of HLA-identical cadaver grafts,as well as recipients of living related grafts,may be less likely to develop acute rejec-tion. These are the individuals who shouldbe targeted for dose reduction or drug elimi-nation. Also, use of nephrotoxic agentsmight be avoided in those patients with“marginal” graft function. Immunosup-pression-associated metabolic disturbances(e.g. hypertension, bone loss) should bereduced and managed as much as possiblein all patients, but especially in those pa-tients with pre-existing disorders such ascardiovascular disease, diabetes or os-teoporosis. This has spurred particular in-terest in the use of steroid sparing regimens.Lastly, patient compliance may improveoutcomes, and simplifying regimens andminimizing unpleasant side effects canachieve this goal. The ultimate ambition,short of the promise of drug-free immu-nosuppression, is to reduce mortality in the

long-term and to improve the quality oflife for all patients.

REFERENCES1. Calne RY, Rolles K, et al. Cyclosporin A ini-

tially as the only immunosuppression in 36recipients of cadaveric organs. Lancet 1979;2:1033-6.

2. Kahan BD. The Rapammune Study Group.Efficacy of Sirolimus compared to azathioprinefor reduction of acute allograft rejection: a ran-domized multicentre trial. Lancet2000;356:194-202.

3. Suthanthiran M, Morris, RE, Strom, TB. Im-munosuppressants: Cellular and molecularmechanisms of action. Am J Kidney Dis 1996;28:159-72.

4. Pirsh JD, Miller J Dirhoi MH, et al. A com-parison of tacrolimus (FK506) andcyclosporine form immunosuppression aftercadaveric renal transplantation. Transplanta-tion 1997;63:977-92.

5. Schuetz EG. Induction of cytochrome p450.Curr Drug Metab 2001;2:139-47.

6. Solez K, Vincenti F, Filo RS. Histopathologicfindings from 2-year protocol biopsies from aU.S. multicenter kidney transplant trial com-paring tacrolimus and cyclosporine; a reportof the FK506Kidney Transplant Study Group.Transplantation 1998;66:1736-40.

7. Sollinger HW, et al. Mycophenolate mofetilfor the prevention of acute rejection in pri-mary cadaveric renal allograft recipients. Trans-plantation 1995;60:226-31.

8. U.S. Renal Transplant Mycophenolate MofetilStudy Group. Mcyophenolate mofetil in ca-daveric renal transplantation. Am J Kidney Dis1999;34:296-303.

9. Denton MD, Magee CC, Sayegh MH. Im-munosuppression strategies in transplantation.Lancet 1999;353:1083-91.

10. Andoh TF, Lindsley J, Fransechini N, et al.Synergistic effects of cyclosporine andrapamycin in a chronic nephrotoxicity model.Transplantation 1996;62:311-6.

Michael A. Thursby, DO, is a RenalFellow, Division of Renal Diseases, Rhode Is-land Hospital.

Angelito F. Yango, MD, is AssociateMedical Director, Divisions of Organ Trans-plantation and Renal Diseases, Rhode IslandHospital, and Assistant Professor of Medi-cine, Brown Medical School.

Reginald Y. Gohh, MD, is Medical Di-rector, Divisions of Organ Transplantationand Renal Diseases, Rhode Island Hospital,and Assistant Professor of Medicine, BrownMedical School.

CORRESPONDENCE:Michael A. Thursby, DORhode Island HospitalDivision of Renal Diseases593 Eddy StreetProvidence, RI 02903phone: (401) 444-8345fax: (401) 444-3283e-mail: [email protected]


IMAGES IN MEDICINEEdited by John Pezzullo, MD

Images in Medicine: We encourage submission to the Images in Medicine section from all medical disciplines. Image(s) should capture the essence of how a diagnosis isestablished, and include a brief discussion of the disease process. The manuscript should be less than 250 words and include one reference. The manuscript and one or twocropped 5 by 7 inch prints should be submitted with the author’s name, degree, institution and e-mail address to: John Pezzullo, MD, Department of Radiology, Rhode IslandHospital, 593 Eddy St., Providence, RI 02903. An electronic version of the text should be sent to the editor at [email protected].

Figure 1. Fundus photographs demonstrating multifocal, round,yellowish choroidal lesions in both eyes.

Figure 2. The bronchial biopsy is shown with Gomori methenaminesilver stain demonstrating the thin-walled Pneumocystis organisms

(arrow). (Original magnification x240).

Pneumocystis Carinii ChoroiditisOphthalmologic consultation was requested in a 34 year-old AIDS patient admitted to the hospital with pneumonia,

who complained of decreased visual acuity. On fundus examination, he was noted to have multiple slightly elevated, oval,yellow-white choroidal lesions bilaterally (Figure 1). While in the hospital, a chest and abdominal CT scan demonstratedmultiple hypodense lesions in the spleen, and diffuse, nodular pulmonary infiltrates. Gomori methenamine silver stain ofa bronchial aspirate (Figure 2) demonstrated the thin walled Pneumocystis carinii organisms (arrow).

Pneumocystis carinii choroiditis is a rare complication of infection with P. carinii. Most cases have occurred in AIDSpatients receiving aerosolized pentamidine for pneumonia prophylaxis, as in this case. Ocular infection produces bilateral,multifocal, plaque-like choroidal lesions concentrated in the posterior pole. There is little inflammation both clinically andhistopathologically, and the lesions cause a modest decrease in visual acuity. The choroidal lesions and visual deficits usuallyimprove after treatment with systemic antibiotics. As antiviral therapies continue to improve, the incidence of P. cariniichoroiditis in patients receiving inhaled pentamidine is likely to rise. The ophthalmologist can play an integral role inscreening and treating these patients.

KING TO, MDMARJORIE A. MURPHY, MD

King To, MD, is Director of the Ophthalmology Residency Program at Rhode Island Hospital and Clinical Professor ofSurgery (Ophthalmology), Brown Medical School.

Marjorie A. Murphy, MD, is Director of Neuro-Ophthalmology at Rhode Island Hospital and Assistant Clinical Professor ofSurgery (Ophthalmology), Brown Medical School.

REFERENCETo K, Friedman AH. CMV retinitis. JAMA 1989;262:3337.

CORRESPONDENCE:King To, M.D., 100 Dudley Street, Providence, RI 02905, phone: (401) 831-4592, e-mail: [email protected]

135Vol. 85 No. 4 April 2002

Diabetes and Heart Disease�Raymond Maxim, MD

Despite a strong correlation between diabetes and heart dis-ease, and the well-documented effectiveness of available

treatments, few patients are adequately monitored and treated.In 1999, diabetes affected more than 10.5 million Americans.1

Almost 8% of the entire population2 and more than 12% ofthose over the age of 65 were diagnosed with diabetes. And, asit stands now, approximately 65% of those individuals with Type2 diabetes will die from heart disease.

