Does Theophylline Have a Role as an Adjunct Agent for Immunosupression in Heart

Does Theophylline Have a Role as an Adjunct Agent for Immunosupression in Heart

Transplantation Patients?

Uz. Dr. Tamer SA YlN, Prof. Dr. Metin ÖZENCİ, Ass. Prof. Mandeep R. MEHRA*

Ankara Üniversitesi Tıp Fakültesi Kardiyoloji Anabilim Dalı, *Ochsner Medicallnstllfions, Director of Advanced Heart Failure and Cardiac Transplantation Section, New Orleans, Louisiana, USA

ÖZET

KALPNAKLiHASTALARlNDA

İMMÜNSÜPRESYON İÇİN TEOFILIN'İN YARDlMCI İLAÇ OLARAK ROLÜ VAR MI?

Yeni

gelişmekte

olan immünsüpresif tedavi rejimlerine

rağmen

kalp nakli

ameliyatlarında

özellikle ilk iiç ayda görülen

rejeksiyorı epizodları

önemli morbidite ve mOJ·tal- ite nedeni olmaya

devanı

etmektedir.

Teofilin post-transplani görülebilen bradikardinin tedavi- sinde yeri olan bir

ilaçtır.

Bu

ilacın aynı

zamanda bir

takım

immün düzenleyici etkilerinin

olduğu

bilinmektedir.

Bu

^çalışmada

post-transp/ant bradikardi nedeniyle teofi- . lin kullamlan 27 hasta ile

aynı

immünsiipresif rejim le te- davi

edilmiş

ve rejeksiyon risk faktörleri benzer olan 29

lıastamn

endomiyokardiyal biopsi

sonuçları,

hücresel ve humoral rejeksiyon

epizodları sıklığı,

hemodinamik

bozukluğa

yol açan rejeksiyon

epizodları

ve ilk rejeksiyo- na kadar geçen süre retrospektif olarak

araştırıldı.

Teofi-

lirı kullanımının

hücresel ve

lııtmoral

rejeksiyon epizod-

larımn sıklığım azaltmadığı,

hemodinamik

bozukluğa

yol açan rejeksiyon

epizodlarına

da etkisi

olmadığı

görüldü.

Ancak teofilin

kullanımı

ile 3

aylık

ortalama biyopsi

skorlarında anlamlı

azalma (kontrol grubu 0.98 ± 0.51, teofilin grubu 0.73 ± 0.42) (p=0.04) ve ilk rejeksiyonun gö rülme süresinde

uzanıa

tespit edildi (kontrol grubu 24

± 21 gün, teofilin grubu 51 ± 26 gün) (p=0.05).

Sonuç olarak teofilinin immün süpresif tedavi rejimlerine eklenmesinin rejeksiyon

epizodları

yönünden olumlu et- kisinin

olabileceğini diişiindük.

Prospekti/. randamize da- ha fa zla

lıastayla yapılacak çalışmaların, ilacın imnıünsupresif

tedavi rejimlerine adjuvan olarak eklenme potansiyelini daha iyi ortaya

^koyacağım düşiiniiyomz.

Anahtar kelimeler: Teofilin, kardiyak transplantasyon, bradikardi

Theophylline, a n old drug mainly used for asthma, chronic obstructive pulmonary disease and treating apnea of preterm infants has been demonstrated to

Recieved: 28 August, revision accepted 31 October 2000 Corresponding author: Tamer

Sayın,

Cemal Gürsel cad ., Yeni Ankara sk, 16/18, Cebeci 1 Ankara

Tlf: (0 3 12) 362 3030 16286 Fax: (0 3 1 2) 363 2289

· E-mail : tamsay @hotmail.com

Sunulan

çalışma

Ochs ner Medical lnstutions, New Orleans, LA, USA'de

yapılmıştır.

Bu

çalışma

"American Society of Transplantation" 1999

Mayıs toplantısında

Chicago'da sözlü bildiri olarak

sunulmuştur.

36

have some immunmodulatory effects in several stud- ies (1-3). It has also proved to be effective in treatin g post cardiac transplant bradycard ia (4-6).

