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Fungal (Candida) endocarditis following open-heart surgery
Fungal (Candida) endocarditis following open-heart surgery A. R. W. Climie, M.D., and N. Rachmaninoff, M.D., Detroit, Mich.
l h e initial description of fungal endocar ditis appeared in 1940 1 and was soon suc ceeded by additional reports in all of which the infection had occurred in drug addicts following self-administered intravenous in jections.2' 3 By 1958 Merchant and his as sociates4 were able to collect a total of 34 cases of mycotic endocarditis from the literature, one third being caused by one of the species of Candida, and lesser numbers by Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Aspergillus, and Mucor. Many of the latter infections were secondary to other debilitating disease, or steroid and antimetabolite therapy. With the advent of open-heart surgery it has become apparent that postoperative en docarditis is a complication of considerable significance. In a series of 2,263 cardiac operations for congenital or acquired dis ease, Denton and his colleagues5 found 20 cases (0.88 per cent) of post-surgical bac terial endocarditis, whereas Koiwai and Nahas6 found an incidence of 1 per cent in 1,190 cases. Fungal endocarditis is of less common occurrence and is sufficiently rare to prohibit the meaningful determination of an incidence rate within any one institu tion. The first patient with postoperative mycotic endocarditis was described by From the Department of Pathology, Harper Hospital, 3825 Brush Street, Detroit, Mich. 48201. Received for publication April 5, 1965.
Koelle and Pastor7 in 1956, and since then additional publications have brought the total of cases to 17. Fourteen of these were reviewed in 1963 by Jamshidi and his coworkers8 who found that 9 were due to Candida albicans and 5 to other Candida species. More recent reports include another case of Candida albicans endocarditis,9 the first example of Aspergillus endocarditis fol lowing cardiac surgery,10 and the first re corded case of endocarditis due to a fungus of the genus Paecilomyces.11 The present two reports of mycotic endocarditis follow ing open-heart surgery bring the total to 19, the etiologic agent being Candida albicans in 10, another Candida species in 7, and Aspergillus and Paecilomyces in 1 each. Case reports CASE 1. The patient was a 32-year-old white man who was admitted to the hospital Nov. 15, 1962, with a complaint of progressively increasing dyspnea on exertion. When he was 14 years of age he had had an attack of rheumatic fever, after which he was told he had a damaged valve in his heart. Prior cardiac catheterization had indi cated the presence of aortic stenosis and insuffi ciency. He had been treated with digitalis, low salt diet, and 0.5 Gm. of sulfonamide daily. On physical examination, blood pressure was 148/48 mm. Hg. Pulse pressure was increased and the heart was slightly enlarged to the left. There was a Grade 3 blowing diastolic murmur, loudest at the left sternal border. The remainder of the physical examination was not remarkable. Blood count, urinalysis, and blood chemistries were within normal limits. Five days after admission, an aortic valvulo-
43 1
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Thoracic and Cardiovascular Surgery
plasty was performed with the use of cardiopulmonary bypass and hypothermia. The noncoronary cusp of the valve was almost completely dis placed into the ventricular cavity, and was posi tioned below the level of the other two cusps. This cusp was moderately calcified as was the commissure between the posterior and the left cusps. Repair consisted of elevating the noncoronary cusp and suturing it to the right cusp, con verting the valve into a bicuspid form which ap peared to be fairly competent. The postoperative course was satisfactory apart from an intermittent fever reaching 100.6° F. This gradually responded to antibiotics and the patient was discharged on Jan. 4, 1963. Second admission. The patient was re-admitted on May 7, 1964. He had been well for the first year after operation, but 6 months prior to this admission he noted development of unusual fa tigue accompanied by almost continuous tachy cardia. On physical examination, blood pressure was 160/44 mm. Hg and pulse was 110 per minute and of Corrigan type. A Grade 4 diastolic murmur was heard at the right sternal border with radiation toward the apex. A systolic mur mur was also present at the left sternal border. The heart was enlarged to the left and the maxi mum impulse was palpable at the mid-clavicular line. The remainder of the examination was not remarkable. Routine laboratory data were within normal limits. Because of the severe symptomatology, aortic valvulotomy was performed with the use of cardiopulmonary bypass with hypothermia. The status of the valve had reverted to that prior to the original operation. The entire diseased valve was excised and a homologous aortic valve was trans planted. This appeared to function competently and the operation was terminated. A postoperative fever developed, with the temperature fluctuating up to 102° F. daily. There was a leukocytosis of 24,600 per cubic millimeter with an absolute neutrophiiia. Splenomegaly developed 35 days postoperatively. From a total of 15 blood cultures, four taken 44 and 46 days after operation, re