Three areas where significant gains can be made to lowerthe risk of heart disease in individuals with diabetes are the treat-ment of lipids, lowering blood pressure and addressing otherpatient-modifiable patient cardiovascular risk factors.

LIPIDS IN HEART DISEASEThe typical lipid pattern in diabetic individuals is an el-

evated triglyceride level and decreased HDL level. LDL levelsdo not usually differ from those who do not have diabetes.However, the LDL in diabetics may be smaller, denser and moreatherogenic. The single, strongest predictor of cardiovascularrisk is the decreased HDL level.

HMG CoA reductase inhibitors and fibric acid derivativesare effective in reducing cardiovascular disease in diabetics. TheScandinavian Simvastatin Survival Study3 reduced cardiovascu-lar disease in diabetics with elevated LDL. Other studies havesupported the effectiveness in reducing CHD by statin drugs.In the Veterans Affairs High-Density Lipoprotein CholesterolIntervention Trial,4 gemfibrozil lowered risk for cardiovascularevents in those with existing cardiovascular disease by 24%.

Treatment recommendations for dyslipidemia from theAmerican Diabetes Association5 are much more aggressive thancurrently practiced by physicians in most communities. In the2002 Clinical Practice Recommendations, those individuals withexisting heart disease and LDL levels > 100 mg/dl should haveboth pharmacological and medical nutritional therapy (MNT)initiated concurrently. The combined MNT and pharmaco-logical therapy recommendations are the same for diabetics with-out existing CHD and LDL levels > 130 mg/dl. For thosepatients with no preexisting CHD and LDL levels < 130 mg/dl, MNT can be started alone or in concert with pharmacologi-cal therapy for three months. If goals of LDL <150 mg/dl is notreached then pharmacological therapy should be introduced.

Options for pharmacological therapy to raise HDL are lim-ited. Nicotinic acid is the most effective agent available but isrelatively contraindicated due to its negative effect on glycemiccontrol. Fibric acid derivatives are effective and are the first linechoice after, or in conjunction with, weight loss, exercise andsmoking cessation.

Hypertriglyceridemia is positively affected by improved gly-cemic control. Therefore, efforts to lower triglyceride levels should

begin after optimizing glycemic control. Fibric acid derivativesand high dose statins are effective second line therapies. Combi-nation therapies with statins, fibrinates, or nicotinic acid can beused with appropriate precautions. The level of triglyceride atwhich to initiate pharmacological therapy is less clear-cut, but isstrongly recommended after 400 mg/dl.5

HYPERTENSIONOne of the more dramatic findings in the United King-

dom Prospective Diabetes Study (UKPDS)6 was the effect thattreating hypertension had on the complications from diabetes.For each decrease of 10 mmHg in systolic blood pressure, therewas an 11% decrease in risk for myocardial infarction indepen-dent of glycemic control or initial blood pressure.

Despite overwhelming evidence that treating hypertensionreduces risk for cardiovascular disease and stroke, only 25% ofpatients are adequately controlled. In an observational studypublished in the February issue of The Archives of Internal Medi-cine, only 38% of patients with poorly controlled hypertensionfor at least six months had a change in pharmacological therapy.7

Contrary to available evidence, the physicians surveyed werewilling to accept a higher blood pressure.8

Current recommendations for patients with diabetes andhypertension are to initiate pharmacological therapy for a sys-tolic blood pressure (SBP) > 140 mm/Hg or a diastolic bloodpressure (DBP) of > 90 mmHg. For patients with SBP between130-139 mmHg or DBP, between 80-89 mmHg treatmentshould begin with lifestyle changes and behavioral therapy for 3months. Those patients not meeting SBP <130 and DBP <80should begin pharmacological therapy.

PATIENT MODIFIABLE RISK FACTORSIn addition to the above modifiable risk factors, patients

can effect change in their smoking status, physical activity, weightloss and fat consumption. Evidence suggests that physician coun-seling is effective in producing behavior change in these areas.The 1999 Behavioral Risk Factor Surveillance System1 (BRFSS,a national bienially administered survey) data looked at fourcounseling topics crucial to good diabetes care. Survey respon-dents with diabetes were asked if they had received counselingabout weight loss, smoking cessation, exercise and low-fat diets.Respondents were advised to lose weight in only 48% of physi-cian visits. Additionally, patients were counseled to exercise only67% of the time, to eat less fat 78% of the time, and to quitsmoking 78% of the time. Some of the reasons primary carephysicians gave for the low prevalence of counseling includedlack of time, minimal training in counseling techniques and un-certainty that they can effect change in patient behavior.


CONCLUSIONIn Rhode Island, only 75% of Medicare beneficiaries with

diabetes had at least one lipid profile evaluation in the last twoyears (unpublished Medicare fee-for-service claims data 1999-2000). It is clear that physicians need to become more aggres-sive in their treatment of lipid disorders and hypertension if ourpatients are to realize the gains evidence demonstrates are ob-tainable. It is equally clear that despite a lack of confidence inour counseling skills, patients depend upon their physicians toprovide that counseling. We should actively seek out additionaltraining in counseling techniques and behavior change to im-prove our skills and increase our confidence in our counselingabilities. After all, we are still the most powerful voice when itcomes to changing our patients behavior.

REFERENCES1. Egede LE, Zheng D. Modifiable car diovascular risk factors in adults

with diabetes: P revalence and missed oppor tunities for physician coun-seling. Arch Intern Med 2002; 162:427-33.

2. American D iabetes Association. Scr eening for diabetes. Diabetes Care2002;25, Supplement 1,:S21-4.

3. Herman WH, Alexander CM, Cook JR, et al. E ffect of simv astatintreatment on car diovascular resource utilization in impair ed fastingglucose and diabetes: F indings fr om the Scandinavin S imvastatinSurvival Study. Diabetes Care 1999;22:1771-8.

4. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondar yprevention of cor onory heart disease in men with lo w levels of high-density lipoprotein cholester ol: Veterans Affairs H igh-Density Lipopro-tein Cholester ol Intervention Trial Study Group. NEJM 1999;341:410-8.

5. American D iabetes Association. M anagement of dyslipidemia in adultswith diabetes. Diabetes Care 2002;25, Supplement 1:S74-7.

6. American D iabetes Association. I mplications of the U nited Kingdom P ro-

spective Diabetes Study. Diabetes Care 2002; 25, Supplement 1:S28-32.7. Oliveria SA, Lapuer ta P, McCarthy BD, et al. Physician-related bar-

riers to the effectiv e management of uncontr olled hyper tension. ArchIntern Med 2002;162:413-20.

8. American D iabetes Association. Treatment of hyper tension in adultswith diabetes. D iabetes Care 2002;25, Supplement 1: S71-73.

