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Unexpected death in early life
U N E X P E C T E D D E A T H IN EARLY L I F E JAMES B. ARE:g, M.D., AND JUAN SOTOS,M.D.* P H I L A D E L P H I A , PA. ORTUNATELY, instances of sudunexpected death occurring in previously healthy infants and children or in those with apparently only mild illnesses are uncommon in the experience of most physicians. When such tragedies do occur every effort must be made to determine the exact cause of death. Not only must death from criminal causes be excluded but also, whenever possible, the family must be made to understand that they were in no manner responsible for the death of their child. An adequate explanation of such deaths can be obtained only by complete post-mortem examination, clinical observations usually being too brief to warrant any conclusions. Both the clinician and the pathologist performing the necropsy should be cognizant o~ the types of lesions which may be responsible for sudden death in early life, and even their combined efforts may fM1 to demonstrate an adequate cause of death in a relatively small percentage of such infants and children. 1 In the majority of instances, however, an adequate cause of death will be demonstrated by complete post-mortem studies, including histologic, bacteriologic, and chemical studies, combined with clinical ob-
F den,
F r o m St. C h r i s t o p h e r ' s H o s p i t a l f o r Child r e n a n d t h e D e p a r t m e n t s of P e d i a t r i c s a n d P a t h o l o g y , T e m p l e U n i v e r s i t y School of M e d i cine. *Present address : Children's Hospital, C o l u m b u s , Ohio.
servations whenever these are available. During the six-year period, 1949 to 1954 inclusive, there were 95,195 new admissions to the outpatient department of St. Christopher's Hospital for Children, and 18,366 infants and children were admitted to the hospital. Thirty-three patients were dead at the time of arrival, ten died in the outpatient department and seventy-one died within twenty-four hours after admission to the hospital. This represents a mortality of 1.0 per 1,000 total admissions. The over-M1 mortality for patients admitted to the hospitat during this same period was 17.9 per 1,000. Autopsies were performed on 103 of these 114 patients (90 per cent); this represents 31 per cent of all autopsies conducted by the hospital during this period of time. Seventy-six of the 114 patients died during the first year of life. The greatest frequency was during the first two months of life, this period accounting for thirty-five of the 114 deaths. Eighteen patients were between 1 and 2 years of age, and only twenty were older than 2 years. Eighty-five deaths occurred during the months September through April and twenty-nine occurred during the four remaining months. Males and femMes were approximate]y equally represented. Seventy-eight patients were
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Eleven of t h e sixteen patients in white and thirty-six were Negro; this racial distribution is comparable to whom septicemia was considered to be that of the general admissions to the TABLE I. CAUSES OF DEATH hospital. 42 Before any discussion of the vari- Infections Congenital malformations 18 ous lesions encountered at post-mor- Miscellaneous 25 tern examination of these patients is U n d e t e r m i n e d 18 Total 103 begun, certain differences between this material and that commonly reported TABLE I~. :INFECTIONS AS A CAUSE OF DEATH in the literature as " s u d d e n d e a t h " in infants and children should be Septicemia 16 Bronchopneumonia 6 noted. F o r the most part the present Leptomeningitls 6 series consists of infants and children Acute epiglottitis, laryngotracheitis or trueheobronchitis 3 in whom clinical manifestations of Ecthyma gangrenosum 3 illness were present for a variable but Miscellaneous 8 Total 42 usually short period of time prior to death, but in whom for various reasons the severity of the illness was t h e primary cause of death were innot appreciated. Moreover, all pa- fants 6 months or less of age, one of tients dying within twenty-four hours whom died during the neonatal period. after admission to the hospital are in- Only two patients in this group were cluded, regardless of the presence or over 2 years of age. One child, aged absence of previous hospital admis- 2 years 9 months, in whom symptoms sions. Therefore, in approximately had been apparent for only two days, one-third of the 103 patients upon died as a result of staphylococcal pyewhom autopsies