vealed a growth of Candida species, not albicans. At this time the patient was started on amphotericin B. Other postoperative antibiotic therapy is shown in Fig. 1. Fifty-one days following operation, the patient developed the first of a series of episodes of cardiac arrest and ventricular fibrillation which at first responded to cardiac massage and defibrillation. However, signs of cardiac failure progressed and death occurred on July 14, 1964, 62 days postoperatively. Autopsy findings. The lungs were expanded and edematous, weighing 800 and 700 grams. There were bilateral pleural effusions, 1,000 ml. in each cavity. The heart weighed 710 grams. The cir cumference of the mitral valve was 9 cm. and the cusps were slightly thickened. The right cusp of the aortic valve was replaced by a grayish-yellow bulky vegetation measuring 3.5 by 3.0 by 1.5 cm. (Fig. 2). In certain areas, the vegetation was friable and granular. No infarcts were found in any organs, although permission to examine the brain was denied. Microscopically, the mitral valve showed flbrosis and some vascularization. The aortic ring was calcified. The vegetation on the aortic valve consisted of a colony of Candida growing on and through the necrotic homograft. The bulbous portion at the tip of the vegetation consisted of a tangled mass of pseudohyphae, many of which showed localized swellings. At the attachment of the homograft to the aorta there was a severe inflammatory reaction characterized by a neutrophilic infiltrate and micro-abscess formation. Yeast forms were found in the ab scesses which extended through the aortic wall into the adjacent epicardial fat and atrial wall. The microscopic appearance of the fungus was in every way characteristic of Candida (Fig. 3). CASE 2. The patient was a 38-year-old white man who was admitted to the hospital on May 24, 1964, as an emergency case because of in capacitating dyspnea. He had been known to have valvular heart disease for at least 3 years, and a clinical diagnosis of aortic stenosis and, possible, mitral stenosis had been made. Cardiac catheterization had showed a differential pressure at the
Drug Daily POM Procdrn PwkJIin 4,800,000 t»«. Streptomycin 2.0 grama liosons 1.0 grams ProeapNin Sogrom* CMoraiTftiifllcol 1.0 grams MystscKn F
CASE 2
=
AppwtdKtomy
Post-optralfv* Dayt
Fig. 1. Antibiotics administered postoperatively.
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aortic valve of approximately 100 ml. of mercury. Physical examination showed a man with ex treme dyspnea, cervical venous distension, enlarge ment and tenderness of the liver, and minimal peripheral edema. The blood pressure was 100/70 mm. Hg, and the pulse was 108 per minute. Clini cally, the heart was slightly enlarged to the left, and there was a Grade 3 systolic murmur radiat ing into the neck. Moist râles were present
Fig. 2. Case 1. Aortic valve shows massive vege tation on right cusp of homograft.
throughout both lung fields. Admission blood count, urinalysis, and blood urea nitrogen were within normal limits. A roentgenogram of the chest showed cardiac enlargement, especially of the left atrium, and prominent vascular markings were present in both lung fields with small bi lateral pleural effusions. On June 4, 1964, a severely stenotic and calci fied aortic valve was removed with the use of cardiopulmonary bypass and hypothermia, and a homologous aortic valve was sutured in place. At the completion of the procedure the cardiac ac tion was regular and strong. A day later a chest x-ray film showed gross enlargement of the cardiac silhouette compared with the preoperative examination, but the lungs were well aerated. By July 9, 35 days postoperatively, the heart had decreased to normal in size and configuration. On that day the patient vomited, and complained of cramping abdominal pain. The temperature re mained 98.6° F., but there was slight tenderness in the right iliac quadrant. Leukocyte count was 9,200 per cubic millimeter, and urinalysis was not remarkable. By the next day the leukocyte count had risen to 13,200 per cubic millimeter, with an absolute neutrophilia. Tenderness, guarding, and rebound tenderness were noted in the right lower quadrant, and a diagnosis of acute appendicitis was made. An appendectomy was performed under local anesthesia, but the appendix did not appear abnormal and, on histologie examination, no evidence of inflammation was found. Three
Fig. 3. Case 1. Solid growth of Candida pseudomycelia at edge of vegetation. (Gomori methenamine silver xl62; reduced %.)
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days after the appendectomy, on July 13, the pa tient complained of pain in the left leg. Popliteal and posterior tibial pulsations were absent, al though a femoral pulse was palpable. Under local anesthesia an embolus was removed from the femoral artery. Histologie examination of the em bolus showed the presence of pseudomycelia and spores typical of the morphology of Candida spe cies. A diagnosis of fungal endocarditis was made.
Fig. 4. Case 2. Aortic valve shows bulky vegeta tion on left cusp of homograft.
Thereafter the temperature fluctuated daily to 101.6° F., but 9 blood cultures taken on subse quent days remained sterile. Antibiotic therapy is summarized in Fig. 1. Mysteclin-F (tetracyclineamphotericin B), 250 mg. four limes daily, was instituted 9 days after the open-heart surgery and continued until death. Ten days after embolectomy a systolic murmur was heard down the left sternal border which had not been present before. Death took place on Aug. 11, 1964, 70 days after ad mission and 59 days after the open-heart surgery. Autopsy findings. The lungs were edematous and there was a bilateral hydrothorax of 500 ml. of clear fluid. The heart weighed 750 grams and there was concentric hypertrophy of the left ventricle. The cusps of the mitral valve were thickened as were the chordae tendineae. The aortic valve had a circumference of 7 cm. and residual particles of calcium were present at the annulus. The left leaflet of the homograft was the site of a grayish yellow, bulky vegetation measuring 3.5 by 2.0 by 1.5 cm. (Fig. 4). Infarcts were present in the spleen and kidneys. Candida species (not albicans) was cultured from the vegetation on the aortic valve. Micro scopically, the mitral valve showed fibrous thickening without vascularization, and the aortic ring contained calcific deposits. The affected cusp of the homograft was largely necrotic and replaced by a mass of fibrin con-
ΗΚ&ΒΛ^&ΙΤΒΝΪ
*Λ
Fig. 5. Case 2. Tangled pseudomycelia of Candida at edge of vegetation. (Gomori methenamine silver xl62; reduced %.)
