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The children's hospital medical center, Boston, Mass.
CLINICAL
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M.D., Editor Gordon F. Vawte~, M.D., Assistant Editor
heart failure, which was controlled, and twice developed recurrent evidence of infection, with streptococci cultured from the throat, and a rise in antistreptolysin titer from 400 to 1,200 units. These infections responded to penicillin. He was discharged to a foster home at 4 ~ e years of age. Regular follow-up during the next 4 years showed generally good health. The heart continued to be enlarged. He received a regular program of antibiotics as prophylaxis against streptococci. At the age of 9 years he rejoined his family and from that time on continued the follow-up clinic appointments only sporadically. He was very erratic in taking the prophylactic penicillin. At 1 5 ~ years of age he had a streptococcal infection which was not treated. Three days before the second admission he developed pain in his heels, but no objective signs of arthritis. On the next day, severe pain in the heels prevented walking. One day before admission he developed bilateral sharp chest pain, especially precordially, accentuated by deep breathing and b y lying flat. It was relieved by splinting the chest or sitting upright. The symptoms increased
T ~ I s was the sedond admission of a 16year-old white male who had fever and chest pain for 3 days. At 3 ~ z years of age he developed persistent pain in both feet, fever, and night sweats. A heart murmur was noted at an outside hospital, where he was given penicillin. He was discharged two months later without a specific diagnosis. He remained a t home on bed rest for 5 months. During this time he had anorexia, slow weight loss, some dyspnea, and tachycardia. He did not have painful joints, rash, nodules, or sore throat. Two days before the first admission to The Children's Hospital Medical Center at 31~2 years of age he had a high fever. On admission he appeared acutely ill and had a temperature of 104 ~ F. The area of cardiac dullness was enlarged. An apical systolic thrill, a Grade 3 apical regurgitant systolic murmur transmitted to the back, neck, and axilla, a Grade 2 apical mid-diastolic rumble, and a pericardial friction rub were heard. Corrected erythrocyte sedimentation rate was 72 ram. per hour. Antistreptolysin titer was 1,585 units. I-Ie remained in the hospital for 9 months. Soon after admission he developed congestive 607
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Clinical pathological conference
and he presented, spontaneously, at the hospital. O n physical examination the patient was a well-developed, acutely ill 16-year-old male. Temperature was 104 ~ F.; pulse, 128 per minute; respirations, 32 per minute; and blood pressure, 118/80 mm. Hg. There was no pulsus paradoxus. Circinate, erythematous lesions with sharp borders were transiently present over the skin of the trunk. There was no venous distention in the neck. Examination of the chest showed slight left precordial prominence, shallow, rapid, symmetrical respirations, and clear lungs, with no r~les, rhonchi, or rubs. T h e heart was hyperactive, with apical impulse in the sixth intercostal space, 2 cm. lateral to the midclavicular line. Grade 3 apical regurgitant systolic m u r m u r was transmitted to the axilla. A Grade 1 mid-diastolic rumble was present at the apex. Liver and spleen were not felt. All joints were nontender and not swollen. T h e laboratory findings included an hematocrit of 42 per cent, white blood cells 16,400 per cubic millimeter, 74 per cent polymorphonuclear leukocytes, 22 per cent lymphocytes, and 4 per cent monocytes. Urinalysis was normal. Culture of urine gave no growth. Corrected erythrocyte sedimentation rate was 22 mm. per hour. C-reactive protein was 3-plus. Antistreptolysin titer was 625 (6 months previously, 400). Six blood cultures were negative. T h r o a t cultures grew beta hemolytic streptococci. Typhoid 0 agglutinins were: 1:20, 2-plus; 1:40, 1-plus. Typhoid H agglutinins were negative. T h e remaining febrile agglutinins were negative. Total proteins were 6.3 Gm. per 100 ml. Electrophoretic pattern was normal. O n chest x-ray, the heart was enlarged, with a left ventricular predominance. Vascular markings were within normal limits. L u n g fields were clear. Electrocardiogram showed: P-R interval, 0.16 second; axis, plus 75 ~, with patterns of left ventricular h y p e r t r o p h y plus right ventricular h y p e r t r o p h y and left ventricular strain with S-T and T wave changes in Leads II, I I I , and V 4, 5, and 6.
April 1963
COURSE
Aspirin (40 rag. per pound) and penicillin were begun. For 10 days the fever varied between 101 ~ F. and 104 ~ F., despite salicylate levels as high as 37 rag. per cent. O n day 4, respirations increased and there was some distress. Occasional r~les were heard at the left base. Pulmonary vasculature was now congested with small pleural effusions bilaterally. T h e heart appeare& somewhat larger than before. He was given digitalis. O n the sixth day he had less, but still occasional, chest pain. Penicillin was changed to chlortetracycline and salicylates were stopped. There were no signs of congestive failure. O n the eighth day, he developed pain, tenderness, and redness of the left wrist and left middle toe. O n the twelfth day he appeared very ill. The physical findings were unchanged. He was started on 60 rag. of prednisone daily. O n the thirteenth day he suddenly became dyspneic and cyanotic. Within 2 hours he developed hypotension and died. DR. SIDNEY FARBER. Years ago, Dr. Levine told me that he was leaving Pediatrics because all of its problems were solved. Today we are honored that Dr. Levine is once again beginning his career in Pediatrics. DR. SAMUEL A. LEVINE.~ Don't take that too literally for I have been a pediatrician for many years. Thirty-five years ago I may have been able to help you with cardiologic problems, but you have bcen standing on your own two feet very well for a long time. Now to begin my philosophic notes concerning the patient before us. When we learn that a cardiac murmur was heard at 3 years of age, I would like to know if a murmur had been heard before this, sometime during the first year, perhaps. It ought to be a "must" that any doctor who delivers a child, or sees a child after the first few days of life, perhaps even a pediatrician, enter on his notes whether or not there is a murmur. Such a murmur may well have little or no significance, but the only way to find out is to know, at the outset, whether it was there, or not. *=Dr. Samuel A. Levine is Clinical Professor of Medicine, Emeritus, Harvard Medical School, and Consultant in Cardiology, Peter Bent Brigham Hospitals Boston, Mass.