Raymond B. Maxim, MD, is a Clinical Coordinator at RIQP,Staff Physician at Roger Williams Medical Center, and ConsultantMedical Director to the Rhode Island Medicaid program.

CORRESPONDENCE:Raymond Maxim, MDphone: (401) 528-3265fax: (401) 528-3210e-mail: [email protected] #6SOW-RI-DIA-02-12

The analyses upon which this publication is based were performed un-der Contract Number 500-99-RI02, entitled “Utilization and QualityControl Peer Review Organization for the State of Rhode Island,” spon-sored by the Health Care Financing Administration, Department ofHealth and Human Services. The content of this publication does notnecessarily reflect the views or policies of the Department of Health andHuman Services, nor does mention of trade names, commercial prod-ucts, or organizations imply endorsement by the U.S. Government.

The author assumes full responsibility for the accuracy and com-pleteness of the ideas presented. This article is a direct result of theHealth Care Quality Improvement Program initiated by the Health CareFinancing Administration, which has encouraged identification of qualityimprovement projects derived from analysis of patterns of care, and there-fore required no special funding on the part of this Contractor. Ideasand contributions to the author concerning experience in engaging withissues presented are welcomed.

Drug Product Expiration Dates:Practice Implications�

Celia P. MacDonnell, PharmD, RPh, and Norman A. Campbell, JD, PhD, RPh

Advances in Pharmacology

Are expired drugs still safe and effective? Health care pro-fessionals have been grappling with this question since

1979, when the Food and Drug Administration (FDA) be-gan to require prescription drug dating. The FDA initiallyintended to set uniform stability testing and reporting guide-lines. With the ever-rising cost of prescription drugs it is cru-cial that the expiration dates of both prescription andnon-prescription drugs are determined for a maximum pe-riod of time while maintaining optimal efficacy.

The expiration date of a drug product is normally deter-mined by estimating the time at which 95% one-sided lowerconfidence interval of a quantitative drug characteristic (e.g.assay) intercepts the lower specification limit.1 Stability dataon test batches are generated for a period of 12 months priorto submission of the regulatory dossier. If statistical analysisthen demonstrates that the batches are similar, the data arepooled, to yield an overall estimate of expiration date. If thestability data from all of the batches cannot be pooled, an

overall expiration date will be defined using the data from theleast stable batch tested.1

Statistical analysis is not the only factor germane to thedetermination of drug stability. Dr. C. Rhodes from the Ap-plied Pharmaceutical Sciences Department at the Universityof Rhode Island notes that the stability of pharmaceutical prod-ucts “encompasses many potential routes of degradation.” Theconventional classifications of degradation of pharmaceuticalproducts are chemical, physical, or biological. Degradation ofthese products may additionally be classified by the adverseeffects of the instability of a pharmaceutical product as modi-fying efficacy, safety or ease of use or patient acceptability. Interms of efficacy the most obvious effect is loss of potency ofthe drug.2

Environmental conditions and proper storage are key tothe determination of safety and efficacy of any drug product.The shelf life of a drug is defined as the time during which thedrug product will maintain greater than 90% of the label claim

137Vol. 85 No. 4 April 2002

potency. The estimation on the time thatwill elapse before potency is less than 90%of the label claim includes specific limits ofstorage conditions. Although shelf lives maybe estimated by accelerated stability testingprotocols, real-time product stability test-ing is necessary to validate stability claims.2

Additionally, the manufacturer’s determinedproduct expiration dates only apply if spe-cific storage requirements are met from thetime the product leaves the manufactureruntil it is supplied to the user.3

In 1985 the FDA began a partnership with the Depart-ment of Defense (DOD). This collaboration was initiated bya Government Accounting Office (GAO) audit of U.S. AirForce contingency hospitals in Western Europe. The auditidentified stockpiles of medical supplies near the manufactur-ers’ expiration dates. The imminent replacement of these ma-terials represented a significant monetary impact to the AirForce. As a result, the idea of extending the shelf lives of theseproducts began to be explored. The FDA developed an ap-proach for controlled accelerated aging, coupled with com-puter modeling and laboratory testing, to predict the continuedstability of the active components of the products.4

On March 28, 2000, The Wall Street Journal featured anarticle addressing the FDA’s Shelf Life Extension Program andthe issue of medication potency past expiration dates. The Jour-nal reported that after 15 years of testing, about 90% of thedrugs tested in this military program were safe and effectivefar past their original expiration date.5

Although under the FDA’s guidance drug shelf life ex-tensions are occurring in the military sector, these recommen-dations cannot be extrapolated to the private sector at thistime. In a recent telephone interview, Ms. Donna Porter, fromthe FDA’s Office of Regulatory Affairs, issued a strong warn-ing against such conclusions. Ms Porter, who has also beeninvolved with the Military Shelf Life Extension Program forthe past 15 years, warns that the drugs largely being tested forstability do not necessarily apply to the private sector. Includedin the products being tested on a yearly basis are items such asantidotes for biological warfare. She also calls attention to thefact that military personnel are a young, healthy group. Theirmedical needs as well as their pharmaceutical needs are notrepresentative of the general population. Medications com-mon to an elderly population such as nitroglycerin, insulinand digoxin were not part of the testing.

Ms Porter also emphasized the fact that the medicationsbeing tested by the FDA for the military are continuously storedunder controlled conditions. It is well known that storage inhigh humidity may interfere with the dissolution characteris-tics of some oral formulations. Carbamazepine tablets, for ex-ample, when stored under humid conditions have failed todissolve and have been associated with clinical failure.6

Whether or not outdated drugs are harmful is a questionthat requires further research. However, the potency they main-tain varies with the drug, and the storage conditions, particu-larly humidity. Health care professionals who prescribe,

administer and/or dispense prescription-only drugs should factor this informationinto their decisions.

It is important to note the use or dis-tribution of a drug product after its FDA-mandated expiration date may have legalconsequences which should be discussedwith institutional or person legal counsel.Under provisions of the Federal Food Drugand Cosmetic Act (FDCA) such distribu-tion may constitute the prohibited act of...”misbranding...”7 by mislabeling, subject-

ing violators to criminal and civil sanctions. In addition theseexpired drug products may be considered contraband and there-fore subject to seizure by federal and/or state authorities.

Licensing boards may look to distribution or administra-tion of drug products beyond their labeled expiration dates asunprofessional conduct or substandard practice with concomi-tant sanctions. In Rhode Island, statutory and regulatory pro-visions require dispensed prescriptions to bear a “beyond usedate” determined as not later than six months if themanufacturer’s date is less than one year or 12 months from thedate of dispensing if the labeled date exceeds a year.8

Should a patient be harmed by a subpotent or superpo-tent drug or its degradation products, a plaintiff could allegenegligent malfeasance or substandard practice. In either case, apractitioner-defendant could be in danger.