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taining pseudohyphae. The outer surface of the vegetation was an almost pure colony of Candida, but growth was sparser in the deeper areas. Many of the pseudophyphae showed bul bous swellings and the over-all appearance of the organism was characteristic of Candida species (Fig. 5). Abscesses were present in the aortic ring and adjacent aortic wall and epicardial tissue. No organisms were identified in the infarcts of the spleen or right kidney.
Discussion It seems probable that the incidence of mycotic endocarditis following open-heart surgery will increase until a satisfactory fungicidal agent becomes available for ther apy. It is, therefore, important that etiologic factors, clinical and pathologic features, and therapeutic procedures be reviewed in the hope that a better understanding of the dis ease may result. Clinical features. The literature contains reports of 19 patients with fungal endocar ditis following cardiac surgery. 716 The age of these patients ranged from 22 to 48, with an average of 34 years, and all but 4 were males. Eighteen of the 19 patients had ac quired heart disease, the aortic and mitral valves each being affected in 9 cases. The interval from the surgical procedure to the first symptom definitely attributable to endo carditis ranged from 12 days to 6 months. Fever was a constant finding and usually first brought the infection to attention. There was rarely a significant change in the nature of a pre-existing cardiac murmur. A char acteristic feature was embolization to rela tively large arteries, such as those in the legs. This occurred in 15 of 19 cases and is due to breaking off of portions of the bulky vegetation seen in mycotic endocar ditis. Not only is this feature clinically useful in the differential diagnosis between bac terial and mycotic endocarditis but, in 2 cases*·13 in addition to our Case 2, mycelia have been identified histologically in the thrombus removed at embolectomy, thus establishing the diagnosis. In retrospect, it is probable that the episode diagnosed as acute appendicitis in our Case 2 was actu ally the initial manifestation of peripheral embolization. Other clinical features are in-
distinguishable from those of bacterial endo carditis and include petechiae, splenomeg aly, and cardiac failure. Blood cultures were positive for the fungus in 14 of the 19 patients, but in several the report was not available until after death. The growth of fungi from the blood in this type of case must always be considered of potential significance and must not be discarded from consideration as representing accidental contamination of blood or culture medium. This is especially important in view of the fact that 9 of the 19 cases of endocarditis were due to fungi not generally considered pathogenic, par ticularly Candida species other than albicans. In our second case, negative blood cultures may be accounted for by the ad ministration of Mysteclin-F from the ninth postoperative day. The fact that a positive culture was obtained from the vegetation at autopsy presumably means that the amphotericin B satisfactorily sterilized the blood but was unable to penetrate the val vular lesion in sufficient concentration to be effective. Predisposing factors. Concurrent or prior antibiotic therapy has been a feature of many cases of mycotic endocarditis. In 14 of the 19 patients reviewed, antibiotics had been administered either preoperatively or postoperative]y, frequently in massive doses. Penicillin and streptomycin were most com monly used, but chloramphenicol, tetracycline, and erythromycin were also given to a few patients. Soler-Bechara and his as sociates17 state that in 28 (76 per cent) of 37 cases of Candida endocarditis in the literature there had been prior antibiotic therapy. A similar connection has been noted between other systemic fungal infec tions and antibiotic treatment,18 and it has been suggested that the drugs destroy in testinal bacteria which otherwise compete with fungi for the available food supply, thus preventing overgrowth of the latter.10 Huppert and his co-workers-0 deny this pathogenetic mechanism as they believe the change in intestinal bacterial flora following antibiotic therapy is qualitative rather than
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Thoracic and Cardiovascular Surgery
quantitative. They speculate that antibiotics may destroy certain bacteria which normally exert a restrictive or antibiotic effect on Candida, thus allowing Candida to grow unchecked. Apart from these speculations there is objective evidence that certain antibiotics actually stimulate the growth of Candida. Foley and Winter21 demonstrated that peni cillin enhances the growth of Candida spe cies in chick embryos and in rabbits. Their results with in vitro testing suggested a simi lar stimulating action on the part of peni cillin, but other investigators 19 ' 20 were un able to find any enhancement of growth of Candida albicans following addition of penicillin, chloramphenicol, or streptomycin to cultures. It seems clear, therefore, that there is a definite association between prior antibiotic therapy and mycotic endocarditis but the nature of the relationship remains obscure. Unfortunately, in many cases, mas sive antibiotic therapy is instituted whenever a diagnosis of endocarditis is