- Email: [email protected]
Cytomegalovirus nucleic acids in allografted hearts
CORRESPONDENCE
TABLE 1. Perception of Autopsy Practice Among Sophomore Students at Tulane University School of Medicine Yes (5%) I.
Have you ever seen an autopsy
2.
Do you think advances in diagnostic capabilities have diminished the value of autopsies? Would vou allow an autopsy to be performed on yourself if there were unresolved medical queslions? Would you allow an autopsy to be performed on a member of your family if there were unresolved medical questions?
3. 4. 5.
being
performed?
No (‘5)
Only on Film/ TV (‘%I
16 (12.6)
68 (53.9)
Yes (%)
No CT)
46 (36.5) Don’t Know/No Opinion (%)
20 (15.8)
70 (55.5)
36 (28.6)
91 (72.2)
12 (9.5)
23
( 18.2)
92 (73.0)
IO (7.9)
34
( 19.0)
72 (57.1)
35 (27.X)
I9 (15.1)
94 (74.6)
I6 (12.7)
16 (12.7)
24 (19.0)
x4 (66.6)
I8 (14.3)
78 (61.9)
36 (28.6)
12 (9.5)
>5(%“0)
<5(%
1
O(B)
I8 (14.3)
96 (76. I )
12 (9.5)
Increase
Decrease
Don‘t Know/No Opinion
TO (55.5)
20 (15.8,
36 (28.6)
If‘ vou were an intern on a case on which you wanted to have an autopsy performed, would you feel comfortable asking the patient’s relatives for consent? If you were to receive formal instruction in asking for autopsy consent. would you feel more comfortable? D’r)you think the pathology course has given you enough instruction on the value, need. and problems associated with autopsies? Do you think witnessing autopsies should be mandatory in medical school?
6. 7. 8.
9.
III your opinion, how many autopsies should medical students witnes? in medical school?
IO.
In your
opinion.
the value of autopsies
is going
to
in the 1990s.
and Gerber, it is that it perpetuates. in a small measure, the concept that autopsies should be performed for “unresolved medical questions.” The clear lesson from the many studies about the autopsy that have been performed in modern times (during the 1980s) is that physicians, with 01 without sophisticated technology. cannot always identif! whether there are medical questions still to be answered.2-” It is only after the autopsy is completed that we can determine whether there were “unresolved medical questions.” As Wagner has recently re-emphasized. the autopsy is the moral obligation of the pathologist and is the unique contribution that pathology can still bring to the care of the patient.’
I. Goldman
L, Sayson R, Robbins S. et al: The value of aurop?y in threr J Med 308:1000-1005. 1989 2. Ander-son REI The autopsy as an instrument of quality assessment, classjfication of pr~mortem and postmortem diagnostic discrepancies. Arch Pathol Lab Med 10X:408-413. 1984 3. Hill RR, Anderson RE, Vance RI’: The autopsy: A professional oblegation dissected. HUM PATHOL ?1:127. 1990 (editorial) ,4. (Zottrcau C. McIntyre L, Favara BE: Professional attitudes toward the autopsy: A surve! vf clinicians and pathologists. Am J Clin Parhol 9?:67.1675. 1989 medical
eras.
N Engl
To I& Editor:-The letter by Drs Hoda and Gerber further documents some of the problems confronting the autopsy in the 1990s. Although the group of medical students cited in this letter. and most practicing physicians, are intellectually supportive of the need to perform autopsies, this study confirms that we, as physicians, are not comfortable with the problems (of death. The difficulty in dealing with death contributes to the diminishing number of autopsies performed, while the diminished number of autopsies contrihutes to a lack of information about death and a lack of opportunity fol- students and young physicians to contemplate death. Renee C. Fox has eloquently reviewed the purposes of the autopsy in helping medical students develop ideas and concepts about death that can possibly influence their future lives, both in terms of the practice of medicine and in terms of their own psychological comfort.’ The subsections of her chapter exemplify the benefits of the autopsy: “training in detached concern.” “training for uncerof time,” “training in tainty,” “ training in the managemenr of a professional self medical morality,” and “development the autopsy allows students to image.” As Fox indicates, begin to deal with issues of death in an effective and constructive manner-, while reinforcing the special privilege accorded physicians who are allowed to dissect bodies in order to search after truth. If there is any quarrel with this contribution by Hoda
.4. (Cedars-Sinai Los Angeles,
STEPHEN
GELLER.