were performed a mia secondary to an acute osteomyewell-recognized pre-existing disease, litis of the fibula; multiple abscesses often of a serious nature, was known were present in the heart, kidneys, to have been present for some time and lungs. prior to death. The present material In three patients death was attributis thus not entirely comparable with ed to the presence of bilateral adrenal that often reported as "sudden death" hemorrhages associated with purpura in previously healthy infants and (Waterhouse-Friderichsen syndrome) children and, instead, is more indica(Fig. 1). The infants were 5, 11, and tive of the disease processes respon- 20 months of age. In one of these insible for death following brief and fants symptoms were of twenty-four apparently mild illnesses. hours' duration; in the remaining two, The causes of death among the 103 mild symptoms were present for several patients upon whom post-mortem ex- days, followed by a severe illness of aminations were performed are listed six and one-half and twenty-four hours, in Table I. As with most reported respectively. IIistologic evidence of series of unexpected deaths, infections meningitis, although minimal, was were the leading cause of death, 2-G present in all these infants; in one it accounting for forty-two of the 103 was confined to the spinal leptodeaths. These are tabulated in Table meninges; the meningitis was not II. recognized macroscopically. Neisseria
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meningitidi microorganisms were isolated from the blood, cerebrospinal fluid, and nasopharynx of one infant during life, but cultures of the blood and cerebrospinal fluid obtained post mortem were sterile. An atypical meningococcus was isolated from the blood stream of one infant, but blood cultures in the third infant revealed no growth. Nevertheless, because of
Fig. 1.---Bilateral
adrenal
the blood been reportedJ -9 That a comparable clinical picture may occur in the absence of massive adrenal hemorrhage has been demonstrated by Rich, 1~ who described degenerative changes in the adrenal cortex in association with severe acute infections. Blood cultures obtained either during life, immediately post mortem, or at the time of autopsy grew pneu-
hemorrhage. The resDonsible o r g a n i s m d u r i n g life o r a t t h e t i m e of a u t o p s y .
the clinical and pathologic findings these last two infants are included in this group. The mechanism responsible for death in patients with the WaterhouseFriderichsen syndrome is unknown. Conflicting evidence regarding the role of adrenal insufficiency has appeared, and only rarely have low levels of 17-hydroxyeorticosteroids in
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was
not
identified either
mococci in eight instances and beta hemolytic streptococci in four. In five of these patients the positive blood culture was the only significant finding, no apparent portal of entry being demonstrable at autopsy. In the remaining seven patients, however, the positive blood culture was associated with other evidences of inf e c t i o n which were demonstrable at
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n e c r o p s y ; in two patients there was an associated dermatitis and in one patient each there were pneumonia, necrotizing bronchiolitis, bilateral otitis media, acute omphalitis, and pneumococcal peritonitis associated with lipoid nephrosis. In the entire series of 103 patients there were ten in whom death m a y be considered as having occurred suddenly and u n e x p e c t e d l y in a previously healthy infant. The ages of these ten patients varied from 5 weeks to 4 months. In four of these, death was~ attributed to pneumocoecal septicemia, in two, to beta hemolytic streptococcal septicemia, and in four no cause of death was demonstrated (Table III). In one of these infants dying with septicemia a mild scrotal dermatitis was present, another had bilateral otitis media, and in the remaining four no significant findings were present other t h a n the positive blood culture. TABLE I I I . CAUSES OF SUDDEN, UNEXPECTED DEATHS IN PREVIOUSLY I{EALTtIY INFANTS
Pneumoeoeea] septicemia Beta hemolytic streptococcal septicemia Undetermined Total
4 2 4 10
The significance of positive blood cultures obtained during the agonal period or after death is difficult to evaluate, and the importance of even pathogenic organisms in post-mortem blood cultures is questioned b y some investigators, s In general, however, positive blood cultures of pneumococci, beta h e m o 1 y t i c streptococci, meningococei, or Hemophilus influenzae are obtained at post-mortem examination only from patients in whom other evidences of infection are apparent, or those in whom death
