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Conduction System in Children with Acquired Immunodeficiency Syndrome
special report Conduction System in Children with Acquired Immunodeficiency Syndrome* Saroja Bharati, M.D., F.C.C.R; VVay \( joshi, M.D.; Edward M. Connm; M.D.; kimes M. Oleske, M.D.; and Maurice Lev, M.D., F.C.C.R
Six children died of acquired immunodeficiency syndrome (AIDS), four of them females, ages 7 months, 13 months, 2 years 8 months, and 4 years; and two of them males, aged 211. and 7 years. They were bom to IV drug-addicted
parents. The conduction system (CS) and the entire heart
were studied by serial section. In all cases the heart was hypertrophied and enlarged; one had total thrombotic occlusion of the right coronary artery with extensive infarction of the ventricular septum. Vascular changes also were found in all hearts, involving small arteries, arterioles, and venules. In the arteries, they involved the intima, media, and adventitia, and perivascular areas in a degenerative and inftammatory process. The elastic tissue was especially affected. A nonspeci6c myocarditis was present in four
histologic findings of the heart in acquired T heimmunode6ciency syndrome (AIDS) in
children':" and in adults 12-25 have been described in the literature. Although various types of ECG abnormalities'<" have been documented clinically in children with AIDS, the conduction system thus far, to our knowledge, has not been studied pathologically. We therefore studied the conduction system and the entire heart in six children who died of AIDS. MATERIALS AND METHODS
All six children were diagnosed to have AIDS and treated at Children's Hospital, Newark, NJ, where they died. There were four ·From the Congenital Heart and Conduction System Center, The Heart Institute for Children of Christ Hospital and Medical Center, Oak Lawn, IL; Department of Pathology Rush University-Presbyterian St. Lukes Medical Center, Chicago; Department of
Pathology andPediatrics, Children's Hospital ofNew Jersey, United
Hospitals Medical Center, Newark; and University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark; and Department of Clinical Pathology and Diagnostic Medicine, Greenville, NC. Aided by grant HL 30558-06 from the National Institutes of Health, National Heart Lung and Blood Institute, Bethesda, MD. Reprint requests: Dr. Bharati, Congenital Heart and Conduction System Center; 11745 Southwest Highway, Palos His; IL 60463
cases and epicarditis in all. Changes in the summit of the ventricular septum were present in four cases, consisting of increased 6brosis and arteriolosclerosis. The CS changes varied in location, showing either vasculitis, myocarditis, or fragmentation of the bundle with lobulation and&brosis. The changes in the conduction system were not as severe as the changes in the surrounding myocardium. In one case the ECG was abnormal, showing left hemiblock. This corresponded to the 6nding of 8brosis, vacuolization of cells, and space formation in the left bundle branch. (Chat 1989; 96:406-13)
Ics =
condudion system; HIV = hUID8D immunocle8eieneyvirus
I
females and two males, and the ages ranged from seven months to seven years. All children were born to IV drug-addicted mothers and/or fathers, and some of the parents had AIDS and died of this disease. Antibody titers against human immunodeficiency virus (HIV) were measured by an enzyme-linked immunosorbent assay and confirmed by Western blot techniques. Each case showed defective cell-mediated immunity, indicated by skin anergy, reduced number of peripheral T cells, reversal of helper to suppressor T cell ratio, raised peripheral B cells, and polyclonal hypergammaglobulinemia. In all cases, culture of blood and urine done for bacteria, fungi, acid-fast organisms, and viruses were negative, except in case 1, where group B p-streptococcus and in case 3, where Candida were isolated. In cases 1 and 4 Candida was isolated from the esophagus and in case 1, Pneumocyatis carinii from the lungs. In case 2, P carinii, herpes 1, and Candida were isolated from the lungs, and in case 4, Aspergillus was isolated from the lung. The complete autopsies were performed at Children's Hospital and have previously been reported. 1.1 The hearts were fixed in 10 percent formalin solution and later submitted to two of us (S.B. and M.L.) for study of the conduction system. The gross findings in the heart are given in Table 1.
Conduction System Studies Methods: The sinoatrial (SA) node and its approaches, the atrioventricular (AV) node and its approaches, and AV bundle, and Conduction SystemIn Children withAIDS(Bharati et 8/)
Table I-Grou Autoply Findings in the Heart
Chamber Size
CaseNo.
Cardiomegaly
1
+
Biatrial and left ventricular hypertrophy and enlargement
2
+
3
+
Biatrial and left ventricular hypertrophy and enlargement Right atrial and ventricular hypertrophy and enlargement Dilatation of left ventricle
4
+
Hypertrophy and dilatation of all chambers
5
+
6
+
Biatrial hypertrophy and enlargement Left ventricular hypertrophy Right atrial and biventricular hypertrophy and enlargement
the bundle branches up to the level of the moderator band were serially sectioned. Every 10th or 20th section was retained in all of these structures up to the level of the muscle of Lancisi. Every 20th or 40th section was retained in the bundle branches more distally. The upper two-thirds of the atrial septum was serially sectioned, and every 40th section was retained. The remainder of the heart was cut into blocks, and two sections were taken from each block. Thus, the entire atrial septum and the ventricular septum to the level of the anterolateral papillary muscle of the right ventricle were serially sectioned as above, and most of the parietal wall of the right and left ventricle were cut into blocks and sampled. Alternate sections were stained with hematoxylin-eosin and Weigert-van Gieson stains. In this manner, a total of 1,392 sections were studied in case 1, 1,912 in cases 2, 1,632 in case 3, 2,252 in case 4, 2,460 in case 5, and 1,572 sections in case 6. This method of study has previously been described...• The findings were equated with
those found in the normal hearts ofthe same age group.•.30 FINDINGS·
The findings in the conduction system and the entire heart are given in Tables 2 and 3. The term myocarditis, as used in this article, implies an in6ltration of mononuclear cells, with or without necrosis of the myocytes. This agrees with the terminology of Roldan et aI. 19 It does not agree with the terminology of Reilly et al,23 Anderson et al,24 and Baroldi et al,25 who follow Aretz et al31 in calling a condition myocarditis only when, in addition to the infiltration of inflammatory cells, there is degeneration or necrosis of myocytes. DISCUSSION
The pathologic findings in the cases of AIDS in adultsl!-25 (with the exception of the heart) are (a) meningitis, (b) encephalitis, (c) pneumonitis, (d) lymphoid depletion, (e) esophagitis, (f) oral pathology, (g) herpes simplex, (h) Kaposi'ssarcoma, and (i) malignant lymphoma. The organisms involved in the secondary *In this article arterioles are 0.3 mm or 300 or less up to the capillaries. Small arteries are larger than 0.3 mm.