Medical (2~
MD Center
I. Fox RC:: 1 hc autopsy: Its place in the attltudc learning of second war medical studwxq. In Essavs in Medical Sotir~log~. New York. NI’. 1979. pp 91-77 2. Goldman L. Sayson R, Robbins S. ct al: Thr valuc~ of the atttops\ tn three medical eras. N Engl1 Med 308: IOOOlnO.5.1983 3. Landefeld CS, Chren MM, Myers A, et al: Dlag-nwtir yield of the autopsyin a universitv hospital and a cnmmumtv hospilal. N Fngl J Med 31x:1249-1254. 198X 4. Zarling E,J, Sexton H. Milnor I’. Jr: Fatlure to diagnose acute tnsorardial infarction: Thr clinical pathologic exprrit-ru c nt a large ~ommuntt\ hospital. JAMA 250:1177-IIXI. 1983 5. Pelletier LL. Jr. Klntzou F. Lancaster H: Thr autopry: Its role m the evaluation of patient care. J Gen Intern Med 4:300-303. 1989 6. Middleton K. Clarke E. Homann S. et al: An dutopsv-based study of. diagnostic errors in geriatrtc and nongeriatri( aciult pattents. Arch Intern Med 149:1X09-1812, 1989 7. Wagner LR: The autopsy: Our moral obligwon. (.AP Tctdar 4: IX. 1990 Qtomegalovirus
Nucleic Acids in Allografted Hearts
To he E&or:-After heart transplantation, most recipients develop cytomegalovirus ((IMV) infection.’ Cvtomeg981
HUMAN PATHOLOGY
Volume 21, No. 9 (September 1990)
FIGURE 1. Coronary artery from a heart with severe transplant-related accelerated arteriosclerosis showing extensive hybridization of the CMV probe to numerous spindle-shaped cells within the arterial wall. (Magnifications: A. x30; 8, x180.)
alovirus seropositive organ donors may be a source of this infection. and CMV infection has recently been associated with the development of rejection and accelerated arteriosclerosis in these patients.‘,:’ We report the identification of CMV nucleic acids in the coronary arteries of five heart transplant recipients. Paraffin-embedded sections of coronary arteries obtained from an explanted heart from a patient with severe transplant-related accelerated arteriosclerosis and from 10 autopsied recipients were examined using in situ DN,4 hybridization with a %-labeled nick translated probe derived nucleic acids were from CMV DNA. ’ Cytomegalovirus identified (Fig 1) in the arterial walls of the hearts from two of two patients who died of acute rejection, in three of seven hearts from patients with accelerated arteriosclerosis (43%). and in neither of two patients who died of other causes. Although focal endothelial cell positivity was identified, the strongest hybridization was in cells morphologically consistent with smooth muscle cells. Hybridization was not detected in any of the hearts when a control probe, a vector without CMV DNA, was used. This pattern of hybridization suggests, but does not rigorously prove, that CMV DNA is present in the coronary arteries of these hearts. Although our findings do not prove a causal relationship, they do provide further evidence that CMV infection may play a role in allograft rejection and transplant-related arteriosclerosis.” Cytomegalovirus infection may promote rejection and arteriosclerosis through a number of rnechanisms, including direct endothelial cell injury. the induction of class II major histocompatibility complex (MHC) antigens, immunologic cross-reactivity between human CMV and MH<: antigens, and altered metabolism of cholesterol by smooth muscle cells.“-’
982
The demonstration of CMV nucleic acids in the walls of coronary arteries also suggests that these arteries may be a site of latency of this virus.H,g Latent CMV in coronary arteries is a potential source for the transmission of CMV during heart transplantation. Further studies are needed to rigorously establish the presence or absence of CMV in the coronary arteries of transplanted hearts. RALPH H. HRL~BAIG,MD TZYY-CHOOU WV, MD, PhD WILLIAM E. BESCHORNER, MD DUKE E. CAMERON, MD RICHARD F. AMBIIVDER. MD, PhD WILLIAM A. BAUMGARTNER, MD BRUCE A. RErrz, MD GROVER M. HUTCHINS, MD The Johns Hopkins Medical Institutions Baltimore, MD
