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Fatal acute rheumatic fever in childhood despite corticosteroid therapy
Fatal
acute
despite A note
rheumatic
corticosteroid on the spectrum
T
of patients
in childhood
therapy of childhood
he incidence of death in childhood frolli rheumatic heart disease has been declining in the t7nitecl States for 3 decades.’ The role of ;ltlrenocorticotrol,hir hornlone ;wd adrenal c-orticosteroids in the continuing decline in the mort:Jit>~ rate during the past 2 decades has bee11 debated widely. and remains uncertain. Xevertheless, death front rheumatic ca-ditis is 110~ ~I~COI~II~OII in children treated with these agents and is rare during an initial attack of rheumatic fever.” Such occurred, however, in 2 children recently studied by us. Each died of different causes, which represent widel?. separate hands in the spectrum of rheunjatic heart disease in chiltlrell. Report
fever
rheumatic
fever
eJectlOll-t) pe murmur at the left sternal edge were present. .I leukoq te count was LL,OOO per cubic millimeter; anti-streptolvsin 0 titer, 62.5 Todd Ilnith; corrected sedimelltationrate, ,117 mm. per hour; and C-reactive protein, reactive. 111 the hospital, the temperature rose to 10.3” I.‘., arthritis of both knee5 developed while that of the mklex subsided, and the systolic murmur hecnme loudest at the cardiac apex and radiated to the left axilla and back. The fever and arthritis responded favorably to aspirin and prednisolme (31 mg. per da!-), but on her eighteenth da). of hospitalization, the twentieth day of illllesb. she developed d>.spnea, tachypnen, tach\.cardia (1 70 per mirlrlte), a ventricrllar gallop, hepntomegnl! , and died.
Poticnt 2. A 9-\,ear-old girl W:I> well until 1 j i year-. before death when hhe developed t\-pica1 signs and ~\mptotns of acute rheumatic fever. She remailled ill the hospital during the entire ll&year period. .\ loud murmur typical of mitral regurgitation was heard when she was first examined and remained thereafter. Congestive cardiac failure was present throughm~t the illness. but it cippeared to be levy
1;ig. 1. ‘The hc,irt IL Case 1. q, Opelled right ;~tr:un~ (K.-l. ), right ventricle (K. 1.. 1, and slightI>, but diffusely thickened tricuspid valve. b, Opened left atrium (1,.;4. 1, left ventricle (L. I’.). and
>evere when the child was receiving prednisone (up to 10 mg., daily) and more severe when this medication was discontinued. First degree heart block was present until the last weeks of life when atrial iibrillation developed. She died unexpectedly. Necropsv (A67-185) disclosed generalized cardiomegaly (w-eight. 320 grams; expected weight, 115 grams); severe tibro& of the mitral valve with a fixed, severely incompetent orifice; a left atrial jet lesion; normal aortic, tricuspid and pulmonic v‘llves; ,Ind normal pericardium. Histologically, moht m!‘ocardial liberh of each cardiac chamber were hypert rophied, but no inflammatorycell:, or .Aschotf I)odies were found (Fig. 3).