Other Findings Anomalous muscle bundle in left ventricle Anomalous distribution of coronary arteries Hypertrophied supravalvular ridge Aneurysmal dilatation of ascending aorta
Aneurysm of right coronary artery with thrombotic occlusion Infarction of ventricular septum Aneurysmal dilatation of ascending aorta High origin of both coronary ostia Dilatation of ascending aorta Hypertrophy of supravalvular ridge Thickened mitral valve
causation of these entities are Pneumocystis, Toxoplasma, Cytomegalovirus, Cryptococcus, Aspergillus, Nocardia, Candida, Strongyloides, Zygomecytes, and others. The findings in the heart12.13.HS,16.18,19.21-25 in AIDS in adults are myocarditis, nonbacteriaI thrombotic endocarditis of the AY, aortic, and pulmonic valves, epicarditis, and rare coronary narrowing, and malignant lymphoma and Kaposi's sarcoma. The immunologic abnormalities described in adults include lymphopenia, low total peripheral T cells, with decrease in T-helper and inversion of the ratio of Thelper to T-suppressor cells. The pathologic findings in the cases of AIDS in children':" (with the exception of the heart) are (A) failure to thrive, (B) interstitial pneumonia of (a) Pneumocqstis carini; type and (b) lymphoid interstitial type, (c) moderate to severe anemia, and (d) hepatosplenomegaly and ascites. Histologically there are marked arterial changes throughout the body. The small and medium-sized arteries show fragmentation of elastic fibers, calcification of the media, vasculitis, and perivasculitis. The heart in children3.4.6.11 grossly shows cardiomyopathy with hypertrophy and dilatation of the right side and sometimes of the entire heart, and pericarditis with and without effusion. There may be thickening and nodularity of the tricuspid valve, and occasionally thrombosis of a main coronary artery Histologically there is fragmentation of the elastic fibers of vessels with calcification, vas-
culitis, and perivasculitis. The immunologic findings, in addition to those mentioned for the adult, are atrophy of thymus, lymphoid depletion of the spleen, and Peyers patches. All of the hearts reported here were hypertrophied and dilated (Table 1). Aside from case 3, no cause for this hypertrophy was present in the main coronary arteries or in the valves. In case 3, there was thrombosis and occlusion of the beginning of the right CHEST I 96 I 2 I AUGUST; 1989
407
Table ! -FintlingI of tile Conduction .".,.". Case No.
SA Node No change
2
3
Mononuclear cells and neutrophils within and on periphery; epicarditis Slight 6brosis
Approaches to SA Node
Atrial
Approaches
toAV Node
Increase in thickness of media ofarterioles, &brosis of epicardium wI mononuclear cell in<ration
Mild to moderate &brosis
Mononuclear cell in<ration wI mild to moderate &brosis; edema of fat tissue; dilatation of veins and lymphatics
Myocarditis
Myocarditis wI 6brosis (Fig 2)
Septum
:5
408
Recent thrombus in SA nodal artery, small hemorrhage
No change
AVNode
Penetrating
AVBundle
Marked thickeningof adventi-
Lobulation Increase in connective tissue
No change
Increase in spaces; increased vacuolation of cells
Fint part surrounded by &brous tissue; Third part could not be followed
Nocbange
Nocbange
Increase in spaces; 6brosis
Fibrosis and destromon
Fibrosis; increase in spaces
Myocarditis; Thickeningofadventitia of arteries, w/infiltration of mononuclear
First partin tramyocardial; 6brosis of first and second parts; third part could not be followed Calci6catiOD in Intand second parts; third part not identi&ed
tiaol
small arteries and arterioles (Fig 1); AVnode entered central &brous body from above Mononuclear cells, proliferatlon of intima and me-
Branching
Branch
dia olarterioles
Focal calcification in epicardium; arterioles thickened
Organizing infarct and myocarditis; calci6cation in internal elastic Iam-
4
Remorrhage, mononuclear cells, and &broblasts
Left Bundle
AVBundle
Epicarditis with hemorrhage; thickeningof media of some arterioles; vein proliferation of intima and thickeningof media Epicarditis, myocarditis, hemor-
Mella of arteries (Fig 3) and arterioles Fibrosis of nerves; fatty in61tration
Myocarditis, epicarditis, pro-
Fibrosis, myocarditis; disruption of elastic tissue; bemorrhage;
Partly situated within central &brous
body
infiltra-
tion of cells in adventitia ofarteries Ramus septi 6brosi thickened and narrowed; proliferation of media, mononuclear cells in adventitia of arterioles Fibrosis and thickeningofad-
Right Bundle
Branch
cells
Moderate 8brosis; fatty in61tration
Fatty in<ration; Fragmentation sandwiched between bulbar and main ventricular muscle (Fig 4)
Slight6broDilatation of capilsis laries, wI mononuclear cell in<ration
Fibrosis of 6ntand second
Thickening of adventitia w/in81-
No change
No change
Fintpart surrounded by 8brotic tisue;sec(continued)
Increase in spaces wI 6brosis wlvacuo-
parts
Conduction SyItem InChIkhn with AIDS (Bhatall et aI)
T.blel.~
rhage, s-
brosls, neuritis 6brosis ofadventitia wi mononuclear cell prol~ra-
tion of small arterles
and arte-
6
No change
rioles Epicardltis; calci6cation of media wi mononuclear cells in adventitia
lueration of adventitia, 6brosis
and
mononuclear cell ln6ltration of small arteries (FigS) Prollferation of muscle ofmedla
wlfibro-
sis oradventitia,
mononu-
clear cells in adventitia, calcification of media of small arteries
ventitia ofarteriales wi ln6ltration of mononuclear cell
tration of cells of AVnodaI artery
Fatty me-tamorphosis, hemorrhage and fat necrosis;
No change
lar degeneration of Purkinje cells
No change
No change
vascular
changes; 6brosis of nerves and calci6cation ofmyocytes and nerves
Enlargement of space's
and part normal
First part intramyocardial; myocarditis in end ofsecond and beginning of third parts
\
FIGURE I, Case 1. Marked thickening of the adventitia of small arteries and arterioles, by collagenous tissue in the AV node ~ert-van Geison, original magni6cation x 45). N = AV node; A=atriaI septum; V=ventrlcular septum.