I. Dun~mefJS, White LT. HO M, ct al: Morbidity ot cytomegalovirus infection in rectp~ents of heart or heart-lung transplants who received cyclospurine. J Infect Die 159:1182-t 191. 1985 2. tirattan MT. Moreno-Cabral CE, St;rnes VA. et al: Cytomegalovirus infection ia associated with cardiac allograft rejection and atherosclerosis. JAMA 261:3561-3X6. IYXY 3. Wreghitt TC, Hakim M. Gray JJ, et al: A detailed study of cytonwgalwiws infections in the first 160 heart and heart/lung transplant recipients at Papworth Hospital. Cambridge. England. Transplant Proc 19:2495-2496. 19x7 4. Amhinder RF. Newman C, Hayward (24. et al: Lack ot associatwn ut cytomegalovirus with endemic Atriran Kaposi’s sarcoma. J Infect Dis 156:193-1Y7. 1987 5. van Es A. Baldwin WM, Oljans PJ, et dl: Expression ot HLA-DR on .I‘ lyrnplrocvtes following renal transplantation. and association with gnttrejection ep~sodez and rytomegalowrus infectiorr. Transplantation 37:65-69. 19&l
BOOK REVIEWS
The presence of three cases of mesothelioma in a single family, two of the cases through indirect exposure to asbestos and the third without any contact at all, raises the possibility (as mentioned by Hammar et al) that genetic factors mav be important in the development 01. some mesothelio-
JUAK A. MARCELo LILIAXA
PKECEKUI-TI. MD MAYORGA. D4LIrRZO.
MD
MD
~UAI~ALUPE ~‘ALLOT’I‘A, MD
Is There
a “Genetic
Model” in the Genesis of
.\LICIA IX. LA CAXAL.
MD
Malignant Pleural Mesothelioma? 7’0 thr Ed/f0r:-With reference I( h Mesothelioma: A Report of Two Fa 9 3 lished in your journal,’ we would lik 3 5 have l~~llowed ant1 that we believe reis f tietic component in the genesis of ma c 9 $hP t helioma. ‘l’he patient is a -IO-year-old WC 5 r-ight thoracic pain. A chest x-ray filn$ fusion. A percutaneus pleural biopsy pi pleural mesothelioma (epithelial type $ c-onfirmed! after thoracotomy. The pa rxposed tl) asbestos and a careful ex: gical material by microscopy did not I ‘l‘he interest of’ the case lies in the father and an aunt (father’s sister) die st)thelioma at the ages of 60 and 65 yt 1). .l‘he patient’s grandfather works years and both his children lived with children h
0
M;
+4-
g z z E 2
ie to the letter
zY
oncerning out S PA I‘HOLOC’I Dr l’recerutti viding another se is somewhat r article in that en exposed to .en exposed to lies in his lung anally exposed people with a to specific carwith a certain ‘e cellular reequently, have to occur. This nly a relatively asbestos expo~ng tissue de-
E: M:
group of parmine if they ‘an HLA hap\ could potenincreased risk ) have an inct of asbestos. r- ‘recerutti and
II
QH.
QH.
q60
040
65q
E: M:
E:
2 & g
M:
2 h
FIGURE 1. Family history: E, exposure to asbc _ H, healthy.
BOOK REVIEWS
the International academy of Pathology Meetings in Washington, DC. It is noteworthy, however, that most of the chapters review and cover published data generated after that meeting, with publications cited through 1989. To follow up on a single course and to be comprised of only 11 chapters, I found the monograph to be surprisingly complete and to be an excellent review of most ot the common and important problems in gastrointestinal pathology.
Gastrointestinal Pathology. H Goldman, H Appelman, and N Kaufman (,eds). New York, NY, Williams & Wilkins, 1990,386 pages. $71.X). ?‘his monograph was generated by the participants of the 1988 Long Course of Gastrointestinal Pathology held at
983
TABLE 1. Perception of Autopsy Practice Among Sophomore Students at Tulane University School of Medicine Yes (5%) I.