suspected, and in the rare case, due to a fungus, the treat ment may potentiate the growth of the organism. Other factors which undoubtedly play an etiologic role in postoperative endocarditis, bacterial or fungal, include the presence of a raw surface and foreign material at the site of surgery which act as loci for develop ment of a thrombus which then becomes secondarily infected. Source of infection. Candida is virtually a constant inhibitant of the intestinal tract and it is possible that under appropriate circumstances it may gain entry to the cir culation. Other sources include the pump oxygenator, from which Candida has been cultured in at least 2 instances,15 and intra venous needles or catheters.17 Treatment. Treatment has been quite un satisfactory. All 19 patients described in the literature died of their disease, in spite of intensive treatment with amphotericin B and other mycostatic drugs in those patients in whom the diagnosis was made before death. Until more potent and safer fungicidal drugs become available the only hope
for these patients is surgical removal of the vegetation. This has been accomplished suc cessfully by Kay22 in a patient with Candida tricuspid endocarditis, with an apparent 6 months' cure. The infection did not follow open-heart surgery but was related to an interventricular septal defect. Persellin13 at tempted surgical removal of a Candida vege tation which developed following aortic valvulotomy, but the patient died shortly there after. Summary This paper describes 2 additional patients with mycotic endocarditis which developed after open-heart surgery and brings to 19 the number of such cases recorded. The clinical features of the 19 cases are reviewed and emphasis is placed on the constancy of fever and the frequency of embolization to large arteries as large fragments of the bulky vegetations are dislodged into the cir culation. Blood cultures during life will be positive in approximately 75 per cent of cases. Predisposing factors are discussed, the most important of which appears to be antecedent or concurrent administration of large doses of antibiotics, particularly peni cillin and streptomycin. Therapy has proved unsatisfactory in all postoperative cases, but surgical removal of the vegetation has re sulted in apparent cure in 1 patient with a spontaneous infection. REFERENCES 1 Joachim, H., and Polayes, S. H.: Sub-acute Endocarditis With Systemic Mycosis (Monilia), J. A. M. A. 115: 205-208, 1940. 2 Wikler, A., et al.: Mycotic Endocarditis. Report of a Case, J. A. M. A. 119: 333-336, 1942. 3 Zimmerman, L. E.: Candida and Aspergillus Endocarditis: With Comments on the Role of Antibiotics in Dissemination of Fungus Disease, Arch. Path. 50: 591-605, 1950. 4 Merchant, R. K., et al.: Fungal Endocarditis: Review of the Literature and Report of 3 Cases, Ann. Int. Med. 48: 242-266, 1958. 5 Denton, C , et al.: Bacterial Endocarditis Following Cardiac Surgery, Circulation 15: 525-531, 1957. 6 Koiwai, E. K., and Nahas, H. C : Subacute
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7
8
9
10
Bacterial Endocarditis Following Cardiac Surgery, Arch. Surg. 73: 272-278, 1956. Koelle, W. A., and Pastor, B. H.: Candida Albicans Endocarditis After Aortic Valvulotomy, New England J. Med. 225: 997-999, 1956. Jamshidi, A., Pope, R. H., and Friedman, N . H.: Fungal Endocarditis Complicating Cardiac Surgery, Arch. Int. Med. 112: 370-376, 1963. Simmons, N. A., and Turner, P.: Candida Endocarditis After Cardiac Surgery, Brit. M. J. 2: 1041-1042, 1963. Newman, W. H., and Cordell, A. R.: Aspergillus Endocarditis After Open-Heart Surgery. Report of a Case and Review of Literature, J. THORACIC & CARDIOVAS. SURG. 48:
11
12
13
14
652-660,
1964. Uys, C. J., et al.: Endocarditis Following Cardiac Surgery Due to the Fungus Paecilomyces, S. Afr. Med. J. 37: 1276-1280, 1963. Louria, D. B., and Dineen, P.: Amphotericin B in the Treatment of Disseminated Moniliasis, J. A. M. A. 174: 273-280, 1960. Persellin, R. H., Haring, O. M., and Lewis, F. J.: Fungal Endocarditis Following Cardiac Surgery, Ann. Int. Med. 54: 127-134, 1961. Hyun, B. H., and Collier, F . C : Mycotic Endocarditis Following Intracardiac Opera tions. Report of Four Cases, New England J. Med. 263: 1339-1341, 1961.
15 Andriole, V. T., et al.: Candida Endocarditis. Clinical and Pathologic Studies, Am. J. Med. 32: 251-285, 1962. 16 Sänger, P. W., et al.: Candida Infection as a Complication of Heart Surgery, J. A. M. A. 181: 88-91, 1962. 17 Soler-Bechara, J., et al.: Candida Endocarditis, Am. J. Cardiol. 13: 820-824, 1964. 18 Brown, C , Jr., et al.: Fatal Fungus Infections Complicating Antibiotic Therapy, J. A. M. A. 152: 206-207, 1953. 19 Woods, J. W., Manning, I. H., and Patterson, C. W.: Monilial Infections Complicating the Therapeutic Use of Antibiotics, J. A. M. A. 145: 207-211, 1951. 20 Huppert, M., MacPherson, D . A., and Cazin, J.: Pathogenesis of Candida Albicans Infection Following Antibiotic Therapy. I. The Effect of Antibiotics on the Growth of Candida Albicans, J. Bact. 65: 171-176, 1953. 21 Foley, G. E., and Winter, W. D., Jr.: In creased Mortality Following Penicillin Therapy of Chick Embryos Infected With Candida Albicans var. Stellatoidea, J. Infect. Dis. 85: 268-274, 1949. 22 Kay, I. H., et al.: Surgical Cure of Candida Albicans Endocarditis With Open-Heart Surgery, New England J. Med. 264: 907-910, 1961.