')
FIGURE 2, Case 2. Myocarditis in the atrial septum (Hematoxylineosin, original magni6cation x 150). CHEST I 9Il I 2 I AUGUST, 1989
408
FIGURE 5, Case 5. Increase in adventitia of small artery in atrial septum, with thickening of collagen fibers and an infiltration of mononuclear cells in adventitia and periarterial tissue (Hematoxylineosin, original magnification x 60). A =atrial septal myocardium. Arrows delineate the artery.
coronary artery with infarction of the ventricular septum. The hypertrophy of the supravalvular ridge in cases 1 and 5 was apparently not obstructive. Histologically, however, there was considerable narFIGURE 3, Case 3. Small artery in atrial fat tissue showing degenerative changes with calcification in the internal elastic lamella with an infiltration of mononuclear cells in the adventitial and in the fat tissue adjacent (Hematoxylin-eosin, original magnification x 150). F = fat tissue .
FIG URE 4, Case 4. Area of fragmentation of the lower part of the bundle with Mahaim fibers going into the ventricular septum with increased fibrosis of the ventricular septum (Weigert-van Geison, original magnification x 22). B =bundle of His; AM =aortieo-mitral anulus , V =ventricular septal musculature; A =atrial septal musculature; Arrows demarcate the area of fragmentation of the bundle, mahaim fibers, and summit of the ventricular septum .
410
FIGURE 6, Case 3. Calcification ofa branching arteriole in the summit of the ventricular septum, with an increase in collagenous tissue in the adventitia of the branch . Calcium is present in the lumen and wall (Hematoxylin-eosin, original magnification x 225) . M = myocytes. Arrows point to the branching arteriole.
Conduction SystemIn ChIldren wlth AIDS (Bhtutlti lit 11./)
Table 3-Hiltologic Finding. in Other Areaa of the ReGrt Case No.
Summit of Ventricular Septum
1
Focal 6brosis slight in6ltration of mononuclear cells; marked thickening and narrowing of some large arterioles and small arteries, 6brosis on left side Increase in collagen, 6broblasts, and mononuclear cells in adventitia of arterioles Organized infarct; arteries proliferation of intima, destruction of internal elastic lameUa,degeneration in media and mononuclear cells in adventitia; increase in connective tissue on left side; myocarditis 6brosis of nerve; calci6ed material in lumen of arterioles (Fig 6) Increase in connective tissue left side; proliferation of intima and media of large arterioles; dilatation of lymphatics Marked increase in connective tissue; thickening of intima with proliferation of adventitia (Fig 7) Increase in 6broelastosis of both sides; marked arteriolosclerosis; fibrosis of nerves
2
3
4
5
6
Central Fibrous Body
Aortic Valve
Left Atrium and Ventricle
Right Atrium and Ventricle
Basophilic degeneration
No change
Thickening and narrowing of large arterioles, increased 6broelastosis of endocardium
Periarterial fibrosis of myocardium and epicardial fibrosis
No change
Vacuolar, basophilic degeneration of spongiosa
Chronic epicarditis; Perivascular fibrosis throughout myocardium
Epicarditis, myocarditis
Enlarged; areas of hemorrhage
Basophilic degeneration of spongiosa
Myocarditis; thickening of adventitia of vessels
Myocarditis; calci6cation of myocytes, epicarditis; degeneration of elastica of vessels wI calci6cation
No change
Vacuolization of spongiosa
Epicarditis; thickening of small arteries, mononuclear cell infiltration of myocardium
Fibrosis
No change
Vacuolar degeneration of spongiosa
Epicarditis; vascular changes of arteries and arterioles as elsewhere in myocardium
Epicarditis; vascular changes as elsewhere in myocardium
No change
Increased, vacuolated spongiosa
Epicarditis and periarteritis in myocardium
Epicarditis; mononuclear cells around vessels in myocardium
rowing of some of the small coronary arteries and arterioles in all cases, which could be a cause of the hypertrophy Likewise, the presence of myocarditis in four cases could produce hypertrophy. It is doubtful whether the epicarditis present in all cases would be a cause of hypertrophy. The histologic changes in the heart in our cases which deserve discussion in addition to the changes in the conduction system are: (1) the vascular changes, (2) the myocarditis and epicarditis, and (3) the sclerosis in the summit of the ventricular septum. The vascular changes are most outstanding, and the findings extend those mentioned in the literature. The least change was the hypertrophy of the smooth muscle of the media, proliferation of the collagenous
tissue of the adventitia, and perivascular increase in connective tissue. These were present in all six hearts in the small arteries and arterioles. The adventitia and the perivascular areas in these vessels were infiltrated with mononuclear cells and fibroblasts. In some cases, the cells of the intima were also proliferated. A more advanced change in the coronary arteries was seen in case 3. This involved the main coronary arteries as well as the smaller arteries. Here, the internal elastic lamella was disrupted and calcified. The calcific masses so produced pressed on the surrounding layers of the arteries. In other cases, masses of calcific material replaced all or part of a vessel wall and in some cases filled the lumen. The external elastic lamella was similarly involved in some CHEST I 98 I 2 I AUGUS'T. 1989
411
,
.'
FICURE 7,
Case 5 . Large arteriole in the ventricular septum showing proliferation of the intiffilland the collagenous tissue of theadventitia (Weigert-van Geison, original magni6cation X 300). V = ventricular septal musculature. Arrow points to the arteriole .