Have you ever seen an autopsy
2.
Do you think advances in diagnostic capabilities have diminished the value of autopsies? Would vou allow an autopsy to be performed on yourself if there were unresolved medical queslions? Would you allow an autopsy to be performed on a member of your family if there were unresolved medical questions?
3. 4. 5.
being
performed?
No (‘5)
Only on Film/ TV (‘%I
16 (12.6)
68 (53.9)
Yes (%)
No CT)
46 (36.5) Don’t Know/No Opinion (%)
20 (15.8)
70 (55.5)
36 (28.6)
91 (72.2)
12 (9.5)
23
( 18.2)
92 (73.0)
IO (7.9)
34
( 19.0)
72 (57.1)
35 (27.X)
I9 (15.1)
94 (74.6)
I6 (12.7)
16 (12.7)
24 (19.0)
x4 (66.6)
I8 (14.3)
78 (61.9)
36 (28.6)
12 (9.5)
>5(%“0)
<5(%
1
O(B)
I8 (14.3)
96 (76. I )
12 (9.5)
Increase
Decrease
Don‘t Know/No Opinion
TO (55.5)
20 (15.8,
36 (28.6)
If‘ vou were an intern on a case on which you wanted to have an autopsy performed, would you feel comfortable asking the patient’s relatives for consent? If you were to receive formal instruction in asking for autopsy consent. would you feel more comfortable? D’r)you think the pathology course has given you enough instruction on the value, need. and problems associated with autopsies? Do you think witnessing autopsies should be mandatory in medical school?
6. 7. 8.
9.
III your opinion, how many autopsies should medical students witnes? in medical school?
IO.
In your
opinion.
the value of autopsies
is going
to
in the 1990s.
and Gerber, it is that it perpetuates. in a small measure, the concept that autopsies should be performed for “unresolved medical questions.” The clear lesson from the many studies about the autopsy that have been performed in modern times (during the 1980s) is that physicians, with 01 without sophisticated technology. cannot always identif! whether there are medical questions still to be answered.2-” It is only after the autopsy is completed that we can determine whether there were “unresolved medical questions.” As Wagner has recently re-emphasized. the autopsy is the moral obligation of the pathologist and is the unique contribution that pathology can still bring to the care of the patient.’
I. Goldman
L, Sayson R, Robbins S. et al: The value of aurop?y in threr J Med 308:1000-1005. 1989 2. Ander-son REI The autopsy as an instrument of quality assessment, classjfication of pr~mortem and postmortem diagnostic discrepancies. Arch Pathol Lab Med 10X:408-413. 1984 3. Hill RR, Anderson RE, Vance RI’: The autopsy: A professional oblegation dissected. HUM PATHOL ?1:127. 1990 (editorial) ,4. (Zottrcau C. McIntyre L, Favara BE: Professional attitudes toward the autopsy: A surve! vf clinicians and pathologists. Am J Clin Parhol 9?:67.1675. 1989 medical
eras.
N Engl
To I& Editor:-The letter by Drs Hoda and Gerber further documents some of the problems confronting the autopsy in the 1990s. Although the group of medical students cited in this letter. and most practicing physicians, are intellectually supportive of the need to perform autopsies, this study confirms that we, as physicians, are not comfortable with the problems (of death. The difficulty in dealing with death contributes to the diminishing number of autopsies performed, while the diminished number of autopsies contrihutes to a lack of information about death and a lack of opportunity fol- students and young physicians to contemplate death. Renee C. Fox has eloquently reviewed the purposes of the autopsy in helping medical students develop ideas and concepts about death that can possibly influence their future lives, both in terms of the practice of medicine and in terms of their own psychological comfort.’ The subsections of her chapter exemplify the benefits of the autopsy: “training in detached concern.” “training for uncerof time,” “training in tainty,” “ training in the managemenr of a professional self medical morality,” and “development the autopsy allows students to image.” As Fox indicates, begin to deal with issues of death in an effective and constructive manner-, while reinforcing the special privilege accorded physicians who are allowed to dissect bodies in order to search after truth. If there is any quarrel with this contribution by Hoda
.4. (Cedars-Sinai Los Angeles,
STEPHEN
GELLER.