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Number 4
The rest of the initial history sounds like rheumatic fever in a rather young child. I don't think many of us see as much rheumatic fever as we did 30 or 40 years ago, and I don't see much at all, being more concerned of late with deciding whether the anterior descending coronary artery is wide open, partially occluded, or completely occluded. Perhaps this is partly because we now have specialists in rheumatic fever. In any case, from here on we will be pounding away at rheumatic fever, which is what I think this adult had and from which he died. Shortly before the first admission here, he had fever of 104 ~ F., rather high for rheumatic fever, but more often seen in the very young than in the more grown-up patients with rheumatic fever. A systolic thrill was noted. The only thing this generally useless cardiologic finding tells me is that the murmur will be good and loud and, therefore, it is of particular use to art observer who is deaf. In other words, I have never felt a thrill when the corresponding murmur was not at least Grade 3 or, more commonly, Grade 4 or 5 intensity. You must, of course, decide that the thrill has a definite duration, a "purr" so to speak, in order to distinguish it from the impact of a hyperdynamic heart, as in thyrotoxicosis. A Grade 3 regurgitant systolic murmur transmitted to the back, neck, and axilla tells us that murmurs are transmitted in all directions, if they are loud, and particularly when they hit bone. While there may be an element of transmission through the stream of blood, an aortic systolic murmur is transmitted to the neck mainly because it originates in a structure, the valve area, close to the neck. Mitral systolic murmurs are well heard in the axilla for similar reasons. For example, pulmonary systolic murmurs are well heard in the neck because of proximity, not because turbulent pulmonary blood is carried up the carotid artery. The fact that a Grade 2 apical mid-diastolic rumble and a pericardial friction rub were both heard indicates that someone was unusually clever, or that these sounds were heard at different times, perhaps after the friction rub disappeared and someone later heard the mid-diastolic rumble. As far as the friction rub goes, these a r e - - o r at least used to b e - - h e a r d in rheumatic pericarditis, more often in those patients with aortic insufficiency than in those with mitral disease. At least, this is the way things turn out more often that/ not; patients with rheumatic pericarditis,
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when examined years later, more often have aortic rather than mitral valvular disease. Since one doesn't expect to find rheumatic mitral stenosis at the age of 3, if this diastolic murmur is real it probably represents that diastolic nmrmur found in dilated hearts where t h e r e is no mitral stenosis. One might want to consider this a relative mitral stenosis resuIting f r o m cardiac dilatation. This, however, is not a loud murmur, as described in this hospital many years ago in acute rheumatic carditis, but is a faint Grade 1 or perbaps Grade 2 sort of "ruff, ruff" sound. A characteristic to and fro friction rub is one of the physical signs you can hang your hat on. However, the to and fro murmur of aortic insufficiency may be enveloped by the sounds of a friction rub. You have only to wait for the friction rub to disappear, as it soon does, and then the presence of aortic insufficiency can be recognized, since this m u r m u r seldom disappears, and certainly not commonly in less than a week. Sometimes, a pericardial friction rub may have only a systolic component and the diastolic component may have two parts. A late phase, which disappears with atrial fibrillation, probably represents atrial contraction. In any event, the boy was hospitalized for 9 months, as still may be the practice, but I think we used to keep the patients with acute rheumatic fever in bed too long. It is a different story, however, when a patient develops congestive heart failure while in the hospital. During the hospitalization he twice had recurrent infection, streptococci were cultured twice, the antistreptolysin titer rose and the infections were controlled with penicillin. I wonder what the incidence of positive culture of the same kind of streptococcus is in patients here when they don't have rheumatic fever? DR. B. F. MASSELL. One series indicates that the average nonrheumatic child, not receiving penicillin, will have 1 streptococcal infection every 14 to 15 months. DR. D. H. CARVER. If yOU count one colony or more as a positive, 35 per cent of the general school population in this area will harbor streptococci. The difficulty has been to know what number of streptococci might be significant. DR. LEVlNE. I don't know whether you have to have a lot of streptococci around to be sick. i do know that children may harbor fairly many streptococci and still seem well. Well, the child did well for 4 years after discharge to a foster
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Clinical pathological con[erence
home. However, the h e a r t continued to be enlarged, and we are not clearly told t h a t the cardiac m u r m u r s changed. I suspect that this means t h a t at least the diastolic m u r m u r remained. Now, after return to his own family and a certain loss of medical control, we come to his final admission. Can anyone tell me w h a t m o n t h of the year this was? DR. CARVER. November. DR. LEVINE. W h e n was the first illness, at the age of 3? DR, CARVER. I n February. DR. LEVlNE. T h e peak m o n t h for acute rheumatic fever used to be M a r c h - - " T h e Ides of M a r c h . " T h e mothers of rheumatic children used to say: " I f only M a r y can get through the Spring, she'll be all right." I think t h a t this still holds for first and recurrent attacks. W h a t is there about M a r c h for children who are vulnerable to rheumatic fever? I would refer you to a p a p e r published m a n y years ago by W a d e H. Brown. 1 He was studying experimental syphilis in animals and found 100 per cent "takes" during certain m o n t h s and only 50 per cent in other months. He studied the various organ weights at different months of the year, a n d it intrigued me t h a t in March, the endocrine system was at low ebb. I n particular, h e found low weights of thyroid, adrenal, and pituitary glands. M y opinion, m a n y years ago, was t h a t there is some relationship between the endocrine system and vulnerability to infections and other diseases, and this may have something to do with the periodicity of rheumatic fever in our population. Thirty-two years ago I wrote on a clinical concept of r h e u m a t i c fever, saying: " T h e r e is another phase of the problem w h i c h I feel has not received sufficient attention. I refer to the condition of the host or patient, the internal environm e n t in which the disease develops, and especially . . . of the role of the glands of internal secretion." Now, we know t h a t in a military c a m p of 10,000, there may be 1,000 cases of sore throat, and a certain n u m b e r of new cases of r h e u m a t i c fever. O f 1,000 with sore throats, 100 m a y develop r h e u m a t i c fever, about one fourth of w h o m h a d r h e u m a t i c fever before or have a family history of r h e u m a t i c fever. W h y are these few so vulnerable to an agent w h i c h changes little, if at all, from host to host? Speculation bids m e to urge an endocrinologist to attack this problem. I n any event, the patient returned, severely i11, at 16 years of age, with a characteristic pleuritis
April 1963
Fig. I. Massive enlargement of the cardiac silhouette and evidence of ptilmonary congestion at 4 years of age.