arteries. Degenerative changes were seen in the smooth muscle of the media, with changes as previously described in the adventitia. Veins and capillaries showed proliferative and in some cases calcific changes. The changes in the elastic tissue are similar and extend those reported previously" An epicarditis was found over the entire heart in all. A nonspecific myocarditis was found in cases 2,3, 5, and 6. In cases 2 and 6, this involved the atrial septum and the right ventricle . In case 3, it was found in the atrial and ventricular septa . In case 5, it involved the atrial septum. What is the cause of this myocarditis? It may be an extension of the epicarditis, or both the myocarditis and epicarditis may be due to the in8ammatory changes in the vascular tree . They are not directly related to known organisms, as these were not found histologically by us, or cultured from the myocardium at the Children's Hospital. Whether they are related to products of organisms not yet isolated or to an autoimmune mechanism is not within the 412
realm of the present discussion. The pathologic changes in the summit of the ventricular septum in our cases are of interest. We have previously studied these changes in the young and with advancing age.32-34 They consist of increased fibrosis of the summit with various secondary degenerative changes and arteriolosclerosis. They come on normally after the age of about 40. In our cases 1, 3, 4, and 5, these changes were very severe . This is completely abnormal in small children. These changes may be important in the genesis of conduction system lesions. The pathologic changes in the conduction system varied from case to case. In general, vascular changes including thrombosis were noted in the SA and/or the AV nodes similar to those described in the surrounding myocardium . However, a myocarditis was noted in one SA node and in the second and third part of the right bundle branch in another case. Parenchymal changes were noted in the AV bundle and the left bundle branch . All of these changes are not as severe as those seen in the myocardium of the atria and ventricles in our cases. Electrocardiograms were taken in cases 1,4,5, and 6, and were negative in cases I, 4, and 6. In case 5, however, there was left anterior hemiblock. This corresponds well with the fibrosis, vacuolization of cells, and space formation seen in the left bundle branch in this case. In the literature, ECG abnormalities in cases of AIDS in children and adults have been noted . This includes right axis deviation, right ventricular hypertrophy, left ventricular hypertrophy, T-wave changes,8.8 right bundle branch block,uo .25 ST-T-wave abnormalities,110 and ventricular tachycardia .ll3•u It can therefore be anticipated that changes in conduction and the conduction system of a mild or severe nature will be reported in future cases of AIDS. The changes in the conduction system in our cases may be related to various causes. The marked increase in fibrosis of the summit of the ventricular septum, which was present in most cases, can produce degenerative and fibrotic changes in the bundle and bundle branches. The SA node lies adjacent to the epicardium . Changes in the SA node may thus be related to the epicarditis that was present in all cases. The vascular changes in the conduction system and the myocarditis of the right bundle branch in case 6 are part of the general vasculitis of the heart in AIDS. The conduction system, the entire myocardium, and the fibrous skeleton of the heart are affected in children who have AIDS. The changes in the conduction system are less severe than those in the myocardium . In some cases the atria are more involved than the ventricles, and sometimes the right ventricle more than the left ventricle. The common denominator that
emerges in the pathologic change is the vascular changes. These changes may involve the larger coronary arteries to be accompanied by thrombosis and infarction. In the large, medium, and small coronary arteries, a prominent feature in the pathology is the involvement of the elastic tissue. In the small coronary arteries and arterioles, the periarteritis stands out. The venules and capillaries are also involved. The relationship of this pathologic change to infantile periarteritis nodosa, Kawasaki's disease, and collagen disease needs further elucidation. It is not known whether the changes are primarily due to the HIV virus or to its antibody or are secondary to the immune deficiency phenomenon. 1b date, we are not aware of any experimental data showing that the HIV virus affects blood vessels directly. REFERENCES 1 Oleske J, Minnefor A, Cooper R Jr, Thomas K, dela Cruz A, Ahdieh H, et al. Immune de&ciency syndrome in children. JAMA 1983; 249:2345-49 2 Joshi ~ Oleske JM, Minnefore AD, Singh R, Bokhari T, Rapkin RH. Pathology of suspected acquired immune de&ciency syndrome in children: a study of eight cases. Pediatr Patholl984; 1:71-87 3 Sherron ~ Piclroft" AS, Ferrer PL, Tamer D, Scott GB. Echocardiographic evaluation of myocardial function in pediatric AIDS patients [Abstract]. Am Heart J 1985; 110:710 4 Issenberg HJ, Charytan M, Rubinstein A. Cardiac involvement in children with acquired immune deficiency [Abstract]. Am
Heart J 1985; 110:710
5 Marion ~ WlZOia AA, Hutcheon RG, Rubinstein A. Human T-cell lympbotropic vims type In (HTLV-III) embryopathy: a new dysmorphic syndrome associated with intrauterine HTLVIII Infection. Am J Dis Child 1986; 140:638-40 6 Steinherz LJ, Bochstein )A, Robins J. Cardiac involvement in congenital acquired immunodeficiency syndrome. Am J Dis Child 1986; 140:1241-44 7 Joshi ~ Pawel B, Connor E, Sharer L, Oleslci JM, Morrison S, et al. Arteriopathy in children with acquired immune deficiency syndrome. Pediatr PathoII987; 7:261-75 8 Stewart JM, Kaul A, Cromiscb DS, Woolf PIC, Cewita MH. Congestive heart failure in children with human immunodeficiency virus infection [Abstract]. Circulation 1987; 76(suppl 4):514 9 Lipshultz SE, Chanock S, Sanden S~ Colan SD, Perez-Atayde A, McIntosh IC. Cardiac manifestations of pediatric human immunodeficiency virus (HIV) infection [Abstract]. Circulation
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10 Joshi Gadol C, Connor E, Oleske JM. Mendelson J, MarinGarcia J. Dilated cardiomyopathy in children with acquired immunode8cieDC)' syndrome: a pathologic study of &ve cases. Hum Patholl988; 19:69-73 11 ~l RL, Alboliru ET, McSherry CD, Levine OR, Antillon JR. Congenital heart defects in children of human immunode&ciency virus: positive mothers [Abstract]. Circulation 1988; 78(suppl pt 1):11-17 12 Reichert CM, O'Leary TJ, Levens DL, Simrell CR, Macher AM. Autopsy pathology in the acquired immune deficiency syndrome. Am J Patholl983; 112:357-82 13 Silver MA, Macher AM, 8eichert CM, Levens DL, Parrillo JE, Longo DL. et ale Cardiac involvement by Kaposi's sarcoma in acquired immune de6ciency syndrome (AIDS). Am J Cardiol 1984; 53:983-85