Comment Although acute rheumatic fever occurs in patients under 4 years of age,” it does so infrequently, and we are aware of only 14 cltildrenJ-l’t \\ho, like Patient 1, died of acute rheutinatic fever before 4 years of age and wlto mere found at ttecrops)to have Ascltoff bodies. Photomicrograpltic demonstration of the Aschoff bodies \V;LS presented in 5 of tlietn.J~7 As&oft’ bodies during the first fen ,tre said to be :llJSent weeks of acute rheumatic fever,ta and adrenal corticosteroids have been reported to decrease tnnrkedl~~ the cellular reaction
in
rheunx~tic
rxyocarditis.‘”
The
heart
of
Patient 1, however, contained nutnerous, typical As&off Ijodies and an exuberant cellular reaction despite a total syntptomatic illness of only 20 days and treatment Ivith large doses of prednisolone. In contrast to Patient 1, whose death was prirnaril>. due to acute rheumatic tnyocarditis, Patient 2 died of severe mitral regurgitation. Although it is reasottable to believe that acute rheumatic cat-ditis was present at the beginning of her illness, no itifl3n~niatory lesions were present at tiecrops!’ l! i l-ears later, and excelIt the In\-ocardium was for hJ-pertrophy, norntal. Cardiac failure in children with rheumatic heart disease suggests that the rheumatic carditis is still active,lF and in Patient 2 this suggestion was supported 1)~ the transient, but apparently beneficial effects of predttisone. Her cardiac failure, however, was due to an operativel>cot-rectablc mechanical defect, mitral ittcompetence, and mitral valve replacetnent might have been lifesaving. Rheumatic mitral regurgitation has beeti considered
Gg. 2. ITor legend
Fig. 3. For
legend
see opposite
page.
see opposite
page.
Futul
childhood
rhectnmtic
f’eveu despite
corticosteroids
537
Fi g. 2. Photomicrographs in Case 1. .I, Inflammatory nodule in the left atria1 endocardium, consisting of a necrotic center surrounded by large mononuclear cells and a peripheral zone of polymorphonuclear neutrophils. R. Posterior mitral leaflet containing fibrinoid material, polymorphonuclear neutrophils, and large mononuclear cells. C and D, .Aschoff bodies consisting of altered collagen surrounded by large, mononuclear (Anitschkow) cells, and gi.lnt cells. (Hematoxylin and eosin stains; _1, X 160, R and C, X-h(K), and I), X 628; each reduced 1~~. 25 per cent.) I;ig. .?. Interior of heart of Cn\e 2. (I, Opened left atrium showing the incompetent mitral valve orifice (0.) and the contracted anterior (.,I.) and posterior (I’.) leaflets. The dashed line encloses an area of thickened endorardium on the posterior wall. This lesion almost certainly resulted from the impact of a jet of blood regurgitated through the incompetent mitral orifice from the left ventricle during ventricular systole. The myocrrdium beneath this lesion showed histologic features of severe degeneration, but this was the only portion of myocardium that showed changes other than hypcrtrophy. h, Close-up of the opened mitral valve. Both leaflets and the chordae tendineae are thick and shortened. No calcium deposits are present. clnt. and Post., anterior and posterior leaflets, respectively; A-L and P-M, anterolateral and posteromedinl papillary muscles, respectively.
;I lxnign lesion iI1 certain selected groups of patients,‘7 but in Patient 2 it caused death 134 years after the initial episode of acute rheumatic fever.
K EF E RE N c E s 1.
~Inssell, B. F., Amezcua, F., and Pelargonio, S.: Evolving picture of rheumatic fever: Data from 10 years at the House of the Good Samaritan, J.l\.M.:I. 188:287, 1963. 2. A joint report by the Rheumatic Fever Working l’arty of the hfedical Research Council of Great Britain and the Subcommittee of Principal Investigators of the American Council of Rheumatic Fever and Congenital Heart Disease, :lmericnn Heart Association. The evolution of rheumatic heart disease in children. Five-year report. of a cooperative clinical trial of ACTH, cortisone, and aspirin, Circulation 2250.1, 1960. .i. Logue, IZ. B., and Hurst, J. IV.: Rheumatic fever during the first few years of life, and its differentiation from endocnrdial fibrosis, r1n1. J. M. SC. 223:6%3, 1952. -1. McIntosh, I~., and Wood, C. I,.: Rheumatic infections occurring in the first three years of life, .\m. J. Dis. Child. 49:835, 1935. 5. Fischer, V. E: Rheumatic heart disease at one ycnr, .I\m. J. L)i<. Child. 48590, 1934. 6. Schwarz, H.: ~111 unusual case of acute rheum;rtic fever in an infant, in Contributions to the medical sciences in honor of Dr. Emanuel Libmarl, New York, 1932, The International Press, vol. 3, p. 1061. 7. hl urphy, (;. E. : ‘J‘he characteristic rheumatic k-ions of striated and of non-striated or smooth muscle cells of the heart, &ledicine 42:73, 1963.