REFERENCES1. Truman KG, Lyons RA, Coleman MSH, Drug Dev. Ind. Pharm.,

21, 1429-1437 (1995).2. B. Kommanaboyina, C.T. Rhodes, Drug Dev. Ind. Pharm., 25,

857-868 (1999).3. U.S. Pharmacopeial Convention, Inc., Pharmaceutical dosage

forms, in The United States Pharmacopeia 23/National Formulary18,Supp. 8, Author, Rockville, MD,1995.

4. FDA/CDER/DDMAC.5. Wall Street Journal March 28,2000.6. The Medical Letter, Vol 38(Issue979), July 19,1996.7. FDCA Sec.301.8. RIGL 21-31-15(1)(1).

Celia P. MacDonnell, PharmD, RPh, is Coordinator, Profes-sional Practice Laboratory, College of Pharmacy, University of RhodeIsland.

Norman A. Campbell, JD, PhD, RPh, is Professor of Phar-macy Administration Emeritus, College of Pharmacy, Universityof Rhode Island.

CORRESPONDENCE:Celia P. MacDonnell, PharmD, RPhCollege of PharmacyUniversity of Rhode Island41 Lower College RoadKingston, RI 02881phone: (401) 874-2615fax: (401) 874-2717

�

The shelf life of a drug isdefined as the time

during which the drugproduct will maintain

greater than 90% of thelabel claim potency.


Edited by Jay S. Buechner, PhD

Diabetes: An Epidemic of a Chronic Disease� �Barbara Kondilis, MSW, MPH, Joann Lindenmayer, DVM, MPH, and Dona Goldman, RN, MPH

Rhode Island Department of Health

Patricia A. Nolan, MD, MPH, Director of Health

Health by Numbers

Diabetes is the seventh leading cause of death in the UnitedStates and often leads to heart disease, stroke, blindness,

or amputation of the leg or foot.1 In Rhode Island, diabeteswas the underlying cause of death for 266 deaths during 1996and was a contributing cause through its complications foranother 693 deaths.2

The prevalence of diabetes has been increasing in recent de-cades at near epidemic rates. Nationally approximately 8.5 mil-lion persons (3.2% of the population) were diagnosed with diabetesin 1996. Between 1980 and 1996 the prevalence of diagnoseddiabetes increased by 2.7 million persons, representing an increaseof 19% in the age-adjusted prevalence rate.3 For every two casesof diabetes that are diagnosed, there is an additional case that hasnot been diagnosed. As of the year 2000, an estimated 70,000Rhode Islanders ages 18 and older had diabetes (with46,000 cases diagnosed).

Type 2 diabetes represents 95% of all cases of dia-betes. There is a strong association between obesity andthe development of Type 2 diabetes.4 Obesity has beenincreasing both nationally and in Rhode Island, andresearch has shown that lifestyle change, includingweight loss and physical activity, can reduce the inci-dence of diabetes in high-risk populations.5

MethodsRhode Island utilizes the Behavioral Risk Factor

Surveillance System (BRFSS) to track population in-formation on diabetes. The BRFSS is a statewide tele-phone survey of randomly selected adults (ages 18 andolder) who live in households with telephones. It asksrespondents questions about a variety of health-relatedbehaviors. During 1994-1997, the number of inter-views performed was about 1,800 per year (150 permonth); during 1998-2000 it increased to approximately3,600 per year (300 per month). Fifty states and fourterritories perform the BRFSS with funding and meth-odological standards provided by the Centers for Dis-ease Control and Prevention (CDC).6

The BRFSS question used to measure diabetesprevalence for the years 1994-2000 is: “Have you everbeen told by a doctor that you have diabetes?” The sur-vey also asks height and weight of each respondent, fromwhich the body mass index (BMI), defined as weight inkilograms divided by the square of height in meters, iscalculated. A BMI of 25 to 29.9 is considered over-weight, and a BMI of 30 or above is considered obese.

ResultsThe prevalence of diagnosed diabetes has been increasing

in Rhode Island over the period examined, 1994-2000. (Fig-ure 1) In 2000, the prevalence rate among adults, 6.0%, wasnearly one-third higher than the rate in 1994, 4.6%.

Diabetes is far more commonly diagnosed among olderadults than younger adults. (Figure 2) The prevalence rate ishighest among adults ages 65 years or older, followed by ages45-64 years, and ages 18-44 years. The rate increases nearlyfive-fold from the 18-44 age group to the 45-64 age group,then by another 44% among those 65 years and older.

Over the period 1994-2000, the proportion of people whoare obese among adult Rhode Islanders increased from 13.4%

Figure 1. Prevalence of Diagnosed Diabetes among Rhode Island ResidentsAges 18 and Older, by Year, 1994-2000.

Figure 2. Prevalence of Diagnosed Diabetes among Rhode Island ResidentsAges 18 and Older, by Age Group, 2000.

139Vol. 85 No. 4 April 2002

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to 17.1%, or by more than one-quarter. (Figure 3) Increasesin obesity were seen among all age groups, but the increasesamong the elderly (up 36%) and younger adults (up 32%)were noticeably greater than the increase among those ages45-64 (up 11%).

DiscussionThe Diabetes Control Program (DCP) at the Rhode

Island Department of Health is dedicated to integrating healthsystems for improved provider and patient support for betterdiabetes control. The DCP is working towards fulfilling thediabetes-related objectives of Healthy People 2010 on reduc-ing mortality, reducing the disease burden, reducing diseasecomplications, and increasing health services and patient pro-tection, including diabetes education.4 The DCP primarilyfocuses on secondary prevention and is moving to includeprimary prevention with community collaborations and guid-ance from national experts such as the CDC.

National and international studies such as the DiabetesPrevention Program (DPP) study and the Finnish DiabetesPrevention Study have shown that primary prevention of type 2diabetes is possible through weight control and physical activ-ity, particularly in persons with impaired glucose tolerance andother high-risk characteristics.7 Local and national health ini-tiatives face more than programmatic challenges. The ultimatechallenge is to support individuals to modify their behavior toprevent obesity and to better manage their diabetes. This in-cludes larger systemic changes such as environmental modifica-tions (i.e. safer walking areas, modest food portions in restaurants,healthier food and beverage choices in schools), and municipal,state, and national policies that encourage people to make bet-ter dietary choices and that encourage physical activity.

ACKNOWLEDGEMENTS.This work was supported in part by the Rhode Island

Behavioral Risk Factor Surveillance System Cooperative Agree-ment (#U58/CCU100589-19) from the Centers for DiseaseControl and Prevention.