14 Guarda LA, Luna MA. Smith JL, Mansell PWA, Gyorkey F. Boca AN. Acquired immune deficiency syndrome: postmortem findings. Am J Clin PathoII984; 81:549-57 15 Cammarosano C, Lewis W Cardiac lesions in acquired immune de6ciency syndrome (AIDS). J Am Coli Cardioll985; 5:703-06 16 BalasubramaDyaDl MB, Waxman M, KazaI HL, Lee MH. Malignant lymphoma of the heart in acquired immune de6ciency syndrome. Chest 1986; 90:243-46 17 Craddock C, Pasvol G, Bull R, Protheroe A, Hopkin J. Cardiorespiratory arrest and autonomic neuropathy in AIDS. Lancet 1987; 2:16-18 18 Guamer J, Brynes, RIC, Chan WC, Birdson G, Hertzler G. Primary non- Hodgkin's lymphoma of the heart in two patients with the acquired immunodeficiency syndrome. Arch Pathol Lab Med 1987; 111:254-56 19 Roldan EO, Moskowitz L, Hensley G1: Pathology of the heart in acquired immunodeficiency syndrome. Arch Pathol Lab Med 1987; 111:943-46 20 RafJanti S~ Chiaramida AJ, Sen ~ Wright ~ Middleton JR. Chiaramida S. Assessment of cardiac function in patients with the acquired Immunodefleieney syndrome. Chest 1988; 93:59294
21 Levy WS, Varghese PJ, Anderson D~ Leiboff RB, Orenstein JM, Virmani R, et a1. Myocarditis diagnosed byendomyocardial biopsy in human immunodeficiency virus infection with cardiac dysfunction. Am J CardioII988; 62:658-59 22 SteigmanCK, Anderson D~ Macher AM, SenneshJD. Vinnani R. Fatal cardiac tamponade in acquired immunodeficiency syndrome with epicardial Kaposfs sarcoma. Am Heart J 1988; 116:1105-07 23 Reilly JM, Cunnion RE, Anderson D~ O'Leary 1), Simmons JT, Lane HC, et ale Frequency of myocarditis, left ventricular tachycardia in the acquired immune deficiency syndrome. Am J Cardioll988; 62:789-93 24 Anderson D~ Virmani R, Reilly JM. O'Leary T, Cunnion RE, Hobinowitz M, et ale Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome. JAm Coll Cardioll988; 11:792-99 25 Baroldi G, Corallo S, Moroni M, Repossini A, Mutinelli MR, Lazzarin A, et ale Focal lymphocytic myocarditis in acquired immunode&ciency syndrome (AIDS): a correlative morphologic and clinical study in 26 consecutive fatal cases. J Am Coll Cardioll988; 12:463-69 26 Lev M, Widran J, Erickson EE. A method for the histopathologic study of the abioventricular node, bundle, and branches. Arch PathoII951; 52:73-83 27 Lev M, Watne AL. Method for routine histopathologic study of human sinoatrial node. Arch PatboII954; 47:168-77 28 Lev M, Bharati S. A method of study of the pathology of the conduction system for electrocardiographic and His bundle electrogram correlations. Anat Rec 1981; 201:43-49 29 Erickson EE, Lev M. Aging changes in the human atrioventricular node, bundle and bundle branches. J Gerontoll952; 7:112 30 Lev M. Aging changes in the human sinoatrial node. J Gerontol 1954; 9:1-8 31 Aretz HT, Btllingbam ME, Edwards WD. Factor SM, Fallon JT, Fenoglio JJ, et ale Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Patholl987; 1:3-14 32 Lev M. The pathology of complete atrioventricular block. Progr Cardiovasc Dis 1964; 6:317-26 33 Lev M. The normal anatomy of the conduction system in man and its pathology in atrioventricular block. Ann NY Acad Sci 1964; 111:817-29 34 Bharati S, Bauernfeind R, Miller LB, Strasberg B. Lev M. Sudden death in three teenagers: conduction system studies. J Am Coil Cardioll983; 1:879-86 CHEST I 8e I 2 I AUGUST, 1888
413
Six children died of acquired immunodeficiency syndrome (AIDS), four of them females, ages 7 months, 13 months, 2 years 8 months, and 4 years; and two of them males, aged 211. and 7 years. They were bom to IV drug-addicted
parents. The conduction system (CS) and the entire heart
were studied by serial section. In all cases the heart was hypertrophied and enlarged; one had total thrombotic occlusion of the right coronary artery with extensive infarction of the ventricular septum. Vascular changes also were found in all hearts, involving small arteries, arterioles, and venules. In the arteries, they involved the intima, media, and adventitia, and perivascular areas in a degenerative and inftammatory process. The elastic tissue was especially affected. A nonspeci6c myocarditis was present in four
histologic findings of the heart in acquired T heimmunode6ciency syndrome (AIDS) in
children':" and in adults 12-25 have been described in the literature. Although various types of ECG abnormalities'<" have been documented clinically in children with AIDS, the conduction system thus far, to our knowledge, has not been studied pathologically. We therefore studied the conduction system and the entire heart in six children who died of AIDS. MATERIALS AND METHODS
All six children were diagnosed to have AIDS and treated at Children's Hospital, Newark, NJ, where they died. There were four ·From the Congenital Heart and Conduction System Center, The Heart Institute for Children of Christ Hospital and Medical Center, Oak Lawn, IL; Department of Pathology Rush University-Presbyterian St. Lukes Medical Center, Chicago; Department of
Pathology andPediatrics, Children's Hospital ofNew Jersey, United
Hospitals Medical Center, Newark; and University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark; and Department of Clinical Pathology and Diagnostic Medicine, Greenville, NC. Aided by grant HL 30558-06 from the National Institutes of Health, National Heart Lung and Blood Institute, Bethesda, MD. Reprint requests: Dr. Bharati, Congenital Heart and Conduction System Center; 11745 Southwest Highway, Palos His; IL 60463
cases and epicarditis in all. Changes in the summit of the ventricular septum were present in four cases, consisting of increased 6brosis and arteriolosclerosis. The CS changes varied in location, showing either vasculitis, myocarditis, or fragmentation of the bundle with lobulation and&brosis. The changes in the conduction system were not as severe as the changes in the surrounding myocardium. In one case the ECG was abnormal, showing left hemiblock. This corresponded to the 6nding of 8brosis, vacuolization of cells, and space formation in the left bundle branch. (Chat 1989; 96:406-13)
Ics =
condudion system; HIV = hUID8D immunocle8eieneyvirus
I
females and two males, and the ages ranged from seven months to seven years. All children were born to IV drug-addicted mothers and/or fathers, and some of the parents had AIDS and died of this disease. Antibody titers against human immunodeficiency virus (HIV) were measured by an enzyme-linked immunosorbent assay and confirmed by Western blot techniques. Each case showed defective cell-mediated immunity, indicated by skin anergy, reduced number of peripheral T cells, reversal of helper to suppressor T cell ratio, raised peripheral B cells, and polyclonal hypergammaglobulinemia. In all cases, culture of blood and urine done for bacteria, fungi, acid-fast organisms, and viruses were negative, except in case 1, where group B p-streptococcus and in case 3, where Candida were isolated. In cases 1 and 4 Candida was isolated from the esophagus and in case 1, Pneumocyatis carinii from the lungs. In case 2, P carinii, herpes 1, and Candida were isolated from the lungs, and in case 4, Aspergillus was isolated from the lung. The complete autopsies were performed at Children's Hospital and have previously been reported. 1.1 The hearts were fixed in 10 percent formalin solution and later submitted to two of us (S.B. and M.L.) for study of the conduction system. The gross findings in the heart are given in Table 1.