8.
Eigen, L. .A.: Juvenile rheumatic fever: Report of a case in an infant two years of age, Axr. HEART J. 16:36.?, 1938. 9. White, I’. D.: The incidence of endocarditis in earliest childhood, Am. J. Dis. Child. 32536, 1926. 10. Denzer, B. S.: Rheumatic heart disease in children under two years of age: Report of three cases, J.A.M.A. 82:1243, 1924. 1 1. Schroeder, L. C.: Observations on the etiology and pathology of chorea minor, J..A.M..A. 79:181, 1922. 2. Friedberg, C. I<.: Diseases of the heart, cd. 3, Philadelphia, 1966, IV. B. Saunders Company, p. 1321. 3. Smith, A. de{;.: Rheumatism and its manifestations in children under five years, Arch. Pediat. 39:799, 1922. 4. Bnggenstoss, A. H., and Saphir, (I.: Rheumatic disease of the heart, in Gould, S. E., editor: I’nthology of the heart, ed. 2, Springfield, III., 1960, Charles C Thomas, Publisher, p. 655. 5. (;olden, A\., and Hurst, J. i$:.: Alterations of the Icsions of acute rheumatic myocarditis during cortisone therapy, Circulation 7:218, 1953. 16. Masseli, B. I;., Fyler, D. C., and Roy, S. B.: The clinical picture of rheumatic fever: Diagnosis, immediate prognosis, course, and therapeutic implications, Am. J. Cnrdiol. 1:436, 1958. 17. Jhaveri, S., Czoniczer, G., Reider, Ii. B., and Ilassell, B. P.: Relatively benign “pure” mitral regurgitation of rheumatic origin: A study of seventy-four adult patients, Circulation 22:39, 1960.
acute
despite A note
rheumatic
corticosteroid on the spectrum
T
of patients
in childhood
therapy of childhood
he incidence of death in childhood frolli rheumatic heart disease has been declining in the t7nitecl States for 3 decades.’ The role of ;ltlrenocorticotrol,hir hornlone ;wd adrenal c-orticosteroids in the continuing decline in the mort:Jit>~ rate during the past 2 decades has bee11 debated widely. and remains uncertain. Xevertheless, death front rheumatic ca-ditis is 110~ ~I~COI~II~OII in children treated with these agents and is rare during an initial attack of rheumatic fever.” Such occurred, however, in 2 children recently studied by us. Each died of different causes, which represent widel?. separate hands in the spectrum of rheunjatic heart disease in chiltlrell. Report
fever
rheumatic
fever
eJectlOll-t) pe murmur at the left sternal edge were present. .I leukoq te count was LL,OOO per cubic millimeter; anti-streptolvsin 0 titer, 62.5 Todd Ilnith; corrected sedimelltationrate, ,117 mm. per hour; and C-reactive protein, reactive. 111 the hospital, the temperature rose to 10.3” I.‘., arthritis of both knee5 developed while that of the mklex subsided, and the systolic murmur hecnme loudest at the cardiac apex and radiated to the left axilla and back. The fever and arthritis responded favorably to aspirin and prednisolme (31 mg. per da!-), but on her eighteenth da). of hospitalization, the twentieth day of illllesb. she developed d>.spnea, tachypnen, tach\.cardia (1 70 per mirlrlte), a ventricrllar gallop, hepntomegnl! , and died.