Medical (2~
MD Center
I. Fox RC:: 1 hc autopsy: Its place in the attltudc learning of second war medical studwxq. In Essavs in Medical Sotir~log~. New York. NI’. 1979. pp 91-77 2. Goldman L. Sayson R, Robbins S. ct al: Thr valuc~ of the atttops\ tn three medical eras. N Engl1 Med 308: IOOOlnO.5.1983 3. Landefeld CS, Chren MM, Myers A, et al: Dlag-nwtir yield of the autopsyin a universitv hospital and a cnmmumtv hospilal. N Fngl J Med 31x:1249-1254. 198X 4. Zarling E,J, Sexton H. Milnor I’. Jr: Fatlure to diagnose acute tnsorardial infarction: Thr clinical pathologic exprrit-ru c nt a large ~ommuntt\ hospital. JAMA 250:1177-IIXI. 1983 5. Pelletier LL. Jr. Klntzou F. Lancaster H: Thr autopry: Its role m the evaluation of patient care. J Gen Intern Med 4:300-303. 1989 6. Middleton K. Clarke E. Homann S. et al: An dutopsv-based study of. diagnostic errors in geriatrtc and nongeriatri( aciult pattents. Arch Intern Med 149:1X09-1812, 1989 7. Wagner LR: The autopsy: Our moral obligwon. (.AP Tctdar 4: IX. 1990 Qtomegalovirus
Nucleic Acids in Allografted Hearts
To he E&or:-After heart transplantation, most recipients develop cytomegalovirus ((IMV) infection.’ Cvtomeg981
HUMAN PATHOLOGY
Volume 21, No. 9 (September 1990)
FIGURE 1. Coronary artery from a heart with severe transplant-related accelerated arteriosclerosis showing extensive hybridization of the CMV probe to numerous spindle-shaped cells within the arterial wall. (Magnifications: A. x30; 8, x180.)
alovirus seropositive organ donors may be a source of this infection. and CMV infection has recently been associated with the development of rejection and accelerated arteriosclerosis in these patients.‘,:’ We report the identification of CMV nucleic acids in the coronary arteries of five heart transplant recipients. Paraffin-embedded sections of coronary arteries obtained from an explanted heart from a patient with severe transplant-related accelerated arteriosclerosis and from 10 autopsied recipients were examined using in situ DN,4 hybridization with a %-labeled nick translated probe derived nucleic acids were from CMV DNA. ’ Cytomegalovirus identified (Fig 1) in the arterial walls of the hearts from two of two patients who died of acute rejection, in three of seven hearts from patients with accelerated arteriosclerosis (43%). and in neither of two patients who died of other causes. Although focal endothelial cell positivity was identified, the strongest hybridization was in cells morphologically consistent with smooth muscle cells. Hybridization was not detected in any of the hearts when a control probe, a vector without CMV DNA, was used. This pattern of hybridization suggests, but does not rigorously prove, that CMV DNA is present in the coronary arteries of these hearts. Although our findings do not prove a causal relationship, they do provide further evidence that CMV infection may play a role in allograft rejection and transplant-related arteriosclerosis.” Cytomegalovirus infection may promote rejection and arteriosclerosis through a number of rnechanisms, including direct endothelial cell injury. the induction of class II major histocompatibility complex (MHC) antigens, immunologic cross-reactivity between human CMV and MH<: antigens, and altered metabolism of cholesterol by smooth muscle cells.“-’
982
The demonstration of CMV nucleic acids in the walls of coronary arteries also suggests that these arteries may be a site of latency of this virus.H,g Latent CMV in coronary arteries is a potential source for the transmission of CMV during heart transplantation. Further studies are needed to rigorously establish the presence or absence of CMV in the coronary arteries of transplanted hearts. RALPH H. HRL~BAIG,MD TZYY-CHOOU WV, MD, PhD WILLIAM E. BESCHORNER, MD DUKE E. CAMERON, MD RICHARD F. AMBIIVDER. MD, PhD WILLIAM A. BAUMGARTNER, MD BRUCE A. RErrz, MD GROVER M. HUTCHINS, MD The Johns Hopkins Medical Institutions Baltimore, MD