Conduction System Studies Methods: The sinoatrial (SA) node and its approaches, the atrioventricular (AV) node and its approaches, and AV bundle, and Conduction SystemIn Children withAIDS(Bharati et 8/)
Table I-Grou Autoply Findings in the Heart
Chamber Size
CaseNo.
Cardiomegaly
1
+
Biatrial and left ventricular hypertrophy and enlargement
2
+
3
+
Biatrial and left ventricular hypertrophy and enlargement Right atrial and ventricular hypertrophy and enlargement Dilatation of left ventricle
4
+
Hypertrophy and dilatation of all chambers
5
+
6
+
Biatrial hypertrophy and enlargement Left ventricular hypertrophy Right atrial and biventricular hypertrophy and enlargement
the bundle branches up to the level of the moderator band were serially sectioned. Every 10th or 20th section was retained in all of these structures up to the level of the muscle of Lancisi. Every 20th or 40th section was retained in the bundle branches more distally. The upper two-thirds of the atrial septum was serially sectioned, and every 40th section was retained. The remainder of the heart was cut into blocks, and two sections were taken from each block. Thus, the entire atrial septum and the ventricular septum to the level of the anterolateral papillary muscle of the right ventricle were serially sectioned as above, and most of the parietal wall of the right and left ventricle were cut into blocks and sampled. Alternate sections were stained with hematoxylin-eosin and Weigert-van Gieson stains. In this manner, a total of 1,392 sections were studied in case 1, 1,912 in cases 2, 1,632 in case 3, 2,252 in case 4, 2,460 in case 5, and 1,572 sections in case 6. This method of study has previously been described...• The findings were equated with
those found in the normal hearts ofthe same age group.•.30 FINDINGS·
The findings in the conduction system and the entire heart are given in Tables 2 and 3. The term myocarditis, as used in this article, implies an in6ltration of mononuclear cells, with or without necrosis of the myocytes. This agrees with the terminology of Roldan et aI. 19 It does not agree with the terminology of Reilly et al,23 Anderson et al,24 and Baroldi et al,25 who follow Aretz et al31 in calling a condition myocarditis only when, in addition to the infiltration of inflammatory cells, there is degeneration or necrosis of myocytes. DISCUSSION
The pathologic findings in the cases of AIDS in adultsl!-25 (with the exception of the heart) are (a) meningitis, (b) encephalitis, (c) pneumonitis, (d) lymphoid depletion, (e) esophagitis, (f) oral pathology, (g) herpes simplex, (h) Kaposi'ssarcoma, and (i) malignant lymphoma. The organisms involved in the secondary *In this article arterioles are 0.3 mm or 300 or less up to the capillaries. Small arteries are larger than 0.3 mm.
Other Findings Anomalous muscle bundle in left ventricle Anomalous distribution of coronary arteries Hypertrophied supravalvular ridge Aneurysmal dilatation of ascending aorta
Aneurysm of right coronary artery with thrombotic occlusion Infarction of ventricular septum Aneurysmal dilatation of ascending aorta High origin of both coronary ostia Dilatation of ascending aorta Hypertrophy of supravalvular ridge Thickened mitral valve
causation of these entities are Pneumocystis, Toxoplasma, Cytomegalovirus, Cryptococcus, Aspergillus, Nocardia, Candida, Strongyloides, Zygomecytes, and others. The findings in the heart12.13.HS,16.18,19.21-25 in AIDS in adults are myocarditis, nonbacteriaI thrombotic endocarditis of the AY, aortic, and pulmonic valves, epicarditis, and rare coronary narrowing, and malignant lymphoma and Kaposi's sarcoma. The immunologic abnormalities described in adults include lymphopenia, low total peripheral T cells, with decrease in T-helper and inversion of the ratio of Thelper to T-suppressor cells. The pathologic findings in the cases of AIDS in children':" (with the exception of the heart) are (A) failure to thrive, (B) interstitial pneumonia of (a) Pneumocqstis carini; type and (b) lymphoid interstitial type, (c) moderate to severe anemia, and (d) hepatosplenomegaly and ascites. Histologically there are marked arterial changes throughout the body. The small and medium-sized arteries show fragmentation of elastic fibers, calcification of the media, vasculitis, and perivasculitis. The heart in children3.4.6.11 grossly shows cardiomyopathy with hypertrophy and dilatation of the right side and sometimes of the entire heart, and pericarditis with and without effusion. There may be thickening and nodularity of the tricuspid valve, and occasionally thrombosis of a main coronary artery Histologically there is fragmentation of the elastic fibers of vessels with calcification, vas-
culitis, and perivasculitis. The immunologic findings, in addition to those mentioned for the adult, are atrophy of thymus, lymphoid depletion of the spleen, and Peyers patches. All of the hearts reported here were hypertrophied and dilated (Table 1). Aside from case 3, no cause for this hypertrophy was present in the main coronary arteries or in the valves. In case 3, there was thrombosis and occlusion of the beginning of the right CHEST I 96 I 2 I AUGUST; 1989
407
Table ! -FintlingI of tile Conduction .".,.". Case No.