Poticnt 2. A 9-\,ear-old girl W:I> well until 1 j i year-. before death when hhe developed t\-pica1 signs and ~\mptotns of acute rheumatic fever. She remailled ill the hospital during the entire ll&year period. .\ loud murmur typical of mitral regurgitation was heard when she was first examined and remained thereafter. Congestive cardiac failure was present throughm~t the illness. but it cippeared to be levy
1;ig. 1. ‘The hc,irt IL Case 1. q, Opelled right ;~tr:un~ (K.-l. ), right ventricle (K. 1.. 1, and slightI>, but diffusely thickened tricuspid valve. b, Opened left atrium (1,.;4. 1, left ventricle (L. I’.). and
>evere when the child was receiving prednisone (up to 10 mg., daily) and more severe when this medication was discontinued. First degree heart block was present until the last weeks of life when atrial iibrillation developed. She died unexpectedly. Necropsv (A67-185) disclosed generalized cardiomegaly (w-eight. 320 grams; expected weight, 115 grams); severe tibro& of the mitral valve with a fixed, severely incompetent orifice; a left atrial jet lesion; normal aortic, tricuspid and pulmonic v‘llves; ,Ind normal pericardium. Histologically, moht m!‘ocardial liberh of each cardiac chamber were hypert rophied, but no inflammatorycell:, or .Aschotf I)odies were found (Fig. 3).
Comment Although acute rheumatic fever occurs in patients under 4 years of age,” it does so infrequently, and we are aware of only 14 cltildrenJ-l’t \\ho, like Patient 1, died of acute rheutinatic fever before 4 years of age and wlto mere found at ttecrops)to have Ascltoff bodies. Photomicrograpltic demonstration of the Aschoff bodies \V;LS presented in 5 of tlietn.J~7 As&oft’ bodies during the first fen ,tre said to be :llJSent weeks of acute rheumatic fever,ta and adrenal corticosteroids have been reported to decrease tnnrkedl~~ the cellular reaction
in
rheunx~tic
rxyocarditis.‘”
The
heart
of
Patient 1, however, contained nutnerous, typical As&off Ijodies and an exuberant cellular reaction despite a total syntptomatic illness of only 20 days and treatment Ivith large doses of prednisolone. In contrast to Patient 1, whose death was prirnaril>. due to acute rheumatic tnyocarditis, Patient 2 died of severe mitral regurgitation. Although it is reasottable to believe that acute rheumatic cat-ditis was present at the beginning of her illness, no itifl3n~niatory lesions were present at tiecrops!’ l! i l-ears later, and excelIt the In\-ocardium was for hJ-pertrophy, norntal. Cardiac failure in children with rheumatic heart disease suggests that the rheumatic carditis is still active,lF and in Patient 2 this suggestion was supported 1)~ the transient, but apparently beneficial effects of predttisone. Her cardiac failure, however, was due to an operativel>cot-rectablc mechanical defect, mitral ittcompetence, and mitral valve replacetnent might have been lifesaving. Rheumatic mitral regurgitation has beeti considered
Gg. 2. ITor legend
Fig. 3. For
legend
see opposite
page.
see opposite
page.
Futul
childhood
rhectnmtic
f’eveu despite
corticosteroids
537
Fi g. 2. Photomicrographs in Case 1. .I, Inflammatory nodule in the left atria1 endocardium, consisting of a necrotic center surrounded by large mononuclear cells and a peripheral zone of polymorphonuclear neutrophils. R. Posterior mitral leaflet containing fibrinoid material, polymorphonuclear neutrophils, and large mononuclear cells. C and D, .Aschoff bodies consisting of altered collagen surrounded by large, mononuclear (Anitschkow) cells, and gi.lnt cells. (Hematoxylin and eosin stains; _1, X 160, R and C, X-h(K), and I), X 628; each reduced 1~~. 25 per cent.) I;ig. .?. Interior of heart of Cn\e 2. (I, Opened left atrium showing the incompetent mitral valve orifice (0.) and the contracted anterior (.,I.) and posterior (I’.) leaflets. The dashed line encloses an area of thickened endorardium on the posterior wall. This lesion almost certainly resulted from the impact of a jet of blood regurgitated through the incompetent mitral orifice from the left ventricle during ventricular systole. The myocrrdium beneath this lesion showed histologic features of severe degeneration, but this was the only portion of myocardium that showed changes other than hypcrtrophy. h, Close-up of the opened mitral valve. Both leaflets and the chordae tendineae are thick and shortened. No calcium deposits are present. clnt. and Post., anterior and posterior leaflets, respectively; A-L and P-M, anterolateral and posteromedinl papillary muscles, respectively.