Barbara Kondilis, MSW, MPH, is a Public Health Preven-tion Specialist from the CDC, Epidemiology Program Office,Public Health Prevention Service, currently assigned in the RhodeIsland Department of Health, Division of Disease Prevention and

Control, Diabetes Control Program.Joann M. Lindenmayer, DVM, MPH, is Assistant Pro-

fessor (Research), Department of Community Health, BrownMedical School, and chronic disease epidemiologist, Divisionof Disease Prevention and Control, the Rhode Island Depart-ment of Health.

Dona Goldman, RN, MPH, is the Program Director ofthe Diabetes Control Program, Division of Disease Preven-tion and Control, Rhode Island Department of Health, andFaculty at Roger Williams University.

REFERENCES1. McGinnis JM, Foege WH. Actual causes of death in the UnitedStates. JAMA 1993; 270:2207-12.

2. CDC. Rhode Island: Risk factors and preventive services, 1997 and 1998.Source: Behavioral Risk Factor Surveillance System, 1997 and 1998.

3. CDC. National Center for Chronic Disease Prevention and Health Pro-motion. www.cdc.gov/diabetes/statistics/survl99/chap1/contents.htm

4. US Department of Health and Human Services. Healthy People 2010: 2nded. Understanding and Improving Health and Objectives for Improving Health.(2 vols.) Washington, DC: US Government Printing Office. 2000.

5. Diabetes Program Research Group. Reduction in the incidence of type 2diabetes with lifestyle intervention or metformin. NEJM 2002;346:393-403.

6. US Department of Health and Human Services, Public Health Service.Health Risks in America: Gaining Insight from the Behavioral Risk FactorSurveillance System. Atlanta, GA: CDC, undated.

7. Bowman BA. Can Type 2 Diabetes be Prevented? Lecture. Centers forDisease Control and Prevention, Diabetes Program Directors and Coor-dinators Meeting, November 2001.

Figure 3. Prevalence of Obesity among Rhode Island Residents Ages 18and Older,


Asthma, Particulates, and Diesel Exhaust

PUBLIC HEALTH BRIEFING

Edited by John P. Fulton, PhD



Leanne Chiaverini

Asthma exacerbations are caused by irritants known as “trig-gers.” Common triggers include particulate matter and

other substances in tobacco smoke and vehicular exhaust, dustmites, pet dander, cockroach feces, mold spores, pollen, andstrong odors. Activity, respiratory infections, and climate (tem-perature and humidity) can also precipitate asthma attacks.

Particulate matter (PM), one of several major air pollut-ants, is considered an important asthma trigger in urban loca-tions because of the public’s heavy reliance on cars, trucks, andbuses. The U.S. Environmental Protection Agency (EPA) de-fines PM as a mixture of solid and liquid particles in the air. TheEPA and several other federal agencies have labeled it a primaryair pollutant and a probable human carcinogen.1,2 PM less than2.5 micrometers in diameter (PM

2.5), a

common component of exhaust from ve-hicles, power plants, and industrial facili-ties,2 is of particular concern because itssmall size allows it to bypass the body’s de-fenses and easily reach the deepest recessesof the lungs where it is more likely to beretained. Because PM can act as an asthmatrigger, causing a decrease in lung functionand inflammation of the airways, asthmat-ics are at a considerable risk of experienc-ing adverse effects from exposure to it.2-4

Dozens of studies worldwide confirm thatPM (often from diesel fuel) can aggravate orproduce symptoms of asthma and other res-piratory illnesses, retard lung development,and cause premature death, especially amongpeople with cardiopulmonary diseases. Astudy conducted by the National Health andEnvironmental Effects Research Laboratoryfound that exposure to PM promotes air-way inflammation and hyperresponsiveness.5

High levels of PM have been linked withhigh levels of medication use, hospital andemergency room admissions, and work andschool absences.2-4

The EPA estimates that diesel exhaustis the source of more than 20% of the finePM in New England air.6 Diesel exhaustis comprised of hundreds of constituentchemicals, many of which are harmful toboth humans and the environment. Un-der the Clean Air Act, forty of these chemi-cals are classified as “hazardous pollutants;”

some of them have been designated probable human carcino-gens.3 The major pollutants in diesel exhaust include:

Diesel particulate matter (DPM)Polynuclear aromatic hydrocarbons (PAH)Nitrogen oxides (NOx)Volatile organic compounds (VOC), which include hy

drocarbons (HC)Sulfur dioxide (SO2)Carbon monoxide (CO)7

PM is a significant ingredient in diesel exhaust. Composedof more than 98% PM

2.5, these particulates are very small.4

The release of DPM into the atmosphere is caused by poorrefinement of diesel fuel and incomplete fuel combustion, and

Table 1.Encapsulated History of Diesel ExhaustPolicy in the United States

1970: Congress revised the Clean Air Act, requiring 90% CO, HC and NOxreductions from light-duty diesel vehicles by 1976. Authority toregulate motor vehicle pollution was given to the United States EPA.18

1977: Congress amended the Clean Air Act, requiring heavy-duty vehiclesto make 90% CO and HC reductions by 1984, and a 75% NOxreduction by 1985.18

1982: Air Resources Board regulates PM104

1985: EPA, under the Clean Air Act, set emissions standards for new diesel-powered trucks and buses.18

1987: EPA regulates PM104

1990: Congress amended the Clean Air Act, including more stringent controlover PM from diesel engines. EPA placed restrictions on the sulfurcontent of diesel fuel.18

1993: EPA put forth regulations for 80% reduction of sulfur content in fuel,and 60% reduction in particulate emissions from urban buses.18

1993: EPS initiated the Urban Bus Retrofit/Rebuild Program. Required thaturban buses operating under certain conditions use EPA certifiedretrofit pollution control technology or be rebuilt using certified lowemission components during engine rebuilds.1

1994: EPA reduced PM standards for new diesel-powered truck and busengines.18

1996: EPA further reduced PM standards for new diesel-powered truck andbus engines.18

1997: EPA adopted new National Ambient Air Quality Standards for particlesunder 2.5 microns in size.4

2000: EPA adopted new diesel regulations requiring reduced emissions fromnew engines, along with the use of ultra low sulfur fuel. Expected tobe fully implemented in 2010.18

Adapted from: Massachusetts Enhanced Emissions and Safety Test. Diesel Background.http://vehicletest.state.ma.us/dieselbg.html

141Vol. 85 No. 4 April 2002

is directly related to the sulfur and PAH content of the fuel.8

NOx and VOC combine in the atmosphere to create ozone.9

Ozone is the prime ingredient in smog, which is annually re-sponsible for an estimated 6 million asthma attacks and150,000 emergency room visits.10