SA Node No change
2
3
Mononuclear cells and neutrophils within and on periphery; epicarditis Slight 6brosis
Approaches to SA Node
Atrial
Approaches
toAV Node
Increase in thickness of media ofarterioles, &brosis of epicardium wI mononuclear cell in<ration
Mild to moderate &brosis
Mononuclear cell in<ration wI mild to moderate &brosis; edema of fat tissue; dilatation of veins and lymphatics
Myocarditis
Myocarditis wI 6brosis (Fig 2)
Septum
:5
408
Recent thrombus in SA nodal artery, small hemorrhage
No change
AVNode
Penetrating
AVBundle
Marked thickeningof adventi-
Lobulation Increase in connective tissue
No change
Increase in spaces; increased vacuolation of cells
Fint part surrounded by &brous tissue; Third part could not be followed
Nocbange
Nocbange
Increase in spaces; 6brosis
Fibrosis and destromon
Fibrosis; increase in spaces
Myocarditis; Thickeningofadventitia of arteries, w/infiltration of mononuclear
First partin tramyocardial; 6brosis of first and second parts; third part could not be followed Calci6catiOD in Intand second parts; third part not identi&ed
tiaol
small arteries and arterioles (Fig 1); AVnode entered central &brous body from above Mononuclear cells, proliferatlon of intima and me-
Branching
Branch
dia olarterioles
Focal calcification in epicardium; arterioles thickened
Organizing infarct and myocarditis; calci6cation in internal elastic Iam-
4
Remorrhage, mononuclear cells, and &broblasts
Left Bundle
AVBundle
Epicarditis with hemorrhage; thickeningof media of some arterioles; vein proliferation of intima and thickeningof media Epicarditis, myocarditis, hemor-
Mella of arteries (Fig 3) and arterioles Fibrosis of nerves; fatty in61tration
Myocarditis, epicarditis, pro-
Fibrosis, myocarditis; disruption of elastic tissue; bemorrhage;
Partly situated within central &brous
body
infiltra-
tion of cells in adventitia ofarteries Ramus septi 6brosi thickened and narrowed; proliferation of media, mononuclear cells in adventitia of arterioles Fibrosis and thickeningofad-
Right Bundle
Branch
cells
Moderate 8brosis; fatty in61tration
Fatty in<ration; Fragmentation sandwiched between bulbar and main ventricular muscle (Fig 4)
Slight6broDilatation of capilsis laries, wI mononuclear cell in<ration
Fibrosis of 6ntand second
Thickening of adventitia w/in81-
No change
No change
Fintpart surrounded by 8brotic tisue;sec(continued)
Increase in spaces wI 6brosis wlvacuo-
parts
Conduction SyItem InChIkhn with AIDS (Bhatall et aI)
T.blel.~
rhage, s-
brosls, neuritis 6brosis ofadventitia wi mononuclear cell prol~ra-
tion of small arterles
and arte-
6
No change
rioles Epicardltis; calci6cation of media wi mononuclear cells in adventitia
lueration of adventitia, 6brosis
and
mononuclear cell ln6ltration of small arteries (FigS) Prollferation of muscle ofmedla
wlfibro-
sis oradventitia,
mononu-
clear cells in adventitia, calcification of media of small arteries
ventitia ofarteriales wi ln6ltration of mononuclear cell
tration of cells of AVnodaI artery
Fatty me-tamorphosis, hemorrhage and fat necrosis;
No change
lar degeneration of Purkinje cells
No change
No change
vascular
changes; 6brosis of nerves and calci6cation ofmyocytes and nerves
Enlargement of space's
and part normal
First part intramyocardial; myocarditis in end ofsecond and beginning of third parts
\
FIGURE I, Case 1. Marked thickening of the adventitia of small arteries and arterioles, by collagenous tissue in the AV node ~ert-van Geison, original magni6cation x 45). N = AV node; A=atriaI septum; V=ventrlcular septum.
')
FIGURE 2, Case 2. Myocarditis in the atrial septum (Hematoxylineosin, original magni6cation x 150). CHEST I 9Il I 2 I AUGUST, 1989
408
FIGURE 5, Case 5. Increase in adventitia of small artery in atrial septum, with thickening of collagen fibers and an infiltration of mononuclear cells in adventitia and periarterial tissue (Hematoxylineosin, original magnification x 60). A =atrial septal myocardium. Arrows delineate the artery.
coronary artery with infarction of the ventricular septum. The hypertrophy of the supravalvular ridge in cases 1 and 5 was apparently not obstructive. Histologically, however, there was considerable narFIGURE 3, Case 3. Small artery in atrial fat tissue showing degenerative changes with calcification in the internal elastic lamella with an infiltration of mononuclear cells in the adventitial and in the fat tissue adjacent (Hematoxylin-eosin, original magnification x 150). F = fat tissue .
FIG URE 4, Case 4. Area of fragmentation of the lower part of the bundle with Mahaim fibers going into the ventricular septum with increased fibrosis of the ventricular septum (Weigert-van Geison, original magnification x 22). B =bundle of His; AM =aortieo-mitral anulus , V =ventricular septal musculature; A =atrial septal musculature; Arrows demarcate the area of fragmentation of the bundle, mahaim fibers, and summit of the ventricular septum .
410
FIGURE 6, Case 3. Calcification ofa branching arteriole in the summit of the ventricular septum, with an increase in collagenous tissue in the adventitia of the branch . Calcium is present in the lumen and wall (Hematoxylin-eosin, original magnification x 225) . M = myocytes. Arrows point to the branching arteriole.
Conduction SystemIn ChIldren wlth AIDS (Bhtutlti lit 11./)
Table 3-Hiltologic Finding. in Other Areaa of the ReGrt Case No.