;I lxnign lesion iI1 certain selected groups of patients,‘7 but in Patient 2 it caused death 134 years after the initial episode of acute rheumatic fever.
K EF E RE N c E s 1.
~Inssell, B. F., Amezcua, F., and Pelargonio, S.: Evolving picture of rheumatic fever: Data from 10 years at the House of the Good Samaritan, J.l\.M.:I. 188:287, 1963. 2. A joint report by the Rheumatic Fever Working l’arty of the hfedical Research Council of Great Britain and the Subcommittee of Principal Investigators of the American Council of Rheumatic Fever and Congenital Heart Disease, :lmericnn Heart Association. The evolution of rheumatic heart disease in children. Five-year report. of a cooperative clinical trial of ACTH, cortisone, and aspirin, Circulation 2250.1, 1960. .i. Logue, IZ. B., and Hurst, J. IV.: Rheumatic fever during the first few years of life, and its differentiation from endocnrdial fibrosis, r1n1. J. M. SC. 223:6%3, 1952. -1. McIntosh, I~., and Wood, C. I,.: Rheumatic infections occurring in the first three years of life, .\m. J. Dis. Child. 49:835, 1935. 5. Fischer, V. E: Rheumatic heart disease at one ycnr, .I\m. J. L)i<. Child. 48590, 1934. 6. Schwarz, H.: ~111 unusual case of acute rheum;rtic fever in an infant, in Contributions to the medical sciences in honor of Dr. Emanuel Libmarl, New York, 1932, The International Press, vol. 3, p. 1061. 7. hl urphy, (;. E. : ‘J‘he characteristic rheumatic k-ions of striated and of non-striated or smooth muscle cells of the heart, &ledicine 42:73, 1963.
8.
Eigen, L. .A.: Juvenile rheumatic fever: Report of a case in an infant two years of age, Axr. HEART J. 16:36.?, 1938. 9. White, I’. D.: The incidence of endocarditis in earliest childhood, Am. J. Dis. Child. 32536, 1926. 10. Denzer, B. S.: Rheumatic heart disease in children under two years of age: Report of three cases, J.A.M.A. 82:1243, 1924. 1 1. Schroeder, L. C.: Observations on the etiology and pathology of chorea minor, J..A.M..A. 79:181, 1922. 2. Friedberg, C. I<.: Diseases of the heart, cd. 3, Philadelphia, 1966, IV. B. Saunders Company, p. 1321. 3. Smith, A. de{;.: Rheumatism and its manifestations in children under five years, Arch. Pediat. 39:799, 1922. 4. Bnggenstoss, A. H., and Saphir, (I.: Rheumatic disease of the heart, in Gould, S. E., editor: I’nthology of the heart, ed. 2, Springfield, III., 1960, Charles C Thomas, Publisher, p. 655. 5. (;olden, A\., and Hurst, J. i$:.: Alterations of the Icsions of acute rheumatic myocarditis during cortisone therapy, Circulation 7:218, 1953. 16. Masseli, B. I;., Fyler, D. C., and Roy, S. B.: The clinical picture of rheumatic fever: Diagnosis, immediate prognosis, course, and therapeutic implications, Am. J. Cnrdiol. 1:436, 1958. 17. Jhaveri, S., Czoniczer, G., Reider, Ii. B., and Ilassell, B. P.: Relatively benign “pure” mitral regurgitation of rheumatic origin: A study of seventy-four adult patients, Circulation 22:39, 1960.