Children, with airways that are small in diameter andnot fully developed, are especially sensitive to diesel exhaust.“There is no known safe level of exposure to diesel exhaust forchildren, especially those with respiratory illness.”3 Diesel ex-haust may cause difficulty in breathing, especially if airwaysare already inflamed or constricted by asthma. Children ridingon school buses may be exposed to unusually high concentra-tions of DPM. In 2001, the National Resource Defense Coun-cil found this exposure to be as much as four times that ofsomeone riding in a car in front of the bus.11 More recently,an Environment and Human Health, Inc. (EHHI) researchteam found that concentrations of PM

2.5 in school buses were

often 5-10 times higher than average levels measured at fixed-site monitoring stations.3 Concentrations increased when buseswere idling with windows open (especially when queued toload or unload students), when driving on routes with theirwindows closed, and when moving through heavy traffic.3 Inthe United States, 24 million children make nearly 10 billionschool bus rides on 600,000 school buses.3 More than 99%of school buses in the U.S. are powered by diesel fuel.3

Adults are also susceptible to diesel exhaust. Occupationalexposures put more than one million workers at risk for adversehealth effects ranging from headaches and nausea to cancer andrespiratory diseases.12 Those occupations at increased risk in-clude but are not limited to: workers of railroads, mines, load-ing docks, farms, toll booths, and bridges and tunnels; truckdrivers; and auto, truck and bus mechanics/garage workers.12

Sources of diesel exhaust may be categorized into threegroups: mobile sources (cars, trucks, tractors, lawnmowers),stationary point sources (factories, refineries, power plants),and smaller stationary area sources (dry cleaners, gas stations).13

Heavy-duty diesel trucks and buses are a major contributor toair pollution. In the United States, heavy-duty vehicles (suchas semi-trucks, buses, and waste-haulers) account for a mere2% of all on-road vehicles, but produce one third of all nitro-gen oxide emissions and almost two-thirds of all particulatesfrom on-road vehicles.8 Heavy-duty vehicles in Rhode Islandemit 347 tons of PM per year and are responsible for 52% ofthe total PM emitted by all Rhode Island vehicles.8

The United States has been cognizant of improving airquality since the creation of the Air Pollution Control Act in1955.14 Major actions taken in the past three decades to reducepollution from diesel exhaust are summarized in Table 1. TheUrban Bus Retrofit Program, organized in 1993, has retrofittedor rebuilt approximately 10,000 of 42,000 eligible urban buses.1

New diesel regulations adopted by the EPA in 2000 are ex-pected to prevent annually an estimated 8,300 premature deaths,360,000 asthma attacks, 386,000 cases of respiratory symptomsin asthmatic children, 1.5 million lost work days, 7100 hospitaladmissions, and 2400 emergency room visits for asthma.15

Despite these accomplishments and the development ofmore stringent air quality standards, the matters surrounding

diesel exhaust are far from resolved. There are numerous waysto limit emissions of and exposures to diesel exhaust.

• Create and implement anti-idling programs and laws. Anti-idling campaigns, programs, and laws are an inexpensiveand efficient approach to reducing diesel exhaust. Idlingengines emit unnecessary toxins into the air, adding to thelevels of diesel exhaust. For example, idling school busesexpose children to high levels of diesel exhaust. In additionto the health impact, vehicle idling is an environmentalhazard and an expensive practice. Truck drivers often leavetheir engines running during 6-hour sleep periods, burn-ing approximately one gallon of diesel fuel each hour.6 Atthis rate, a vehicle in operation for 300 days will idle away1,800 gallons of fuel per year.6 Each truck releases an an-nual ten pounds of particulate matter into the air, and at$1.25 per gallon, pays an idling fee of $2,250.6 With anestimated 1.3 million large trucks and 4.2 million tractor-trailer rigs on US highways, the costs mount.16 Compa-nies accept this cost because it is convenient (diesels arehard to start when cold) and because running the engineskeeps heaters or refrigerators running. Small generators orauxillary power units that supply heat, air conditioning andpower, provide efficient alternatives to idling.6

• Require, promote or provide incentives to increase the useof cleaner diesel fuels and non-diesel alternatives. Pollu-tion control devices in engines are destroyed by the sulfurin diesel fuel.8 The use of ultra-low sulfur diesel fuel(ULSD), which contains less than 15 parts of sulfur permillion, can reduce PM by 20-25%.6 To support theseefforts, ULSD should be made available nationwide. Emul-sified diesel fuel, which has been mixed with water andother additives, is an option for vehicles that do not remaindormant for long periods. Emulsified diesel fuel can re-duce PM by 50%.6 Other alternatives include battery elec-tric vehicles, hybrid electric vehicles, compressed gases, andfuel cells.8 Buses that run on natural gas emit 60-98% lesscarbon than diesel-powered buses.3

• Retrofit diesel vehicles with pollution control equipment.Heavy-duty vehicles may be retrofitted with interior air fil-ters, oxidation catalysts, and particulate traps.3 Use of thelatter in combination with ULSD can reduce PM emis-sions by 90%.6

• Replace existing Heavy Duty Engines with newer vehicles.“Require and provide financial support for eventual replace-ment of existing diesel fleets with low emission vehicles,especially in areas of the country beyond compliance withcurrent federal pollution standards.”3

• Require routine maintenance and implement routine emis-sions testing. Require on-board equipment and in-useemissions testing to prevent cheating.8

• Federal, state and local governments, and school districtsshould work together to implement the following changesin school bus emissions:

Prohibit school bus idling.Plan and implement a school bus retrofit program.Require routine maintenance and periodic tailpipe


emissions testing.Require the design and installation of air filtration

equipment capable of removing vehicle exhaustfrom air entering bus passenger cabins.

Limit ride duration.Allocate buses with the lowest emissions to the

longest routes, giving priority to communitieswith the poorest outdoor air quality and toroutes that have the highest traffic intensity.

Reconsider location of bus parking lots.Adjust contract provisions to lease retrofit buses

and require clean fuels.3

• Account for other exposures to air pollutants. Develop airquality monitoring programs that consider indoor andwithin-vehicle exposure to air pollution, and establishhealth protective standards accordingly. Create additionalstationary monitoring networks and use personal moni-toring devices to collect data. Efforts to better understandthe variability in exposure should begin by focusing onsusceptible populations.3

• Create safer work environments. Use safe work practices,ventilation, and personal protective equipment to protectworkers who are exposed to diesel exhaust.

• Promote recycling. The burning of diesel fuel is a signifi-cant source of carbon and other greenhouse gas emissions.Recycling reduces the amount of energy used in industrialprocesses and transportation, thus reducing greenhouse gasemissions. Rhode Island recycling efforts in 1995 reducedgreenhouse gas emissions by approximately 30,000 tons ofcarbon equivalent per year, an amount equal to nearly 5%of all industrial carbon dioxide emissions.17

As Rhode Island develops policy to manage PM in the air,the medical and public health communities must work togetherto assure that health concerns are given appropriate weight. Inaddition to formal representation at official policy forums, phy-sicians are well-positioned as credible advocates for improvedair quality.