Despite improvements in immunos uppressive drugs, ine idence of rejection in heart transplantation pa- tients is stili high, especiall y in the first 3 months, causing increased morb idity and mortality (7), This study is performed to investigate th e effects of theo- phylline on cardiac allograft rejectio n in the first 3 months in patients treated with this drug to correct post transplant bradycardia.

PATIENTS and METHODS

To elucidate possible effects of theophylline on patterns of cardiac

allografı

rejection we examined 56 consecutive pa- tients between February 1994 and December 1997. There were 2 group of patients. Group 1 was the theophylline group, group 2 was the control gro up.

lnclusion criteria: To be included all the patients were to have at least 3 months of survival. All needed to be on the same standard regimen of immunosuppress ive therapy which consisted of cyclosporin A , azathiopurine and pred- nisolone. Patients o n theophylline, who formed the study group must have used the drug fo r at least 4 weeks in the first 3 months of

transplanıation.

Exclusion criteria: Patients who died in the first 3 months and patients who were on a different immunosuppressive regimen other than the standard regimen and patients who had used theophylli ne less than 4 weeks were excluded.

Twenty-seven of the patients received theophylline within 72 hours of transplanlation for post

transplanı

bradycardia defined as a pulse rate of less than 70 1 min. and formed the study group. Rest of the patients

<29)

formed the control group.

Detailed donor and recipient related risk factors for rejec-

ıion

were collected. These were donors' and recipients' age, gender and race, panel reactive antibodies (PRA) of the recipients closest to the transplantation , cytomegalovi- rus (CMV) serology of the do nor and the recipient, aver- age number of HLA mismatches, and retrospective cross- match results.

We focused on rejection parameters in the first 3 months.

We examined results of fo llow-up endomyocardial biop-

T.

Sayı11

a11d et al.: Does

Tlıeoplıyllille

Have a Role as a11 Adju11C t Age11t for

lmmwıosupression

i11 He{IJ·t Trallsplall{atioll Patiell{s?

sies (EMB), immunfluorescent staining microscopy analy- sis for vascular rejection, echocardiographic studies and right hea rt cathe terization results.

Cellular rejection was diagnosed with EMB results graded w ith standard ISHL T (International Society of Heart and Lung T ransplanta tion) grading system <7> and elinical as- sessm ent. Grade 2 a nd higher endom yocardial biopsy re- sult wi th elinical sig ns of rejection was noted as an epi- sode of cellular rejection to be treated. Vascular rejection was diagnosed with elin ical assessment and echocardio- graphic findings a nd/or

iınmunfluorescent

mic roscopy findings without a ce llular rejec tion pa tte rn on EMB <B>.

Hemodynamic compromise was noted to be preseni if pa- t ients had signs and symptoms of heart failure and/o r they had a previously normal cardiac index or ejection fraction less than 2.2

lt/ınin/m2

or 45 % respectively. W e also ex- amined time to first rej ection in terms of day s for both groups.

To

exaınine

groups in detail in terms of comparability, we collected cumulative dosages of immunosuppressive thera- py and exposure to inductio n therapy with monoclonal an- tibody directeel against CD3 (helper) lymphocytc (OKT3) in the first 3 months.

. A biopsy score was calcula ted for both groups for the bi- opsies done in the first 3 months. Total score of biopsies in the study period w as divided by the number of the biopsies to have the biopsy score fo r each

patienı.

Seering for an EMB result is de monstrated in Tab le I .

Table 1. Scoring system for biopsy results

ISHLT grade S core

o o

lA

ı

lB 2

2 3

3A 4

38 5

4 6

ISHLT: /ll{ematiollal Society of Heart a11d Lu11g Tra11splall{atio11

According to that system, for example a patie nt with biop- sy results of once zero, twice lA and once 3A will have a biopsy score of l(l x0)+(2x l )+( l x4) } 14 which equals to

1.5.