Fig. 2. At the time of final admission there is an enlarged cardiac silhouette and some evidence of pulmonary congestion.
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and pericarditis, both pretty common in rheumatic fever. The pleuritis occurs more often on the left than on the right, and pleural or pericardial effusion occurs in the more violent types of rheumatic affection. Patients are more comfortable sitting up when they have pericarditis; some children even like to lean forward. The high fever disturbs me, but the rash goes with rheumatic fever. The precordial prominence, nowadays, no longer necessarily means congenital heart disease, but only that cardiac enlargement probably developed early in life. I am surprised, too, that the heart sounds are not decreased. Shallow respirations suggest decreased expansion. I have a spirometer in my office that I bought in 1919; it cost 10 dollars then, and upkeep is about 10 cents a year, plus a little water now and then. It takes about 30 seconds to 1 minute to get a measurement of vital capacity. I think this should be done on every patient one sees. I get more help from it than from an electrocardiogram when I follow a patient with rheumatic vaIvular disease, in whom dyspnea is the threat, or when I follow a case of congestive failure. In an adult, if a normal vital capacity is found
Fig. 3. Five days before death there are patchy densities throughout the lungs, particularly involving the left upper lobe.
Clinical pathological conference
6 I 1
every year, you rest easy, but if there is a progressive decrease in the reading, the patient needs help--nowadays, possibly cardiac surgery. To return to the problems at hand. I am surprised that the liver was not felt. I take it that no clubbing or petechiae were observed. Are the x-rays here? DR. G. B. C. HAnRIS. We have a series of films. The first is at 4 years of age. The cardiac silhouette is huge, with passive congestion of the Iungs (Fig. 1). DR. LEVINE. I wonder how much pericardial fluid contributes to that picture? DR. HARRIS. Later on, the heart is only slightly enlarged, with left ventricular contour and normal pulmonary vasculature. During the last admission the heart is somewhat larger, again with evidence of passive congestion (Fig. 2). A subsequent film shows hazy density in the left upper lobe, which persists and may represent transudate or exudate (Fig. 3). DR. LEVINE. It is no surprise that I conclude that the patient had rheumatic fever and rheumatic carditis. The things that are odd are the fever of 104 ~ F., and that more evidence of pulmonary edema was not found clinically at a time when he was so ill. However, I do not think that the patient had bacterial endocarditis, and doubt a coexistent congenital lesion. However, an element of renal insufficiency may be present. I like to make comparisons between syphilis and rheumatic fever. The spirochete may produce marked cutaneous lesions, may go to the aorta to develop an aneurysm, or may produce tabes dorsalis. Many tabetic individuals never had cutaneous lesions. It is, however, the same spirochete, but the host and his reactions are different. The same streptococcus produces a marked carditis in one, and marked joint pain in another instance of rheumatic fever. We used to see a good many children who had recurrent rheumatic fever year after year, but nothing much happened to the heart. In fact, I suspect that those with mild recurrent attacks do better, as far as the heart is concerned, than those who have one severe attack or transient episodes with complete freedom between times. DR. DAVID D. RUTSTEIN. T h e serious aspects of this illness don't come through in the written record. When he came to the clinic, the main symptom was that of erythema marginatum. We were puzzled by the pulmonary findings on x-ray which seemed disproportionate to the other signs and symptoms until clear-cut joint involvement
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Clinical pathological con[erence
April 1963
Fig. 4. Myocardium. There is an Aschoff nodule at upper left, and a band of scar on the right. (Hematoxylin and eosin stain. Original magnification • developed rather late. The question we could not answer, to our own satisfaction, was whether the pulmonary condition represented congestive failure, primary atypical pneumonia, or some other problem. As time went on it seemed less and less likely to me that this was congestive failure since we never could find evidence of right-sided failure which often accompanies acute rheumatic carditis of severe degree. DR. B. F. MASSELL. I agree that the pulmonary aspect of the problem was puzzling. But when, after omission of aspirin, the joint symptoms developed and the diagnosis of rheumatic fever was even clearer, I tended to think of the pulmonary lesion as part of the rheumatic fever process and thought a second diagnosis was unnecessary. This was almost 5 days before death when we were not aware how seriously ill he was, but this soon became obvious. DR. FARBER. We might poll our various colleagues. DR. CARVER. The house officers and third year medical students favored recurrent rheumatic fever and rheumatic carditis. The fourth year students, in addition, suspected superimposed acute bacterial endocarditis. DR. MASSELL. Dr. Michael, in our laboratory, demonstrated that this boy developed antibodies to Type 20A "streptococcus, isolated from the throat, whereas these organisms had not been present previously.