REFERENCES1. Heavy-duty Diesel Emission Reduction Project Retrofit/Rebuild Com-

ponent prepared by NESCAUM (Northeast States for Coordinated AirUse Management) for the EPA in March 1999.

2. US EPA Office of Air & Radiation, Office of Air Quality Planning &Standards. July 17, 1997. Health and Environmental Effects of Particu-late Matter. www.epa.gov/ttn/oarpg/naaqsfin/pmhealth.html

3. Wargo J, Brown D, Cullen M, et al. Children’s Exposure to Diesel Ex-haust on School Buses. Environment and Human Health, Inc. Feb 2002.

4. NRDC (National Resources Defense Council) and Coalition for CleanAir. Exhausted by Diesel: How America’s Dependence on Diesel En-gines Threatens our Health. April 1998.

5, Gavett SH, Koren HS. The role of particulate matter in exacerbation ofatopic asthma. Int Arch Allergy Immunol 2001;124:109-12.

6. US EPA. Question of the month - What is EPA doing about DieselExhaust.www.epa.gov/NE/questions/index.html

7. Nett Technologies Inc. Frequently Asked Questions About Diesel Emis-sions. 2002. www.nett.ca/faq_diesel.html

8. Farleigh A, Kaplan L. Dangers of Diesel. U.S. Public Interest ResearchGroup Education Fund. 2000. www.pirg.org/reports/enviro/dangerousdiesel/

9. EPA’s Updated Clean Air Standards: A Common Sense Primer. Septem-ber 1997.

10. Illinois Public Interest Research Group. Environmental Preservation andProtection Program. Campaign to Dump Diesel. 2000.www.illinoispirg.org/enviro/diesel/#Anchor-49575

11. Soloman GM, Campbell TR, Feuer GR, et al. No Breathing in the Isles:Diesel Exhaust inside School Buses. National Resources Defense Coun-cil. Jan 2001.

12. Occupational Safety & Health Administration, US Department of Labor.Diesel Exhaust. September 2001. www.osha-slc.gov?SLTC/dieselexhaust/

13. US EPA New England. Air Toxics - What is a point source? June 2001.14. American Meterological Society. Environmental Events: other impor-

tant events occurring around the time of clean air legislation. 1999.www.ametsoc.org/AMS/sloan/cleanair/cleanairenvev.html

15. Press Release: Environment and Human Health, Inc. Releases OriginalResearch Report, Children’s Exposure to Diesel Exhaust on School Buses.Hartford, CT, Feb 7, 2002.

16. IdleAire Technologies. Trucking Industry. 2000. www.idleaire.com/industry.html

17. Recycling and the Environment, Facts about Recycling in Rhode Island.August 1999. Northeast Recycling Council. www.nerc.org/fsheets/ri.html

18. Massachusetts Enhanced Emissions and Safety Test. Diesel Background.vehicletest.state.ma.us/dieselbg.html

Leanne Chiaverini is a Research Associate, Asthma ControlProgram, Division of Disease Prevention and Control, Rhode Is-land Department of Health.

Commentary onPublic Health Briefing

Charles Sherman, MD

The increased prevalence and incidence of asthmaare alarming. Although newer medications have helpedin managing symptoms, only through environmentalcontrol can we expect to greatly lessen the severity of dis-ease.

Leanne Chiaverini has written an excellent briefingon the adverse health effects of particulate matter, espe-cially diesel exhaust particulates, for both asthmatics andnon-asthmatics. She clearly summarizes the significantmorbidity and mortality resulting from exposure to smallparticles. Of great concern is the recent association be-tween diesel exhaust particulates and lung cancer.

Ms. Chiaverini has also outlined several interven-tions that can limit diesel exhaust particulates. The medicalcommunity must support these measures and becomemore vocal in advocating for tougher air pollution stan-dards.

Physicians can get involved in several ways. Theycan testify at legislative hearings. They can write letters tolocal and state representatives, voicing their concerns andthose of their patients. Physicians can also work directlywith school administrators to devise a plan to reduceschool bus emissions (before those emissions drive kidsto your office). Contact Molly Clark of the AmericanLung Association of Rhode Island (MClark@ lungri.orgor 401-421-6487) to find out how to get involved.

I often tell my patients that they would do best tolive in a bubble, where all respiratory triggers could beeliminated. Given that this solution is not viable, we mustcontrol all harmful environmental exposures as a first step.

143Vol. 85 No. 4 April 2002

– A Physician’s Lexicon –

Hands on Medicine

Mainstream medicine, sometimes called allopathic medicine,has never claimed that it possessed a monopoly over the

broad field of health care therapeutics. There had always beencompeting, alternative health care systems, each with its ownpremises, operating philosophy and history.

Homeopathic medicine seeks out drugs which produce ef-fects simulating the visible symptoms of the disease in ques-tion. It then treats the disease in question with extremely small[homeopathic] doses of the same drug in the hopes of achievinga cure. This doctrine was first enunciated by a German physi-cian, Samuel Hahnemann, in 1795 and was called homeopathy[Greek, homos, meaning similar and pathos, suffering.] It mayhave been based on an earlier view of Parcelsus, similia similibuscurantur [like things are cured by like things].

Hahnemann, in 1824, also coined the descriptive word,allopathic [Greek, allos, meaning other, and pathos, meaning suf-fering] to describe the field of conventional medicine.

There have been still other schools of health care such ashydropathy [Gree, idro- , meaning water]; naturopathy [Latin,natura, meaning an untouched existence]; and balneopathy[Greek, balneon, meaning bath] which have emphasized the cura-tive role of bathing, exercise and prudent diet. Many of theseschools have diminished in popularity or have been absorbedby still other schools of therapy.

Chiropodist, a word coined in 1785, defines those practi-

tioners who are concerned with ail-ments of the hand [Gree, cheiro- , meaning hand] or feet [Greek,podos, the foot]. Currently these practitioners refer to their art aspodiatry since virtually all of their skills are now applied to dis-eases of the foot.

Osteopathy [Greek, osteon, meaning bone] was first de-scribed by Andrew Taylor Still, a midwestern practitioner whoadvocated vertebral manipulation or massage to alleviate variousneuromuscular disorders. Current osteopathic thinking is gradu-ally merging with allopathic teaching.

Another advocate of spinal manipulation to counteract al-leged derangement of the neuromuscular system was an Ameri-can, David Daniel Palmer, who constructed a system of care calledchiropractic [Gree, cheiro- , meaning hand and prakticos, mean-ing fit for action]. The Greek, root, cheiro- [sometimes spelledchiro- ] crops up in words such as chiromancy [the reading ofpalms], chirography [handwriting] and chiroptera [the order ofhand-winged mammals, the bats]; and, of course, cheirurgery,the ancient predecessor of the word, surgery.