Summit of Ventricular Septum
1
Focal 6brosis slight in6ltration of mononuclear cells; marked thickening and narrowing of some large arterioles and small arteries, 6brosis on left side Increase in collagen, 6broblasts, and mononuclear cells in adventitia of arterioles Organized infarct; arteries proliferation of intima, destruction of internal elastic lameUa,degeneration in media and mononuclear cells in adventitia; increase in connective tissue on left side; myocarditis 6brosis of nerve; calci6ed material in lumen of arterioles (Fig 6) Increase in connective tissue left side; proliferation of intima and media of large arterioles; dilatation of lymphatics Marked increase in connective tissue; thickening of intima with proliferation of adventitia (Fig 7) Increase in 6broelastosis of both sides; marked arteriolosclerosis; fibrosis of nerves
2
3
4
5
6
Central Fibrous Body
Aortic Valve
Left Atrium and Ventricle
Right Atrium and Ventricle
Basophilic degeneration
No change
Thickening and narrowing of large arterioles, increased 6broelastosis of endocardium
Periarterial fibrosis of myocardium and epicardial fibrosis
No change
Vacuolar, basophilic degeneration of spongiosa
Chronic epicarditis; Perivascular fibrosis throughout myocardium
Epicarditis, myocarditis
Enlarged; areas of hemorrhage
Basophilic degeneration of spongiosa
Myocarditis; thickening of adventitia of vessels
Myocarditis; calci6cation of myocytes, epicarditis; degeneration of elastica of vessels wI calci6cation
No change
Vacuolization of spongiosa
Epicarditis; thickening of small arteries, mononuclear cell infiltration of myocardium
Fibrosis
No change
Vacuolar degeneration of spongiosa
Epicarditis; vascular changes of arteries and arterioles as elsewhere in myocardium
Epicarditis; vascular changes as elsewhere in myocardium
No change
Increased, vacuolated spongiosa
Epicarditis and periarteritis in myocardium
Epicarditis; mononuclear cells around vessels in myocardium
rowing of some of the small coronary arteries and arterioles in all cases, which could be a cause of the hypertrophy Likewise, the presence of myocarditis in four cases could produce hypertrophy. It is doubtful whether the epicarditis present in all cases would be a cause of hypertrophy. The histologic changes in the heart in our cases which deserve discussion in addition to the changes in the conduction system are: (1) the vascular changes, (2) the myocarditis and epicarditis, and (3) the sclerosis in the summit of the ventricular septum. The vascular changes are most outstanding, and the findings extend those mentioned in the literature. The least change was the hypertrophy of the smooth muscle of the media, proliferation of the collagenous
tissue of the adventitia, and perivascular increase in connective tissue. These were present in all six hearts in the small arteries and arterioles. The adventitia and the perivascular areas in these vessels were infiltrated with mononuclear cells and fibroblasts. In some cases, the cells of the intima were also proliferated. A more advanced change in the coronary arteries was seen in case 3. This involved the main coronary arteries as well as the smaller arteries. Here, the internal elastic lamella was disrupted and calcified. The calcific masses so produced pressed on the surrounding layers of the arteries. In other cases, masses of calcific material replaced all or part of a vessel wall and in some cases filled the lumen. The external elastic lamella was similarly involved in some CHEST I 98 I 2 I AUGUS'T. 1989
411
,
.'
FICURE 7,
Case 5 . Large arteriole in the ventricular septum showing proliferation of the intiffilland the collagenous tissue of theadventitia (Weigert-van Geison, original magni6cation X 300). V = ventricular septal musculature. Arrow points to the arteriole .
arteries. Degenerative changes were seen in the smooth muscle of the media, with changes as previously described in the adventitia. Veins and capillaries showed proliferative and in some cases calcific changes. The changes in the elastic tissue are similar and extend those reported previously" An epicarditis was found over the entire heart in all. A nonspecific myocarditis was found in cases 2,3, 5, and 6. In cases 2 and 6, this involved the atrial septum and the right ventricle . In case 3, it was found in the atrial and ventricular septa . In case 5, it involved the atrial septum. What is the cause of this myocarditis? It may be an extension of the epicarditis, or both the myocarditis and epicarditis may be due to the in8ammatory changes in the vascular tree . They are not directly related to known organisms, as these were not found histologically by us, or cultured from the myocardium at the Children's Hospital. Whether they are related to products of organisms not yet isolated or to an autoimmune mechanism is not within the 412
realm of the present discussion. The pathologic changes in the summit of the ventricular septum in our cases are of interest. We have previously studied these changes in the young and with advancing age.32-34 They consist of increased fibrosis of the summit with various secondary degenerative changes and arteriolosclerosis. They come on normally after the age of about 40. In our cases 1, 3, 4, and 5, these changes were very severe . This is completely abnormal in small children. These changes may be important in the genesis of conduction system lesions. The pathologic changes in the conduction system varied from case to case. In general, vascular changes including thrombosis were noted in the SA and/or the AV nodes similar to those described in the surrounding myocardium . However, a myocarditis was noted in one SA node and in the second and third part of the right bundle branch in another case. Parenchymal changes were noted in the AV bundle and the left bundle branch . All of these changes are not as severe as those seen in the myocardium of the atria and ventricles in our cases. Electrocardiograms were taken in cases 1,4,5, and 6, and were negative in cases I, 4, and 6. In case 5, however, there was left anterior hemiblock. This corresponds well with the fibrosis, vacuolization of cells, and space formation seen in the left bundle branch in this case. In the literature, ECG abnormalities in cases of AIDS in children and adults have been noted . This includes right axis deviation, right ventricular hypertrophy, left ventricular hypertrophy, T-wave changes,8.8 right bundle branch block,uo .25 ST-T-wave abnormalities,110 and ventricular tachycardia .ll3•u It can therefore be anticipated that changes in conduction and the conduction system of a mild or severe nature will be reported in future cases of AIDS. The changes in the conduction system in our cases may be related to various causes. The marked increase in fibrosis of the summit of the ventricular septum, which was present in most cases, can produce degenerative and fibrotic changes in the bundle and bundle branches. The SA node lies adjacent to the epicardium . Changes in the SA node may thus be related to the epicarditis that was present in all cases. The vascular changes in the conduction system and the myocarditis of the right bundle branch in case 6 are part of the general vasculitis of the heart in AIDS. The conduction system, the entire myocardium, and the fibrous skeleton of the heart are affected in children who have AIDS. The changes in the conduction system are less severe than those in the myocardium . In some cases the atria are more involved than the ventricles, and sometimes the right ventricle more than the left ventricle. The common denominator that
emerges in the pathologic change is the vascular changes. These changes may involve the larger coronary arteries to be accompanied by thrombosis and infarction. In the large, medium, and small coronary arteries, a prominent feature in the pathology is the involvement of the elastic tissue. In the small coronary arteries and arterioles, the periarteritis stands out. The venules and capillaries are also involved. The relationship of this pathologic change to infantile periarteritis nodosa, Kawasaki's disease, and collagen disease needs further elucidation. It is not known whether the changes are primarily due to the HIV virus or to its antibody or are secondary to the immune deficiency phenomenon. 1b date, we are not aware of any experimental data showing that the HIV virus affects blood vessels directly. REFERENCES 1 Oleske J, Minnefor A, Cooper R Jr, Thomas K, dela Cruz A, Ahdieh H, et al. Immune de&ciency syndrome in children. JAMA 1983; 249:2345-49 2 Joshi ~ Oleske JM, Minnefore AD, Singh R, Bokhari T, Rapkin RH. Pathology of suspected acquired immune de&ciency syndrome in children: a study of eight cases. Pediatr Patholl984; 1:71-87 3 Sherron ~ Piclroft" AS, Ferrer PL, Tamer D, Scott GB. Echocardiographic evaluation of myocardial function in pediatric AIDS patients [Abstract]. Am Heart J 1985; 110:710 4 Issenberg HJ, Charytan M, Rubinstein A. Cardiac involvement in children with acquired immune deficiency [Abstract]. Am
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