DR. GORDON F. VAWTER. The histologic counterpart of a fading abdominal rash consists of moderate perivascular mixed mononuclear and round cell infiltration; the polymorphonuclear infiltrate and fibrinoid degeneration of acute erythema marginatum, was not present in available sections but the findings might well represent the subsiding phase of such a process or represent a mild form of involvement. There were no evidences of right-sided heart failure. Peripheral edema, serous fluid collection, and marked visceral congestion were not noted. The liver was of normal weight and showed only minimal congestion. There was evidence of healed and acute rheumatic carditis involving: (1) thickened, hyperemic visceral and parietal pericardiums which were studded with tiny glistening opaque nodules; (2) aortic and mitral valves and left atrial endocardium (MacCallum's patch), and (3) myocardium (Fig. 4) in association with microscopic phlebitis and an acute panarteritis of intramyoeardial vessels, a rare but significant lesion (Fig. 5). The Aschoff bodies are of subacute type and similar perivascular adventitial reactions were found in periesophageal connective tissue, in diaphragm, and even a single focus in the small bowel. The heart was over twice normal weight, with left atrial enlargement and left ventricular hypertrophy and moderate dilatation. The cusps of
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Clinical pathological con[erence 6 1 3
Fig. 5. Myocardium. There is inflammation of adventitia and intima of the artery. (Hematoxylin and eosin stain. Original magnification • the mitral valve were moderately thickened, with somewhat rolled edges, thick ehordae tendineae, little or no commissural contraction, and the appositional surfaces were the site of rows of tiny active rheumatic vegetations. De. LEVINE. Was this a stenotic valve? DR. VAWTER, Our impression was that this valve would be predominantly insufficient if any
important functional defect were present. The ring of the aortic valve was dilated to twice the circumference of the pulmonic valve, the precursor of insufficiency. However, the cusps, while somewhat thickened, showed no commissural fusion and only minimal rolling and retraction of free margins so that we surmised that the valve was still competent. An acute rheumatic vegeta-
Fig. 6. Lung. Air spaces are filled with edema fluid, and there is an increase in cellularity, principally in relation to alveolar septal walls. (Hematoxylin and eosin stain. Original magnification •
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Clinical pathological con[erence
Fig. 7. A largely mononuclear response, in which many of the cells bear a resemblance to plasma cells is shown. (Hematoxylin and eosin stain. Original magnification x410.) tion involved one cusp. There was no evidence of bacterial endocarditis. The rubbery, dark red, essentially airless lungs were 3 times heavier than normal, and dilated lymphatics were palpable over the pleural surfaces. These changes were most severe in the left upper lobe, but were present everywhere in varying degree. Microscopically there was an extensive pneumonic process, characterized by sloughing o f bronchial epithelium, outpouring of edema fluid, and a cellular response (Fig. 6). The cellular response consists of large, hyperchromatic cells at the level of alveolar septa, of mononuclear or plasmacytoid characteristics, or cells apparently representing modified alveolar lining cells (Fig. 7). This type of cellular response is unusual, in my experience, in simple pulmonary edema, even of subacute duration. Many alveolar walls are lined by hyaline membranes which, by special staining, appear not to contain appreciable amounts of fibrin: indeed, there is very little fibrin anywhere. Active adventitial granulomas or phlebitis were not seen in the lung, apart from considerable perivascular edema and inconspicuous cellular infiltration. Since viral injury has been associated with similar pulmonary lesions, a great many studies were undertaken. There was no rise in antibody titer in acute and convalescent sera for influenza A or B, or adenovirus. Dr. Monroe D. Eaton did not recover his infectious factor from this lung. Additional cultures for virug, performed by Dr. Carver, were negative. At autopsy, bacterial cultures gave no growth. We are left, therefore, with a pneumonitis
April 1963
without demonstrated infectious cause, with features unusual for simple subacute congestion and edema. The pattern of this lethal lesion, we think, fits with acute rheumatic pneumonitis, as distinct from the chronic or healed lesions often described as typical rheumatic pneumonitisY, ~ The concept of rheumatic pneumonitis has remained controversiaI since authoritative observers have denied its specificity or existence, but for the reasons outlined above, we felt that this unusual lesion may well represent such a process. ~ The kidneys, adrenal glands, and thyroid gland were anatomically unremarkable. The anatomic diagnoses are: recurrent rheumatic [ever with erythema marginatum, healed and active rheumatic pericarditis, myocarditis, and vaIvulitis, involving mitral and aortic valves, and acute rheumatic pneumonitis. DR. FARBER. Dr. Janeway? DR. CHARLES A. JANEWAY. T w o things. Obviously this patient had severe rheumatic fever and it is well to remember that this can still occur. Second, it is interesting that this boy was well cared for while he was in the foster home, but that this preventable death occurred while he lived with his own family as an adolescent. Apparently the family attitude and the problems of adolescent adjustment to the "differentness" imposed by the need for continued drug therapy interfered with the program of prophylactic penicillin and visits to the clinic. These are difficult problems in this age group. We might admit to ourselves that were we to treat this boy again, we might proceed differently. Dr. Marian Ropes and others have stressed that it is most unwise to abruptly terminate any sort of therapy in patients with any disease of rheumatic or collagen type since there may follow a clinical relapse or exaggeration of the process. Perhaps this happened here, and hindsight suggests that the salicylates should have been tapered gradually and, at the same time, steroid therapy should have been instituted. I would ask Dr. Vawter whether any cause for a fairly sudden death was found. DR. VaWTE~. We found no dramatic lesion, such as an embolus or hemorrhage in a critical site. DR. L~VlNE. It worries and intrigues me that I used to see Sydenham's chorea in children and "~For an interesting discussion of pulmonary complications of rheumatic fever and rheumatic heart disease, published subsequent to this discussion, see S. E. Moolten: Am. J. Med. 33: 421, 1962.
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teenagers, but never after the age of 21, except in 2 young women. The thing these women had in common was that they were pregnant. Why should a woman who is pregnant develop chorea? Why did the streptococcus, after waiting outside the door all these years, suddenly jump in at the moment of pregnancy? Here we are back again with endocrine problems, it seems.
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6 15
REFERENCES 1. Brown, Wade H.: Constitutional variation and susceptibility to disease, Arch. Int. Med. 44: 625, 1929. 2. Epstein, E. Z., and Greenspan, E. B.: Rheumatic pneumonia, Arch. Int. Med. 68: 1074, 1941. 3. Herbert, P. A., and Manges, W. E.: The Masson body in rheumatic fever, Am.J. Path. 21: 741, 1945.