And then there is the ancient art of acupuncture [Latin, acus,meaning needle or sharpness; and punctura, meaning to perforateor prick]. The Latin root, acus, appears in such words as acute,ague [a corruption of febris acuta] and acumen [Latin, mens, mean-ing reason or understanding; thus sharpness of intellect].

– Stanley M. Aronson, MD, MPH

(a) Cause of death statistics were derived from theunderlying cause of death reported by physicians ondeath certificates.

(b) Rates per 100,000 estimated population of1,048,319

(c) Years of Potential Life Lost (YPLL)

Note: Totals represent vital events which occurred in Rhode Is-land for the reporting periods listed above. Monthly provisionaltotals should be analyzed with caution because the numbersmay be small and subject to seasonal variation.

Rhode Island MonthlyVital Statistics Report

Provisional Occurrence Datafrom the

Division of Vital Records

Vital StatisticsEdited by Roberta A. Chevoya



Number (a) Number (a) Rates (b) YPLL (c)Diseases of the Heart 261 3,106 296.3 4,385.5 **Malignant Neoplasms 206 2,391 228.1 6,694.0 *Cerebrovascular Diseases 45 504 48.1 660.0Injuries (Accident/Suicide/Homicide) 38 380 36.2 6,736.0 **COPD 45 512 48.8 452.5

Reporting PeriodUnderlyingCause of Death April

2001 12 Months Ending with April 2001

Number Number RatesLive Births 1249 13,463 12.8*Deaths 795 10,142 9.7*

Infant Deaths (8) (103) 7.7#Neonatal deaths (6) (89) 6.6#

Marriages 820 8,472 8.1*Divorces 404 3,371 3.2*Induced Terminations 408 5,478 406.9#Spontaneous Fetal Deaths 103 1,018 75.6#

Under 20 weeks gestation (98) (935) 69.4#20+ weeks gestation (5) (83) 6.2#

Reporting PeriodOctober

2001Vital Events

* Rates per 1,000 estimated population # Rates per 1,000 live births** Excludes two deaths of unknown age.

12 Months Ending withOctober 2001


�

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�

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PROVIDENCE, R.I., JANUARY, 1917VOLUME 1NUMBER 1

PER YEAR $2.00SINGLE COPY, 25 CENTS

The Official Organ of the Rhode Island Medical SocietyIssued Monthly under the direction of the Publications Committee

THE RHODE ISLAND MEDICAL JOURNALTHE RHODE ISLAND MEDICAL JOURNAL

� �FIFTY YEARS AGO

[FEBRUARY, 1952]� �NINETY YEARS AGO

[APRIL, 1912]

TWENTY FIVE YEARS AGO

[FEBRUARY, 1977]� �

Janis Gailitis, MD, and Anthony Caputi, MD, contrib-uted “Auricular Fibrillation with Complete Heart Block andAdam-Stoke Syncope.” This case report discussed a 70 year-old woman admitted to Newport Hospital. She had suffered 5episodes of dizziness, followed by fainting, in the year beforeadmission. After treatment (epinephrine hydrochloride1:1,000, with oxygen atrophine with ephedrine), she recov-ered.

In “Acute Myocardial Infarction: Some Observations,”Frank B. Cutts, MD, discussed 216 cases admitted over fiveyears to Rhode Island Hospital. “In general patients were keptat bed rest from 2 to 6 weeks....Mild sedation was prescribedas needed to help promote a placid outlook.”

In “Doctors and Scholars,” Dennis P. McCarthy, OP, PhD,vice president and head, Department of English, ProvidenceCollege), discussed the physician-authors Oliver Goldsmith,Thomas Linacre, and Sir Thomas Browne.

An Editorial congratulated Woonsocket Hospital on itsnew building.

A second Editorial, contributed by the Department of De-fense, offered “Explanations of its Policies and Procedures Re-garding the Doctor Draft Act.”

In “The Relation of Sociology to Law and Medicine,” J. W.Dealey, Professor of Social and Political Science,” noted the rap-prochement of the disciplines (law, medicine, political science) -a change from the view of Plato: “Plato...assumed that the pres-ence of lawyers and physicians denoted a decadent, or at any rate,an imperfect civilization, since neither a natural nor a perfectcivilization would have use for members of either profession.”

Frederick N. Brown, MD, in “As to the Advent of Babies,”described the doctor’s entrance into the mise en scène of child-birth: “What a sympathetic and worrying mother, an anguishedand terrified patient who immediately hails one’s presence as theend of her suffering, often a repellent and obtrusively retiringaunt or sister - who never thought much of the match, anyway -to the good old nurse who has long been a friend of the family,who has watched the case closely and has already deduced byinfallible signs that it is to be a girl, and who already has the burntrag, the cotton twine and the kitchen scissors at hand; who is alsorecognized as the master of ceremonies, and as a matter of enter-tainment, at once - in the presence of the patient and family -launches off into a long, detailed description of the harrowingscenes she has witnessed - one of which presented much the samesymptoms as the patient, and winds up describing the delivery ofeach of her own seven children - and this dear little friend of hersis sick just as she when her little boy was born with the club feet.Either cowering in a corner is the culprit who is responsible forall this present trouble, or else he is careening over the house in acondition of nervous and uncertain flippancy.” Stanley M. Aronson, MD, introduced this issue on the “Fu-

ture of Visual Services in Rhode Island.” The articles included:“Ophthalmology in Medical Student Education: Philosophy,Control of Process,” by Bruce E. Spivey, MD; “Relationship ofOphthalmology to other Science Modalities,” by Arthur H.Keeney, MD, DSci; “A Department of Ophthalmology: A Per-sonal View,” by Steven M. Podus, MD; “Future of Ophthalmol-ogy,” by Carl Kupfer, MD; “Visual Sciences at Brown University:One Possible Approach,” by Harold F. Spalter, MD; “AnotherPossible Approach,” by A. Robert Bellows, MD; and “Draft Ver-sion of the Final Report to the Dean of Medicine from the Com-mittee on Ophthalmology, September 21, 1976.”

John E. Farley, Jr., MD, Chair, Drug Abuse Committee Re-port, contributed an editorial that voiced concern over the misuseof prescribing practices by physicians - a misuse that increased theillegal supplies of controlled substances. Recently the AMA hadpublished guidelines on barbituates; the Rhode Island MedicalSociety had published guidelines on amphetamines in hyperkineses.The Medical Society opposed use of amphetamines in treatmentof intractable obesity.

An editorial, “Glaucoma: A Primer,” mentioned possiblebenefits of marijuana.

medicine health rhodeisland · 2016. 9. 30. · beans to treat pd, however, requires in- ......

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