Table 2. Demographics of patients and donors

Mean age of recipients (years) Female 1 Total in recipients Afro-american /Total in recipients M ean age of donors (years) Female 1 Total in donors

Afro-aınerican

1 Total in do nors NS: Not significall{

Statistical a nalysis: Statistical a nalysis was done using the program "Statistical Prog ram for Social Sciences" with the com puter. Bio psy scores, time to first rejection in

terıns

of days, demographic factors, rejection related risk factors, anel c umulative immunosuppressive regimcn were a ll compareel using Student 's t test and chi-square

tesıs

where appropriate.

RESULTS

Demographics of patients a nd their donors are are presented in Table 2. Both gro ups were similar in terms of age, gender and race.

We analyzed distr ibution of rejection related ri sk factors, cumulative immunosuppressive drugs in the fi rst 3 months, CMV serology of donors and recip- ie nts, a nd CMY infec tion ep isodes in the first 3 months. Theophy lline exposure was 440 ± 104 mg/day for a period of 142 ± 39 days. There we re no statistically significant differences between the theo- phyil ine and control group in terms of these parame- ters (Table 3).

We a lso analyzed number of treated rejection epi- sodes, vascular rejection episodes, rejection episodes with hemody na mic compromise, mean biopsy scores, and time to first rejection e pisodes in both groups. The re was no statistic ally significa nt differ- ence between gro ups in terms of rejection ep isodes, but there was a statistically significant difference re- lated with average biopsy scores and time to first re- jectio n (Table 4).

DISSCUSSION

This stu dy demonstrates that theophy lline may have a positive impact on subclinical (mean biopsy scores and time to first rejection) indices of cellular cardiac a llograft rejection. There we re no differences be- tween the groups regarding ep isodes of treated rejec-

Theophylline gr. Control gr. P value

51.1 ± 11.2 53.7 ± 9.4 NS

3/27

(%ı 1.1)

5/29 (%1 7.2) NS

4 / 27 (%1 4.8) 7/29 (%24.1) NS

30 ± 1 2.4 26.4 ± 10.8 NS

9/27 ± (%33.3) !O /29 (%34.4) NS

10 /27 (%37) 8/29 (%27 .5) NS

..,,.,

Tab le 3. Distribution of rejection related risk factors

No.

ofpatienıs

with PRA>% 10 Mean no. of HLA

ınismatches

No. of patients with

(+)

retrospective

crossınatch

M ean Cy A in 3

nıonths

(mg) Mean azotiopurine in 3

ınonths

(mg) Mean prednisolone in 3

nıontlıs (ıng)

No. of patients w ith OKT3 exposure in 3 months No. of (

+)

CMY serology in recipients No. of (

+)

CMV serology in donors

No. ofTx. With CMY

(+)

donor to CMV (-) recipient.

No of CMY infection episodes Tx: Transplantation

CMV: Cytomegalovirus

PRA: Panel reactive antibodies Cy A: Cyclosporine A Tab le 4. Outcomes of rejection ep isodes in 3 months

No. of treated rejection ep isodes No. of vascular rejection episodes

No. of episodes w ith hemodynamic

conıpromise

. Mean biopsy score in 3 months Time to first rejection (days)

tion, vascul ar rejection and rejection episodes with

hemodynaınic coınproınise.

A lthough theophylline has been used for man y .years, the exact mode of action is unclear (1 0) . The most approved hypothesis are phosphodieste rase en- zyme inhibition, adenosine receptor antagonism, ef- fect on cathecholamine secretion and influence on calc ium ions (10,11 ). Possibl y more than one mecha- nism participate in producing the effects of theo- phylline. In the past decade several studies have demonstrated the

immunınodulatory

effects of theo- phylline (1 2, 1 3,14).