l h e initial description of fungal endocar ditis appeared in 1940 1 and was soon suc ceeded by additional reports in all of which the infection had occurred in drug addicts following self-administered intravenous in jections.2' 3 By 1958 Merchant and his as sociates4 were able to collect a total of 34 cases of mycotic endocarditis from the literature, one third being caused by one of the species of Candida, and lesser numbers by Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Aspergillus, and Mucor. Many of the latter infections were secondary to other debilitating disease, or steroid and antimetabolite therapy. With the advent of open-heart surgery it has become apparent that postoperative en docarditis is a complication of considerable significance. In a series of 2,263 cardiac operations for congenital or acquired dis ease, Denton and his colleagues5 found 20 cases (0.88 per cent) of post-surgical bac terial endocarditis, whereas Koiwai and Nahas6 found an incidence of 1 per cent in 1,190 cases. Fungal endocarditis is of less common occurrence and is sufficiently rare to prohibit the meaningful determination of an incidence rate within any one institu tion. The first patient with postoperative mycotic endocarditis was described by From the Department of Pathology, Harper Hospital, 3825 Brush Street, Detroit, Mich. 48201. Received for publication April 5, 1965.
Koelle and Pastor7 in 1956, and since then additional publications have brought the total of cases to 17. Fourteen of these were reviewed in 1963 by Jamshidi and his coworkers8 who found that 9 were due to Candida albicans and 5 to other Candida species. More recent reports include another case of Candida albicans endocarditis,9 the first example of Aspergillus endocarditis fol lowing cardiac surgery,10 and the first re corded case of endocarditis due to a fungus of the genus Paecilomyces.11 The present two reports of mycotic endocarditis follow ing open-heart surgery bring the total to 19, the etiologic agent being Candida albicans in 10, another Candida species in 7, and Aspergillus and Paecilomyces in 1 each. Case reports CASE 1. The patient was a 32-year-old white man who was admitted to the hospital Nov. 15, 1962, with a complaint of progressively increasing dyspnea on exertion. When he was 14 years of age he had had an attack of rheumatic fever, after which he was told he had a damaged valve in his heart. Prior cardiac catheterization had indi cated the presence of aortic stenosis and insuffi ciency. He had been treated with digitalis, low salt diet, and 0.5 Gm. of sulfonamide daily. On physical examination, blood pressure was 148/48 mm. Hg. Pulse pressure was increased and the heart was slightly enlarged to the left. There was a Grade 3 blowing diastolic murmur, loudest at the left sternal border. The remainder of the physical examination was not remarkable. Blood count, urinalysis, and blood chemistries were within normal limits. Five days after admission, an aortic valvulo-
43 1
Journal of
4 32
Climie and Rachmaninoff
Thoracic and Cardiovascular Surgery
plasty was performed with the use of cardiopulmonary bypass and hypothermia. The noncoronary cusp of the valve was almost completely dis placed into the ventricular cavity, and was posi tioned below the level of the other two cusps. This cusp was moderately calcified as was the commissure between the posterior and the left cusps. Repair consisted of elevating the noncoronary cusp and suturing it to the right cusp, con verting the valve into a bicuspid form which ap peared to be fairly competent. The postoperative course was satisfactory apart from an intermittent fever reaching 100.6° F. This gradually responded to antibiotics and the patient was discharged on Jan. 4, 1963. Second admission. The patient was re-admitted on May 7, 1964. He had been well for the first year after operation, but 6 months prior to this admission he noted development of unusual fa tigue accompanied by almost continuous tachy cardia. On physical examination, blood pressure was 160/44 mm. Hg and pulse was 110 per minute and of Corrigan type. A Grade 4 diastolic murmur was heard at the right sternal border with radiation toward the apex. A systolic mur mur was also present at the left sternal border. The heart was enlarged to the left and the maxi mum impulse was palpable at the mid-clavicular line. The remainder of the examination was not remarkable. Routine laboratory data were within normal limits. Because of the severe symptomatology, aortic valvulotomy was performed with the use of cardiopulmonary bypass with hypothermia. The status of the valve had reverted to that prior to the original operation. The entire diseased valve was excised and a homologous aortic valve was trans planted. This appeared to function competently and the operation was terminated. A postoperative fever developed, with the temperature fluctuating up to 102° F. daily. There was a leukocytosis of 24,600 per cubic millimeter with an absolute neutrophiiia. Splenomegaly developed 35 days postoperatively. From a total of 15 blood cultures, four taken 44 and 46 days after operation, re