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M.D., Editor Gordon F. Vawte~, M.D., Assistant Editor
heart failure, which was controlled, and twice developed recurrent evidence of infection, with streptococci cultured from the throat, and a rise in antistreptolysin titer from 400 to 1,200 units. These infections responded to penicillin. He was discharged to a foster home at 4 ~ e years of age. Regular follow-up during the next 4 years showed generally good health. The heart continued to be enlarged. He received a regular program of antibiotics as prophylaxis against streptococci. At the age of 9 years he rejoined his family and from that time on continued the follow-up clinic appointments only sporadically. He was very erratic in taking the prophylactic penicillin. At 1 5 ~ years of age he had a streptococcal infection which was not treated. Three days before the second admission he developed pain in his heels, but no objective signs of arthritis. On the next day, severe pain in the heels prevented walking. One day before admission he developed bilateral sharp chest pain, especially precordially, accentuated by deep breathing and b y lying flat. It was relieved by splinting the chest or sitting upright. The symptoms increased
T ~ I s was the sedond admission of a 16year-old white male who had fever and chest pain for 3 days. At 3 ~ z years of age he developed persistent pain in both feet, fever, and night sweats. A heart murmur was noted at an outside hospital, where he was given penicillin. He was discharged two months later without a specific diagnosis. He remained a t home on bed rest for 5 months. During this time he had anorexia, slow weight loss, some dyspnea, and tachycardia. He did not have painful joints, rash, nodules, or sore throat. Two days before the first admission to The Children's Hospital Medical Center at 31~2 years of age he had a high fever. On admission he appeared acutely ill and had a temperature of 104 ~ F. The area of cardiac dullness was enlarged. An apical systolic thrill, a Grade 3 apical regurgitant systolic murmur transmitted to the back, neck, and axilla, a Grade 2 apical mid-diastolic rumble, and a pericardial friction rub were heard. Corrected erythrocyte sedimentation rate was 72 ram. per hour. Antistreptolysin titer was 1,585 units. I-Ie remained in the hospital for 9 months. Soon after admission he developed congestive 607
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Clinical pathological conference
and he presented, spontaneously, at the hospital. O n physical examination the patient was a well-developed, acutely ill 16-year-old male. Temperature was 104 ~ F.; pulse, 128 per minute; respirations, 32 per minute; and blood pressure, 118/80 mm. Hg. There was no pulsus paradoxus. Circinate, erythematous lesions with sharp borders were transiently present over the skin of the trunk. There was no venous distention in the neck. Examination of the chest showed slight left precordial prominence, shallow, rapid, symmetrical respirations, and clear lungs, with no r~les, rhonchi, or rubs. T h e heart was hyperactive, with apical impulse in the sixth intercostal space, 2 cm. lateral to the midclavicular line. Grade 3 apical regurgitant systolic m u r m u r was transmitted to the axilla. A Grade 1 mid-diastolic rumble was present at the apex. Liver and spleen were not felt. All joints were nontender and not swollen. T h e laboratory findings included an hematocrit of 42 per cent, white blood cells 16,400 per cubic millimeter, 74 per cent polymorphonuclear leukocytes, 22 per cent lymphocytes, and 4 per cent monocytes. Urinalysis was normal. Culture of urine gave no growth. Corrected erythrocyte sedimentation rate was 22 mm. per hour. C-reactive protein was 3-plus. Antistreptolysin titer was 625 (6 months previously, 400). Six blood cultures were negative. T h r o a t cultures grew beta hemolytic streptococci. Typhoid 0 agglutinins were: 1:20, 2-plus; 1:40, 1-plus. Typhoid H agglutinins were negative. T h e remaining febrile agglutinins were negative. Total proteins were 6.3 Gm. per 100 ml. Electrophoretic pattern was normal. O n chest x-ray, the heart was enlarged, with a left ventricular predominance. Vascular markings were within normal limits. L u n g fields were clear. Electrocardiogram showed: P-R interval, 0.16 second; axis, plus 75 ~, with patterns of left ventricular h y p e r t r o p h y plus right ventricular h y p e r t r o p h y and left ventricular strain with S-T and T wave changes in Leads II, I I I , and V 4, 5, and 6.
April 1963
COURSE
Aspirin (40 rag. per pound) and penicillin were begun. For 10 days the fever varied between 101 ~ F. and 104 ~ F., despite salicylate levels as high as 37 rag. per cent. O n day 4, respirations increased and there was some distress. Occasional r~les were heard at the left base. Pulmonary vasculature was now congested with small pleural effusions bilaterally. T h e heart appeare& somewhat larger than before. He was given digitalis. O n the sixth day he had less, but still occasional, chest pain. Penicillin was changed to chlortetracycline and salicylates were stopped. There were no signs of congestive failure. O n the eighth day, he developed pain, tenderness, and redness of the left wrist and left middle toe. O n the twelfth day he appeared very ill. The physical findings were unchanged. He was started on 60 rag. of prednisone daily. O n the thirteenth day he suddenly became dyspneic and cyanotic. Within 2 hours he developed hypotension and died. DR. SIDNEY FARBER. Years ago, Dr. Levine told me that he was leaving Pediatrics because all of its problems were solved. Today we are honored that Dr. Levine is once again beginning his career in Pediatrics. DR. SAMUEL A. LEVINE.~ Don't take that too literally for I have been a pediatrician for many years. Thirty-five years ago I may have been able to help you with cardiologic problems, but you have bcen standing on your own two feet very well for a long time. Now to begin my philosophic notes concerning the patient before us. When we learn that a cardiac murmur was heard at 3 years of age, I would like to know if a murmur had been heard before this, sometime during the first year, perhaps. It ought to be a "must" that any doctor who delivers a child, or sees a child after the first few days of life, perhaps even a pediatrician, enter on his notes whether or not there is a murmur. Such a murmur may well have little or no significance, but the only way to find out is to know, at the outset, whether it was there, or not. *=Dr. Samuel A. Levine is Clinical Professor of Medicine, Emeritus, Harvard Medical School, and Consultant in Cardiology, Peter Bent Brigham Hospitals Boston, Mass.