The canversion of cAMP is catalyzed by the

enzyıne

phophodiesterase and inhibition of th e activity of this

enzyıne

results in intracellular accumulation of cAMP and activati on of immunologicall y paralytic pathway (15,16). Th eoph ylline has several other ef- fects on T lymphocyte function. Reduced T eel! pro- liferation after antigenic

(1)

and mitogenic

(2)

srimu- lation as well as

diıninished

E-rosette form ation (3)

have been demonstrated . Phytohe magglutinin

stiınu­

lated IL-2 production and IL-2 dependent prolifera- tion of T Jymphocytes are diminished by theophyl-

38

Theophylline gr. Control gr. P value

o

^ı

NS

5.07 ± 0.81 5.14 ± 0.8 NS

2 3 ^NS

38250 ± 8451

ıng

38098 ±

ı ll

88 NS

9296 ± 3977 8974±2121 NS

3869 ± 1038 3572 ± 947 NS

12 16 NS

24 19 NS

18

ıs

NS

3 5 NS

4 3 NS

Theophylline gr. Control gr. P value

7 7 NS

6 4 NS

2 2 NS

0.73 ± 0.42 0.98 ± 0.51 0.04

5 1 ± 26 24± 21 0.05

line in vitro (2, 17). Long

terın

theophy lline therapy in patients wi th asthma increases the number of CD8 or suppressor T cells in peripheral blood and a lso im- pairs the graft versus host reaction of these lympho- cytes (1,18).

Theophylline also acts as an

anti-inflaınmatory

drug through modulation of cytos ine production. After exposure to theophylline, reduction of the anti -in- flammatory cytokine IL- I O is increased, an outcome that results in an inhibitory effect of on the produc- tion of other proinfl ammatory cytokines like IL-2, interferon y, IL-5, tumor necrosis fac tor alpha and IL-8 (19).

In a previous s tudy Shapira e t al ⁽¹²⁾ could s uccess- fully treat steroid

resİstant

renal rejections with ami- nophylline (theophylline ethylenediamine), and they also demonstrated that aminoph ylline treated pa- tients did not show local xenogenic graft-versus host reaction indicating increased T-suppressor activity.

In an animal model of heart tran splantation with rats in which theophylline was used as a single

iınnıun­

nıodulator,

the authors were ab le to prolong s urvival

T.

Sayın

and et al.: Does

Tlıeoplıyl/ine

Have a Role as an

Adjwıcl

Agentfor

lmmwıosupression

in Heart

Trwısplantation

Patients?

hypothesizing two possibilities: first a reduction in the recruitment of spec ific effecto r lym phocytes through a direct inhibition of the ir mitoge nic re- sponse, owing to a theophylline induced cAMP lev- els in these ce lls; second a possibl e cAMP depen- dent activation of suppressor T lymphocytes

(13).

To our knowled ge, this is the first study inves tigat- ing effects of theophylline exposure on rejection in heart transplanlation in ma n. We fo und a positive impact on subclinical rejection episodes (mean biop- sy score) and time to first rejection. Des pite im- provements in immunsupress ive regimens, rejection is sti li a major cause of

ınorbidity

and morta lity.

That is why we believe that any drug that may have a positive impact on this process is worth closer scrutiny.

Limitations of the s tudy: There are several

liınita­

tions of this s tudy. F irs t, it was a retrospective one having inherent kind of problems with that type of researc h. Second, it was a non-randomized study.

Other than those, theophylline levels were not rou- tine ly screened but mainly us ual conventional dos- ages were used. The time interval that theophylline was used may not be long enough (patients who used theophyll ine for at least four weeks were en- rolled in the study).

Conclusion: Theophylline therapy for card iac trans- plantation does not have any effect on treated rejec- tion epis odes, vascular rejection episodes , and episodes with heınodynamic compromise, but it nıay

decrease subclinical (mean biopsy score) indices of cellular cardiac allog raft rejection and increase the tim e to first rejectio n. Large, pros pective,

randonı­

ized studies to further evaluate

İnıportance

of theo- phylline as an adjunct thera py is probably indica ted.

R EFERENCES

ı.

Scord amaglia A, C iprandi G, R uffoni S et al: Theo- phy lline and the immune response : in vitro and in vivo ef - fects. Clin Immuno! Immunopathol 1988;48:238-46 2. Bruserud 0: T he effect of theophyllamine on T-Iym- phocyte activation in vitro. Clin Immuno!