I. Dun~mefJS, White LT. HO M, ct al: Morbidity ot cytomegalovirus infection in rectp~ents of heart or heart-lung transplants who received cyclospurine. J Infect Die 159:1182-t 191. 1985 2. tirattan MT. Moreno-Cabral CE, St;rnes VA. et al: Cytomegalovirus infection ia associated with cardiac allograft rejection and atherosclerosis. JAMA 261:3561-3X6. IYXY 3. Wreghitt TC, Hakim M. Gray JJ, et al: A detailed study of cytonwgalwiws infections in the first 160 heart and heart/lung transplant recipients at Papworth Hospital. Cambridge. England. Transplant Proc 19:2495-2496. 19x7 4. Amhinder RF. Newman C, Hayward (24. et al: Lack ot associatwn ut cytomegalovirus with endemic Atriran Kaposi’s sarcoma. J Infect Dis 156:193-1Y7. 1987 5. van Es A. Baldwin WM, Oljans PJ, et dl: Expression ot HLA-DR on .I‘ lyrnplrocvtes following renal transplantation. and association with gnttrejection ep~sodez and rytomegalowrus infectiorr. Transplantation 37:65-69. 19&l
BOOK REVIEWS
The presence of three cases of mesothelioma in a single family, two of the cases through indirect exposure to asbestos and the third without any contact at all, raises the possibility (as mentioned by Hammar et al) that genetic factors mav be important in the development 01. some mesothelio-
JUAK A. MARCELo LILIAXA
PKECEKUI-TI. MD MAYORGA. D4LIrRZO.
MD
MD
~UAI~ALUPE ~‘ALLOT’I‘A, MD
Is There
a “Genetic
Model” in the Genesis of
.\LICIA IX. LA CAXAL.
MD
Malignant Pleural Mesothelioma? 7’0 thr Ed/f0r:-With reference I( h Mesothelioma: A Report of Two Fa 9 3 lished in your journal,’ we would lik 3 5 have l~~llowed ant1 that we believe reis f tietic component in the genesis of ma c 9 $hP t helioma. ‘l’he patient is a -IO-year-old WC 5 r-ight thoracic pain. A chest x-ray filn$ fusion. A percutaneus pleural biopsy pi pleural mesothelioma (epithelial type $ c-onfirmed! after thoracotomy. The pa rxposed tl) asbestos and a careful ex: gical material by microscopy did not I ‘l‘he interest of’ the case lies in the father and an aunt (father’s sister) die st)thelioma at the ages of 60 and 65 yt 1). .l‘he patient’s grandfather works years and both his children lived with children h
0
M;
+4-
g z z E 2
ie to the letter
zY
oncerning out S PA I‘HOLOC’I Dr l’recerutti viding another se is somewhat r article in that en exposed to .en exposed to lies in his lung anally exposed people with a to specific carwith a certain ‘e cellular reequently, have to occur. This nly a relatively asbestos expo~ng tissue de-
E: M:
group of parmine if they ‘an HLA hap\ could potenincreased risk ) have an inct of asbestos. r- ‘recerutti and
II
QH.
QH.
q60
040
65q
E: M:
E:
2 & g
M:
2 h
FIGURE 1. Family history: E, exposure to asbc _ H, healthy.
BOOK REVIEWS
the International academy of Pathology Meetings in Washington, DC. It is noteworthy, however, that most of the chapters review and cover published data generated after that meeting, with publications cited through 1989. To follow up on a single course and to be comprised of only 11 chapters, I found the monograph to be surprisingly complete and to be an excellent review of most ot the common and important problems in gastrointestinal pathology.
Gastrointestinal Pathology. H Goldman, H Appelman, and N Kaufman (,eds). New York, NY, Williams & Wilkins, 1990,386 pages. $71.X). ?‘his monograph was generated by the participants of the 1988 Long Course of Gastrointestinal Pathology held at
983