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Number 4
The rest of the initial history sounds like rheumatic fever in a rather young child. I don't think many of us see as much rheumatic fever as we did 30 or 40 years ago, and I don't see much at all, being more concerned of late with deciding whether the anterior descending coronary artery is wide open, partially occluded, or completely occluded. Perhaps this is partly because we now have specialists in rheumatic fever. In any case, from here on we will be pounding away at rheumatic fever, which is what I think this adult had and from which he died. Shortly before the first admission here, he had fever of 104 ~ F., rather high for rheumatic fever, but more often seen in the very young than in the more grown-up patients with rheumatic fever. A systolic thrill was noted. The only thing this generally useless cardiologic finding tells me is that the murmur will be good and loud and, therefore, it is of particular use to art observer who is deaf. In other words, I have never felt a thrill when the corresponding murmur was not at least Grade 3 or, more commonly, Grade 4 or 5 intensity. You must, of course, decide that the thrill has a definite duration, a "purr" so to speak, in order to distinguish it from the impact of a hyperdynamic heart, as in thyrotoxicosis. A Grade 3 regurgitant systolic murmur transmitted to the back, neck, and axilla tells us that murmurs are transmitted in all directions, if they are loud, and particularly when they hit bone. While there may be an element of transmission through the stream of blood, an aortic systolic murmur is transmitted to the neck mainly because it originates in a structure, the valve area, close to the neck. Mitral systolic murmurs are well heard in the axilla for similar reasons. For example, pulmonary systolic murmurs are well heard in the neck because of proximity, not because turbulent pulmonary blood is carried up the carotid artery. The fact that a Grade 2 apical mid-diastolic rumble and a pericardial friction rub were both heard indicates that someone was unusually clever, or that these sounds were heard at different times, perhaps after the friction rub disappeared and someone later heard the mid-diastolic rumble. As far as the friction rub goes, these a r e - - o r at least used to b e - - h e a r d in rheumatic pericarditis, more often in those patients with aortic insufficiency than in those with mitral disease. At least, this is the way things turn out more often that/ not; patients with rheumatic pericarditis,
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when examined years later, more often have aortic rather than mitral valvular disease. Since one doesn't expect to find rheumatic mitral stenosis at the age of 3, if this diastolic murmur is real it probably represents that diastolic nmrmur found in dilated hearts where t h e r e is no mitral stenosis. One might want to consider this a relative mitral stenosis resuIting f r o m cardiac dilatation. This, however, is not a loud murmur, as described in this hospital many years ago in acute rheumatic carditis, but is a faint Grade 1 or perbaps Grade 2 sort of "ruff, ruff" sound. A characteristic to and fro friction rub is one of the physical signs you can hang your hat on. However, the to and fro murmur of aortic insufficiency may be enveloped by the sounds of a friction rub. You have only to wait for the friction rub to disappear, as it soon does, and then the presence of aortic insufficiency can be recognized, since this m u r m u r seldom disappears, and certainly not commonly in less than a week. Sometimes, a pericardial friction rub may have only a systolic component and the diastolic component may have two parts. A late phase, which disappears with atrial fibrillation, probably represents atrial contraction. In any event, the boy was hospitalized for 9 months, as still may be the practice, but I think we used to keep the patients with acute rheumatic fever in bed too long. It is a different story, however, when a patient develops congestive heart failure while in the hospital. During the hospitalization he twice had recurrent infection, streptococci were cultured twice, the antistreptolysin titer rose and the infections were controlled with penicillin. I wonder what the incidence of positive culture of the same kind of streptococcus is in patients here when they don't have rheumatic fever? DR. B. F. MASSELL. One series indicates that the average nonrheumatic child, not receiving penicillin, will have 1 streptococcal infection every 14 to 15 months. DR. D. H. CARVER. If yOU count one colony or more as a positive, 35 per cent of the general school population in this area will harbor streptococci. The difficulty has been to know what number of streptococci might be significant. DR. LEVlNE. I don't know whether you have to have a lot of streptococci around to be sick. i do know that children may harbor fairly many streptococci and still seem well. Well, the child did well for 4 years after discharge to a foster
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home. However, the h e a r t continued to be enlarged, and we are not clearly told t h a t the cardiac m u r m u r s changed. I suspect that this means t h a t at least the diastolic m u r m u r remained. Now, after return to his own family and a certain loss of medical control, we come to his final admission. Can anyone tell me w h a t m o n t h of the year this was? DR. CARVER. November. DR. LEVINE. W h e n was the first illness, at the age of 3? DR, CARVER. I n February. DR. LEVlNE. T h e peak m o n t h for acute rheumatic fever used to be M a r c h - - " T h e Ides of M a r c h . " T h e mothers of rheumatic children used to say: " I f only M a r y can get through the Spring, she'll be all right." I think t h a t this still holds for first and recurrent attacks. W h a t is there about M a r c h for children who are vulnerable to rheumatic fever? I would refer you to a p a p e r published m a n y years ago by W a d e H. Brown. 1 He was studying experimental syphilis in animals and found 100 per cent "takes" during certain m o n t h s and only 50 per cent in other months. He studied the various organ weights at different months of the year, a n d it intrigued me t h a t in March, the endocrine system was at low ebb. I n particular, h e found low weights of thyroid, adrenal, and pituitary glands. M y opinion, m a n y years ago, was t h a t there is some relationship between the endocrine system and vulnerability to infections and other diseases, and this may have something to do with the periodicity of rheumatic fever in our population. Thirty-two years ago I wrote on a clinical concept of r h e u m a t i c fever, saying: " T h e r e is another phase of the problem w h i c h I feel has not received sufficient attention. I refer to the condition of the host or patient, the internal environm e n t in which the disease develops, and especially . . . of the role of the glands of internal secretion." Now, we know t h a t in a military c a m p of 10,000, there may be 1,000 cases of sore throat, and a certain n u m b e r of new cases of r h e u m a t i c fever. O f 1,000 with sore throats, 100 m a y develop r h e u m a t i c fever, about one fourth of w h o m h a d r h e u m a t i c fever before or have a family history of r h e u m a t i c fever. W h y are these few so vulnerable to an agent w h i c h changes little, if at all, from host to host? Speculation bids m e to urge an endocrinologist to attack this problem. I n any event, the patient returned, severely i11, at 16 years of age, with a characteristic pleuritis
April 1963
Fig. I. Massive enlargement of the cardiac silhouette and evidence of ptilmonary congestion at 4 years of age.