vealed a growth of Candida species, not albicans. At this time the patient was started on amphotericin B. Other postoperative antibiotic therapy is shown in Fig. 1. Fifty-one days following operation, the patient developed the first of a series of episodes of cardiac arrest and ventricular fibrillation which at first responded to cardiac massage and defibrillation. However, signs of cardiac failure progressed and death occurred on July 14, 1964, 62 days postoperatively. Autopsy findings. The lungs were expanded and edematous, weighing 800 and 700 grams. There were bilateral pleural effusions, 1,000 ml. in each cavity. The heart weighed 710 grams. The cir cumference of the mitral valve was 9 cm. and the cusps were slightly thickened. The right cusp of the aortic valve was replaced by a grayish-yellow bulky vegetation measuring 3.5 by 3.0 by 1.5 cm. (Fig. 2). In certain areas, the vegetation was friable and granular. No infarcts were found in any organs, although permission to examine the brain was denied. Microscopically, the mitral valve showed flbrosis and some vascularization. The aortic ring was calcified. The vegetation on the aortic valve consisted of a colony of Candida growing on and through the necrotic homograft. The bulbous portion at the tip of the vegetation consisted of a tangled mass of pseudohyphae, many of which showed localized swellings. At the attachment of the homograft to the aorta there was a severe inflammatory reaction characterized by a neutrophilic infiltrate and micro-abscess formation. Yeast forms were found in the ab scesses which extended through the aortic wall into the adjacent epicardial fat and atrial wall. The microscopic appearance of the fungus was in every way characteristic of Candida (Fig. 3). CASE 2. The patient was a 38-year-old white man who was admitted to the hospital on May 24, 1964, as an emergency case because of in capacitating dyspnea. He had been known to have valvular heart disease for at least 3 years, and a clinical diagnosis of aortic stenosis and, possible, mitral stenosis had been made. Cardiac catheterization had showed a differential pressure at the
Drug Daily POM Procdrn PwkJIin 4,800,000 t»«. Streptomycin 2.0 grama liosons 1.0 grams ProeapNin Sogrom* CMoraiTftiifllcol 1.0 grams MystscKn F
CASE 2
=
AppwtdKtomy
Post-optralfv* Dayt
Fig. 1. Antibiotics administered postoperatively.
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aortic valve of approximately 100 ml. of mercury. Physical examination showed a man with ex treme dyspnea, cervical venous distension, enlarge ment and tenderness of the liver, and minimal peripheral edema. The blood pressure was 100/70 mm. Hg, and the pulse was 108 per minute. Clini cally, the heart was slightly enlarged to the left, and there was a Grade 3 systolic murmur radiat ing into the neck. Moist râles were present
Fig. 2. Case 1. Aortic valve shows massive vege tation on right cusp of homograft.
throughout both lung fields. Admission blood count, urinalysis, and blood urea nitrogen were within normal limits. A roentgenogram of the chest showed cardiac enlargement, especially of the left atrium, and prominent vascular markings were present in both lung fields with small bi lateral pleural effusions. On June 4, 1964, a severely stenotic and calci fied aortic valve was removed with the use of cardiopulmonary bypass and hypothermia, and a homologous aortic valve was sutured in place. At the completion of the procedure the cardiac ac tion was regular and strong. A day later a chest x-ray film showed gross enlargement of the cardiac silhouette compared with the preoperative examination, but the lungs were well aerated. By July 9, 35 days postoperatively, the heart had decreased to normal in size and configuration. On that day the patient vomited, and complained of cramping abdominal pain. The temperature re mained 98.6° F., but there was slight tenderness in the right iliac quadrant. Leukocyte count was 9,200 per cubic millimeter, and urinalysis was not remarkable. By the next day the leukocyte count had risen to 13,200 per cubic millimeter, with an absolute neutrophilia. Tenderness, guarding, and rebound tenderness were noted in the right lower quadrant, and a diagnosis of acute appendicitis was made. An appendectomy was performed under local anesthesia, but the appendix did not appear abnormal and, on histologie examination, no evidence of inflammation was found. Three
Fig. 3. Case 1. Solid growth of Candida pseudomycelia at edge of vegetation. (Gomori methenamine silver xl62; reduced %.)
Journal of
434
Climie and Rachmaninoff
Thoracic and Cardiovascular Surgery
days after the appendectomy, on July 13, the pa tient complained of pain in the left leg. Popliteal and posterior tibial pulsations were absent, al though a femoral pulse was palpable. Under local anesthesia an embolus was removed from the femoral artery. Histologie examination of the em bolus showed the presence of pseudomycelia and spores typical of the morphology of Candida spe cies. A diagnosis of fungal endocarditis was made.
Fig. 4. Case 2. Aortic valve shows bulky vegeta tion on left cusp of homograft.
Thereafter the temperature fluctuated daily to 101.6° F., but 9 blood cultures taken on subse quent days remained sterile. Antibiotic therapy is summarized in Fig. 1. Mysteclin-F (tetracyclineamphotericin B), 250 mg. four limes daily, was instituted 9 days after the open-heart surgery and continued until death. Ten days after embolectomy a systolic murmur was heard down the left sternal border which had not been present before. Death took place on Aug. 11, 1964, 70 days after ad mission and 59 days after the open-heart surgery. Autopsy findings. The lungs were edematous and there was a bilateral hydrothorax of 500 ml. of clear fluid. The heart weighed 750 grams and there was concentric hypertrophy of the left ventricle. The cusps of the mitral valve were thickened as were the chordae tendineae. The aortic valve had a circumference of 7 cm. and residual particles of calcium were present at the annulus. The left leaflet of the homograft was the site of a grayish yellow, bulky vegetation measuring 3.5 by 2.0 by 1.5 cm. (Fig. 4). Infarcts were present in the spleen and kidneys. Candida species (not albicans) was cultured from the vegetation on the aortic valve. Micro scopically, the mitral valve showed fibrous thickening without vascularization, and the aortic ring contained calcific deposits. The affected cusp of the homograft was largely necrotic and replaced by a mass of fibrin con-
ΗΚ&ΒΛ^&ΙΤΒΝΪ
*Λ
Fig. 5. Case 2. Tangled pseudomycelia of Candida at edge of vegetation. (Gomori methenamine silver xl62; reduced %.)