Inımunopathol

1984;32: 11 1-8

3. Limatibul S, Sh o re A, Dosch HM, Gelfand EW: The- ophylline modu lation o f E-rosette formation: an indicator of T eel!

nıaturation.

C lin Exp Immuno ! 1 978;33:503-

ı

3 4. Bertolet BD, Eagle DA, Conti JB et a l: Bradycardia

afıer hearı

transplantation: reversa l with th eophylline. J

Anı

Coll Cardiol 1 996;28:396-9

S. Redmond JM, Zehr KJ, G illinov MA et a l: Use of theophylline for treatment o f prolonged sinus node dys- function in human orthotopic heart transplantation. J Heart Lung

Transplanı

1993;

ı

2: 133-8

6. Heinz G, Kratochwill C, Buxbaum P et al: Immedi- ale

norınaıization

of profound sinus node dysfunctio n by

anıinophylline

af ter cardiac

ıransplanıation. Anı

1 Ca rdiol

ı

993;7

ı

:346-9

7. Billingham ME, Cary NR, Hammond ME et a l: A working formulation for the

sıandardizaıion

of

nonıencla­

ture in the diag nosis of heart and lun g rejection: Heart Re-

jecıion Sıudy

Group. J Heart

Transplanı

1 990;9:587-96 8. Costanzo MR, Cross AM, Haas GS:

Post-Transplanı

Care/Medical

Coınplications.

In:

Narınan

DJ, Suki WN

ediıors,

Primer On Transplantation. As ton Pub Ltd

ı

997, p: 445-58

9. Kobashiagawa JA, Kirlin JK, Nartel DC et al: Pre- transplantation ri sk factors for acute reject ion after heart

transplanıation:

a

nıultiinstitutional

study. 1

Hearı

Lung

Transplanı ı

993;

ı

2:355-66

ıo.

Vassallo R, Lipsky JJ: Thepohylline:

Recenı

advanc- es in the understanding of its mode of

acıion

and uses in elinical practice. Maya Clin Proc 1998;73:346-54 ll. Serafin WE: Drugs used in the treatment of

ashıma.

In: Gitman AG,

Hardnıan

JG,

Liınbird

LE, Molinoff PB, Ruddon RW, editors.

Goodınan

and Gilman's The Phar-

ınacological

Basis of therapeutics. 9 th ed. New York:

McGraw-Hill; 1996 p 672-8

ı2.

Shapira Z, Shotat B, Boner G et al: Theophylline: a possible

inımunoregulaıor

of T cells. T ransplanlatio n Pro- ceedings 1982;14: 11 3-6

ı3.

Rugarli C, Marni A, Ferrero MA et al: Prolo nged survival o f

experinıental

heart transplanlation induced by theophylline.

Inımunology

Lerters 1983;6:247-50

ı4.

Guillou PJ, Ramsden C, Kerr M et al: A

prospecıive

contro lled elinical trial of aminophylline as an adjunctive

iınınunosuppressive ageııt. Transplaıııaıion proceediııgs

1984;16:

ı218-20

ıs.

Watson J, Epstein R, Cohn M: Cyclic

nucleoıides

as intracellular

nıediators

of the expressian of antigen-sensi- tive cells. Natu re 1 973;246:405-9

16. Goto T, Herherman RB, Maluish A et al: Cyclic AMP as a

nıediator

of prostag landin E-induced suppres- sion of human natural kill er cell activity. J Immuno!

1983; 130: 1350-5

17. Mary D, Aussel C, Ferrua B, Fehlmann M: Regula- tion of interleukin 2 synthesis by c AMP in human T cells.

J Immuno! 1 987;

ı

39:

ı ı

79-84

18. Fink G,

Mittelınan

M, Shotat B, Spitzer SA: Theo- phylline-induced

alıeraıions

in cellular

iınnıunity

in as th- matic patients. Clin Allergy 1987; 17:313-6

19. Mascali JJ, Cvietusa P, Negri J , Borish L: Anti-in-

flanıınatory effecıs

of

theophyıline

: medu lation of cyto- kine production . Ann

Aılergy

Asthm a Immuno !

ı

996;77:34-8