Fig. 2. At the time of final admission there is an enlarged cardiac silhouette and some evidence of pulmonary congestion.
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and pericarditis, both pretty common in rheumatic fever. The pleuritis occurs more often on the left than on the right, and pleural or pericardial effusion occurs in the more violent types of rheumatic affection. Patients are more comfortable sitting up when they have pericarditis; some children even like to lean forward. The high fever disturbs me, but the rash goes with rheumatic fever. The precordial prominence, nowadays, no longer necessarily means congenital heart disease, but only that cardiac enlargement probably developed early in life. I am surprised, too, that the heart sounds are not decreased. Shallow respirations suggest decreased expansion. I have a spirometer in my office that I bought in 1919; it cost 10 dollars then, and upkeep is about 10 cents a year, plus a little water now and then. It takes about 30 seconds to 1 minute to get a measurement of vital capacity. I think this should be done on every patient one sees. I get more help from it than from an electrocardiogram when I follow a patient with rheumatic vaIvular disease, in whom dyspnea is the threat, or when I follow a case of congestive failure. In an adult, if a normal vital capacity is found
Fig. 3. Five days before death there are patchy densities throughout the lungs, particularly involving the left upper lobe.
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every year, you rest easy, but if there is a progressive decrease in the reading, the patient needs help--nowadays, possibly cardiac surgery. To return to the problems at hand. I am surprised that the liver was not felt. I take it that no clubbing or petechiae were observed. Are the x-rays here? DR. G. B. C. HAnRIS. We have a series of films. The first is at 4 years of age. The cardiac silhouette is huge, with passive congestion of the Iungs (Fig. 1). DR. LEVINE. I wonder how much pericardial fluid contributes to that picture? DR. HARRIS. Later on, the heart is only slightly enlarged, with left ventricular contour and normal pulmonary vasculature. During the last admission the heart is somewhat larger, again with evidence of passive congestion (Fig. 2). A subsequent film shows hazy density in the left upper lobe, which persists and may represent transudate or exudate (Fig. 3). DR. LEVINE. It is no surprise that I conclude that the patient had rheumatic fever and rheumatic carditis. The things that are odd are the fever of 104 ~ F., and that more evidence of pulmonary edema was not found clinically at a time when he was so ill. However, I do not think that the patient had bacterial endocarditis, and doubt a coexistent congenital lesion. However, an element of renal insufficiency may be present. I like to make comparisons between syphilis and rheumatic fever. The spirochete may produce marked cutaneous lesions, may go to the aorta to develop an aneurysm, or may produce tabes dorsalis. Many tabetic individuals never had cutaneous lesions. It is, however, the same spirochete, but the host and his reactions are different. The same streptococcus produces a marked carditis in one, and marked joint pain in another instance of rheumatic fever. We used to see a good many children who had recurrent rheumatic fever year after year, but nothing much happened to the heart. In fact, I suspect that those with mild recurrent attacks do better, as far as the heart is concerned, than those who have one severe attack or transient episodes with complete freedom between times. DR. DAVID D. RUTSTEIN. T h e serious aspects of this illness don't come through in the written record. When he came to the clinic, the main symptom was that of erythema marginatum. We were puzzled by the pulmonary findings on x-ray which seemed disproportionate to the other signs and symptoms until clear-cut joint involvement
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April 1963
Fig. 4. Myocardium. There is an Aschoff nodule at upper left, and a band of scar on the right. (Hematoxylin and eosin stain. Original magnification • developed rather late. The question we could not answer, to our own satisfaction, was whether the pulmonary condition represented congestive failure, primary atypical pneumonia, or some other problem. As time went on it seemed less and less likely to me that this was congestive failure since we never could find evidence of right-sided failure which often accompanies acute rheumatic carditis of severe degree. DR. B. F. MASSELL. I agree that the pulmonary aspect of the problem was puzzling. But when, after omission of aspirin, the joint symptoms developed and the diagnosis of rheumatic fever was even clearer, I tended to think of the pulmonary lesion as part of the rheumatic fever process and thought a second diagnosis was unnecessary. This was almost 5 days before death when we were not aware how seriously ill he was, but this soon became obvious. DR. FARBER. We might poll our various colleagues. DR. CARVER. The house officers and third year medical students favored recurrent rheumatic fever and rheumatic carditis. The fourth year students, in addition, suspected superimposed acute bacterial endocarditis. DR. MASSELL. Dr. Michael, in our laboratory, demonstrated that this boy developed antibodies to Type 20A "streptococcus, isolated from the throat, whereas these organisms had not been present previously.