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taining pseudohyphae. The outer surface of the vegetation was an almost pure colony of Candida, but growth was sparser in the deeper areas. Many of the pseudophyphae showed bul bous swellings and the over-all appearance of the organism was characteristic of Candida species (Fig. 5). Abscesses were present in the aortic ring and adjacent aortic wall and epicardial tissue. No organisms were identified in the infarcts of the spleen or right kidney.
Discussion It seems probable that the incidence of mycotic endocarditis following open-heart surgery will increase until a satisfactory fungicidal agent becomes available for ther apy. It is, therefore, important that etiologic factors, clinical and pathologic features, and therapeutic procedures be reviewed in the hope that a better understanding of the dis ease may result. Clinical features. The literature contains reports of 19 patients with fungal endocar ditis following cardiac surgery. 716 The age of these patients ranged from 22 to 48, with an average of 34 years, and all but 4 were males. Eighteen of the 19 patients had ac quired heart disease, the aortic and mitral valves each being affected in 9 cases. The interval from the surgical procedure to the first symptom definitely attributable to endo carditis ranged from 12 days to 6 months. Fever was a constant finding and usually first brought the infection to attention. There was rarely a significant change in the nature of a pre-existing cardiac murmur. A char acteristic feature was embolization to rela tively large arteries, such as those in the legs. This occurred in 15 of 19 cases and is due to breaking off of portions of the bulky vegetation seen in mycotic endocar ditis. Not only is this feature clinically useful in the differential diagnosis between bac terial and mycotic endocarditis but, in 2 cases*·13 in addition to our Case 2, mycelia have been identified histologically in the thrombus removed at embolectomy, thus establishing the diagnosis. In retrospect, it is probable that the episode diagnosed as acute appendicitis in our Case 2 was actu ally the initial manifestation of peripheral embolization. Other clinical features are in-
distinguishable from those of bacterial endo carditis and include petechiae, splenomeg aly, and cardiac failure. Blood cultures were positive for the fungus in 14 of the 19 patients, but in several the report was not available until after death. The growth of fungi from the blood in this type of case must always be considered of potential significance and must not be discarded from consideration as representing accidental contamination of blood or culture medium. This is especially important in view of the fact that 9 of the 19 cases of endocarditis were due to fungi not generally considered pathogenic, par ticularly Candida species other than albicans. In our second case, negative blood cultures may be accounted for by the ad ministration of Mysteclin-F from the ninth postoperative day. The fact that a positive culture was obtained from the vegetation at autopsy presumably means that the amphotericin B satisfactorily sterilized the blood but was unable to penetrate the val vular lesion in sufficient concentration to be effective. Predisposing factors. Concurrent or prior antibiotic therapy has been a feature of many cases of mycotic endocarditis. In 14 of the 19 patients reviewed, antibiotics had been administered either preoperatively or postoperative]y, frequently in massive doses. Penicillin and streptomycin were most com monly used, but chloramphenicol, tetracycline, and erythromycin were also given to a few patients. Soler-Bechara and his as sociates17 state that in 28 (76 per cent) of 37 cases of Candida endocarditis in the literature there had been prior antibiotic therapy. A similar connection has been noted between other systemic fungal infec tions and antibiotic treatment,18 and it has been suggested that the drugs destroy in testinal bacteria which otherwise compete with fungi for the available food supply, thus preventing overgrowth of the latter.10 Huppert and his co-workers-0 deny this pathogenetic mechanism as they believe the change in intestinal bacterial flora following antibiotic therapy is qualitative rather than
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quantitative. They speculate that antibiotics may destroy certain bacteria which normally exert a restrictive or antibiotic effect on Candida, thus allowing Candida to grow unchecked. Apart from these speculations there is objective evidence that certain antibiotics actually stimulate the growth of Candida. Foley and Winter21 demonstrated that peni cillin enhances the growth of Candida spe cies in chick embryos and in rabbits. Their results with in vitro testing suggested a simi lar stimulating action on the part of peni cillin, but other investigators 19 ' 20 were un able to find any enhancement of growth of Candida albicans following addition of penicillin, chloramphenicol, or streptomycin to cultures. It seems clear, therefore, that there is a definite association between prior antibiotic therapy and mycotic endocarditis but the nature of the relationship remains obscure. Unfortunately, in many cases, mas sive antibiotic therapy is instituted whenever a diagnosis of endocarditis is suspected, and in the rare case, due