PEDIATRICS
occurs u n e x p e c t e d l y and in whom no other cause of death is a p p a r e n t a f t e r a complete post-mortem examination. The presence of gram-negative bacilli
(Pseudomonas aeruginosa, Proteus vulgaris, and Eseherichia colt) or enterococci in agonal or post-mortem blood cultures is usually of little or no significance ; occasionally, however, when an a p p a r e n t p o r t a l of e n t r y is present, such as ulcerative lesions in the colon and skin associated with ecthyma gangrenosum, their presence in the blood stream m a y be indicative of an actual septicemia. Staphylococci are usually considered as contaminants unless associated with obvious evideuces of infection p r o d u c e d b y these organisms, e.g., metastatic abscesses. The varied significance of different types of organisms in the blood agonally or after death is not entirely clear. It seems possible, however, t h a t the facility with which different organisms m a y invade the blood stream at this time may be as dependent upon t h e i r location and nmnbers within the b o d y as upon intrinsic differences in the bacteria themselves. Thus, the n o r m a l inhabitants of the gastrointestinal tract, usually present in large numbers, are r a t h e r commonly present in the blood stream a f t e r death, but t h e i r presence is usually of little or no significance. Other organisms, such as pneumococci, beta hemolytic streptococci, and H. influenzae, do not usually attain sufficient numbers in the b o d y to be demonstrated in postm o r t e m cultures unless an associated infection produced b y them is also apparent, or unless t h e y occur as p a r t of an overwhelming infection in infants dying suddenly and unexpectedly.
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The mechanism responsible for death in this group of patients is certainly not clear. In certain instances the septicemia was merely a part of clearly demonstrable infectious processes within the body, e.g., pneumoeoccal peritonitis or leptomeningitis. In one instance the septicemia was present in association with a widespread pnemnonie process and the clinical manifestations were predominantly those of severe diarrhea with associated hyperelectrolytemia; in this patient the metabolic disturbances may well have been the major factor responsible for death. In still other instances, however, the septicemia was present in association with relatively localized infectious processes, such as otitis m e d i a; or no demonstrable loeaIized infection was present. In such instances, when organisms commonly considered as pathogenic are isolated from the blood stream, death is arbitrarily attributed to septicemia, but it must be recognized that this is only an arbitrary and admittedly unsatisfactory explanation of death. Baeteremia per se is probably of relatively frequent occurrence, and many patients with septicemia recover or die only after manifesting signs and symptoms of an infection for some time. In the present group of patients, however, evidences of severe illness were present for twenty-four hours or less in thirteen of the sixteen patients, and in six of these death occurred suddenly and unexpectedly. Since baeteremia cannot be differentiated from septicemia by isolated cultures of the blood, and since the usual clinical manifestations of sepsis were not apparent, it is obviously impossible to prove that death actually was caused by septicemia. It seems highly
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probable that their deaths are in ~ way related to infection, but the exact mechanism must, for the present, remain unexplained. Perhaps an inability to respond to infection, assoelated with diminished levels of gamma globulin, 11 may be important, but preliminary studies in our laboratory have failed to demonstrate any apparent relationship between the levels of gamma globulin demonstrable in blood obrained at autopsy and the occurrence of sudden, unexpected death. F u r t h e r work concerning this aspect of the problem is certainly indicated and is currently being conducted. In six patients death was attributed to bronchopneumonia. In no instance was the presence of only a few neutrophils in the alveoli considered adequate to explain the death of an infant or child; all six patients had histologic evidence of a moderate to severe acute inflammatory process in the pulmonary alveoli. Their