DR. GORDON F. VAWTER. The histologic counterpart of a fading abdominal rash consists of moderate perivascular mixed mononuclear and round cell infiltration; the polymorphonuclear infiltrate and fibrinoid degeneration of acute erythema marginatum, was not present in available sections but the findings might well represent the subsiding phase of such a process or represent a mild form of involvement. There were no evidences of right-sided heart failure. Peripheral edema, serous fluid collection, and marked visceral congestion were not noted. The liver was of normal weight and showed only minimal congestion. There was evidence of healed and acute rheumatic carditis involving: (1) thickened, hyperemic visceral and parietal pericardiums which were studded with tiny glistening opaque nodules; (2) aortic and mitral valves and left atrial endocardium (MacCallum's patch), and (3) myocardium (Fig. 4) in association with microscopic phlebitis and an acute panarteritis of intramyoeardial vessels, a rare but significant lesion (Fig. 5). The Aschoff bodies are of subacute type and similar perivascular adventitial reactions were found in periesophageal connective tissue, in diaphragm, and even a single focus in the small bowel. The heart was over twice normal weight, with left atrial enlargement and left ventricular hypertrophy and moderate dilatation. The cusps of
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Fig. 5. Myocardium. There is inflammation of adventitia and intima of the artery. (Hematoxylin and eosin stain. Original magnification • the mitral valve were moderately thickened, with somewhat rolled edges, thick ehordae tendineae, little or no commissural contraction, and the appositional surfaces were the site of rows of tiny active rheumatic vegetations. De. LEVINE. Was this a stenotic valve? DR. VAWTER, Our impression was that this valve would be predominantly insufficient if any
important functional defect were present. The ring of the aortic valve was dilated to twice the circumference of the pulmonic valve, the precursor of insufficiency. However, the cusps, while somewhat thickened, showed no commissural fusion and only minimal rolling and retraction of free margins so that we surmised that the valve was still competent. An acute rheumatic vegeta-
Fig. 6. Lung. Air spaces are filled with edema fluid, and there is an increase in cellularity, principally in relation to alveolar septal walls. (Hematoxylin and eosin stain. Original magnification •
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Fig. 7. A largely mononuclear response, in which many of the cells bear a resemblance to plasma cells is shown. (Hematoxylin and eosin stain. Original magnification x410.) tion involved one cusp. There was no evidence of bacterial endocarditis. The rubbery, dark red, essentially airless lungs were 3 times heavier than normal, and dilated lymphatics were palpable over the pleural surfaces. These changes were most severe in the left upper lobe, but were present everywhere in varying degree. Microscopically there was an extensive pneumonic process, characterized by sloughing o f bronchial epithelium, outpouring of edema fluid, and a cellular response (Fig. 6). The cellular response consists of large, hyperchromatic cells at the level of alveolar septa, of mononuclear or plasmacytoid characteristics, or cells apparently representing modified alveolar lining cells (Fig. 7). This type of cellular response is unusual, in my experience, in simple pulmonary edema, even of subacute duration. Many alveolar walls are lined by hyaline membranes which, by special staining, appear not to contain appreciable amounts of fibrin: indeed, there is very little fibrin anywhere. Active adventitial granulomas or phlebitis were not seen in the lung, apart from considerable perivascular edema and inconspicuous cellular infiltration. Since viral injury has been associated with similar pulmonary lesions, a great many studies were undertaken. There was no rise in antibody titer in acute and convalescent sera for influenza A or B, or adenovirus. Dr. Monroe D. Eaton did not recover his infectious factor from this lung. Additional cultures for virug, performed by Dr. Carver, were negative. At autopsy, bacterial cultures gave no growth. We are left, therefore, with a pneumonitis
April 1963
without demonstrated infectious cause, with features unusual for simple subacute congestion and edema. The pattern of this lethal lesion, we think, fits with acute rheumatic pneumonitis, as distinct from the chronic or healed lesions often described as typical rheumatic pneumonitisY, ~ The concept of rheumatic pneumonitis has remained controversiaI since authoritative observers have denied its specificity or existence, but for the reasons outlined above, we felt that this unusual lesion may well represent such a process. ~ The kidneys, adrenal glands, and thyroid gland were anatomically unremarkable. The anatomic diagnoses are: recurrent rheumatic [ever with erythema marginatum, healed and active rheumatic pericarditis, myocarditis, and vaIvulitis, involving mitral and aortic valves, and acute rheumatic pneumonitis. DR. FARBER. Dr. Janeway? DR. CHARLES A. JANEWAY. T w o things. Obviously this patient had severe rheumatic fever and it is well to remember that this can still occur. Second, it is interesting that this boy was well cared for while he was in the foster home, but that this preventable death occurred while he lived with his own family as an adolescent. Apparently the family attitude and the problems of adolescent adjustment to the "differentness" imposed by the need for continued drug therapy interfered with the program of prophylactic penicillin and visits to the clinic. These are difficult problems in this age group. We might admit to ourselves that were we to treat this boy again, we might proceed differently. Dr. Marian Ropes and others have stressed that it is most unwise to abruptly terminate any sort of therapy in patients with any disease of rheumatic or collagen type since there may follow a clinical relapse or exaggeration of the process. Perhaps this happened here, and hindsight suggests that the salicylates should have been tapered gradually and, at the same time, steroid therapy should have been instituted. I would ask Dr. Vawter whether any cause for a fairly sudden death was found. DR. VaWTE~. We found no dramatic lesion, such as an embolus or hemorrhage in a critical site. DR. L~VlNE. It worries and intrigues me that I used to see Sydenham's chorea in children and "~For an interesting discussion of pulmonary complications of rheumatic fever and rheumatic heart disease, published subsequent to this discussion, see S. E. Moolten: Am. J. Med. 33: 421, 1962.
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teenagers, but never after the age of 21, except in 2 young women. The thing these women had in common was that they were pregnant. Why should a woman who is pregnant develop chorea? Why did the streptococcus, after waiting outside the door all these years, suddenly jump in at the moment of pregnancy? Here we are back again with endocrine problems, it seems.
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REFERENCES 1. Brown, Wade H.: Constitutional variation and susceptibility to disease, Arch. Int. Med. 44: 625, 1929. 2. Epstein, E. Z., and Greenspan, E. B.: Rheumatic pneumonia, Arch. Int. Med. 68: 1074, 1941. 3. Herbert, P. A., and Manges, W. E.: The Masson body in rheumatic fever, Am.J. Path. 21: 741, 1945.