to a fungus, the treat ment may potentiate the growth of the organism. Other factors which undoubtedly play an etiologic role in postoperative endocarditis, bacterial or fungal, include the presence of a raw surface and foreign material at the site of surgery which act as loci for develop ment of a thrombus which then becomes secondarily infected. Source of infection. Candida is virtually a constant inhibitant of the intestinal tract and it is possible that under appropriate circumstances it may gain entry to the cir culation. Other sources include the pump oxygenator, from which Candida has been cultured in at least 2 instances,15 and intra venous needles or catheters.17 Treatment. Treatment has been quite un satisfactory. All 19 patients described in the literature died of their disease, in spite of intensive treatment with amphotericin B and other mycostatic drugs in those patients in whom the diagnosis was made before death. Until more potent and safer fungicidal drugs become available the only hope
for these patients is surgical removal of the vegetation. This has been accomplished suc cessfully by Kay22 in a patient with Candida tricuspid endocarditis, with an apparent 6 months' cure. The infection did not follow open-heart surgery but was related to an interventricular septal defect. Persellin13 at tempted surgical removal of a Candida vege tation which developed following aortic valvulotomy, but the patient died shortly there after. Summary This paper describes 2 additional patients with mycotic endocarditis which developed after open-heart surgery and brings to 19 the number of such cases recorded. The clinical features of the 19 cases are reviewed and emphasis is placed on the constancy of fever and the frequency of embolization to large arteries as large fragments of the bulky vegetations are dislodged into the cir culation. Blood cultures during life will be positive in approximately 75 per cent of cases. Predisposing factors are discussed, the most important of which appears to be antecedent or concurrent administration of large doses of antibiotics, particularly peni cillin and streptomycin. Therapy has proved unsatisfactory in all postoperative cases, but surgical removal of the vegetation has re sulted in apparent cure in 1 patient with a spontaneous infection. REFERENCES 1 Joachim, H., and Polayes, S. H.: Sub-acute Endocarditis With Systemic Mycosis (Monilia), J. A. M. A. 115: 205-208, 1940. 2 Wikler, A., et al.: Mycotic Endocarditis. Report of a Case, J. A. M. A. 119: 333-336, 1942. 3 Zimmerman, L. E.: Candida and Aspergillus Endocarditis: With Comments on the Role of Antibiotics in Dissemination of Fungus Disease, Arch. Path. 50: 591-605, 1950. 4 Merchant, R. K., et al.: Fungal Endocarditis: Review of the Literature and Report of 3 Cases, Ann. Int. Med. 48: 242-266, 1958. 5 Denton, C , et al.: Bacterial Endocarditis Following Cardiac Surgery, Circulation 15: 525-531, 1957. 6 Koiwai, E. K., and Nahas, H. C : Subacute
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Bacterial Endocarditis Following Cardiac Surgery, Arch. Surg. 73: 272-278, 1956. Koelle, W. A., and Pastor, B. H.: Candida Albicans Endocarditis After Aortic Valvulotomy, New England J. Med. 225: 997-999, 1956. Jamshidi, A., Pope, R. H., and Friedman, N . H.: Fungal Endocarditis Complicating Cardiac Surgery, Arch. Int. Med. 112: 370-376, 1963. Simmons, N. A., and Turner, P.: Candida Endocarditis After Cardiac Surgery, Brit. M. J. 2: 1041-1042, 1963. Newman, W. H., and Cordell, A. R.: Aspergillus Endocarditis After Open-Heart Surgery. Report of a Case and Review of Literature, J. THORACIC & CARDIOVAS. SURG. 48:
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1964. Uys, C. J., et al.: Endocarditis Following Cardiac Surgery Due to the Fungus Paecilomyces, S. Afr. Med. J. 37: 1276-1280, 1963. Louria, D. B., and Dineen, P.: Amphotericin B in the Treatment of Disseminated Moniliasis, J. A. M. A. 174: 273-280, 1960. Persellin, R. H., Haring, O. M., and Lewis, F. J.: Fungal Endocarditis Following Cardiac Surgery, Ann. Int. Med. 54: 127-134, 1961. Hyun, B. H., and Collier, F . C : Mycotic Endocarditis Following Intracardiac Opera tions. Report of Four Cases, New England J. Med. 263: 1339-1341, 1961.
15 Andriole, V. T., et al.: Candida Endocarditis. Clinical and Pathologic Studies, Am. J. Med. 32: 251-285, 1962. 16 Sänger, P. W., et al.: Candida Infection as a Complication of Heart Surgery, J. A. M. A. 181: 88-91, 1962. 17 Soler-Bechara, J., et al.: Candida Endocarditis, Am. J. Cardiol. 13: 820-824, 1964. 18 Brown, C , Jr., et al.: Fatal Fungus Infections Complicating Antibiotic Therapy, J. A. M. A. 152: 206-207, 1953. 19 Woods, J. W., Manning, I. H., and Patterson, C. W.: Monilial Infections Complicating the Therapeutic Use of Antibiotics, J. A. M. A. 145: 207-211, 1951. 20 Huppert, M., MacPherson, D . A., and Cazin, J.: Pathogenesis of Candida Albicans Infection Following Antibiotic Therapy. I. The Effect of Antibiotics on the Growth of Candida Albicans, J. Bact. 65: 171-176, 1953. 21 Foley, G. E., and Winter, W. D., Jr.: In creased Mortality Following Penicillin Therapy of Chick Embryos Infected With Candida Albicans var. Stellatoidea, J. Infect. Dis. 85: 268-274, 1949. 22 Kay, I. H., et al.: Surgical Cure of Candida Albicans Endocarditis With Open-Heart Surgery, New England J. Med. 264: 907-910, 1961.