ages varied from 16 hours to 21/2 years; two were less than 1 month of age. In one patient each the pneumonia was associated with congenital heart disease and otitis media, bilateral otitis media and acute tonsillitis, bilateral otitis media, fetal anoxia, acute omphalitis, and with thromboses of the dural sinuses with infarction of the braitl; in the last patient death may well have occurred as a result of the cerebral changes, but the pneumonia was believed to have antedated the im farction of the brain. In two of the patients in whom death was attributed to pneumonia death occurred after an acute, severe illness of apparently only a few hours' duration. Although mild symptoms were present for some time in several patients, in only one did the acute,
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severe illness exceed twenty-four hours in duration. Leptomeningitis was responsible for the d e a t h of six patients, whose ages r a n g e d f r o m 3 weeks to 2 8 9 years. I n one i n f a n t 22 days old the meningitis was caused b y Proteus morganii and was secondary to a myelomeningocele. I n the r e m a i n i n g p a t i e n t s the responsible organisms were H. influenzae in two, and Mycobacterium tuberculosis, pneumococci, and coliform organisms in one each. The d u r a t i o n of s y m p t o m s in these p a t i e n t s v a r i e d f r o m one a n d one-half days to one week. T h r e e p a t i e n t s died as a result of acute infections of the epiglottis,
three infants whose ages r a n g e d f r o m 2 weeks to 8 months. D i a r r h e a lasting f r o m one to several weeks h a d been present in two and possibly in the t h i r d i n f a n t ; in all there were u l c e r a t i v e lesions of the s c r o t u m and of the p e r i n e u m or buttocks. Ps. aeruginosa microorganisms were obtained in cultures f r o m the stool of one infant. I n the other two, cultures of the blood at the time of p o s t - m o r t e m e x a m i n a t i o n were positive for t h e ' same organism. I n one i n f a n t there were multiple large punched-out ulcers distributed throughout the colon (Fig. 2) ; in another only a mild acute enterocolitis was noted histologically. I n the ~hird infant, 2 months of age, the
Fig. 2.--]V[ultiple u l c e r s of colon. P s e u d o m o n a s aeruginosc4 Streptococcus faeealis, a n d c o l i f o r m o r g a n i s m s w e r e i s o l a t e d f r o m t h e s e lesions, D i a r r h e a h a d b e e n p r e s e n t f o r s e v e r a l w e e k s .
l a r y n x a n d / o r t r a c h e a and bronchi. T h e i r ages v a r i e d f r o m 9 m o n t h s to y e a r s ; only one was less t h a n 2 y e a r s of age. Cultures of the involved areas yielded H. influenzae in one, H. influenzae and pneumococci in one, and Staphylococcus aureus in one. Mild s y m p t o m s were p r e s e n t f r o m one to three d a y s in all of the patients, but the severe illness was as short as two hours p r i o r to the d e a t h of one child in w h o m t h e r e was occlusive swelling of the epiglottis and a r y e p i g l o t t i e folds. E c t h y m a g a n g r e n o s u m was considered responsible for the d e a t h of
l y m p h o i d a g g r e g a t e s of the small and l a r g e intestine were devoid of lymphocytes and were replaced b y a neutrophilic exudate. There was in addition a r e m a r k a b l e p a u c i t y of l y m p h o e y t e s in the mesenterie l y m p h nodes and in the 3/[alpighian corpuscles of the spleen. These findings are similar to those described in a child w i t h "alymphoeytosis, ''12 a n d are suggestive of those associated with a g a m m a g l o b u linemia.13, 14 U n f o r t u n a t e l y , electrop h o r e t i c studies were not available to p r o v e or disprove this diagnosis. I n none of the other p a t i e n t s in the entire series were c o m p a r a b l e evidences
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of lymphocytic depletion present to suggest this diagnosis on a morphologic basis. Death was attributed to acute enteritis in two infants 3 and 5 months of age, respectively. Diarrhea of two to five days' duration had been noted clinically. This was associated with dehydration and, in one infant, with severe acidosis. Pr. vulgaris and coliform organisms were isolated from the stools of both infants. Histologically, increased numbers of myeloid cells and nentrophils were present in the lamina propria of the small bowel and the mesenteric lymph nodes contained increased numbers of neutrophils. Certainly the causative relationship between the organisms isolated from the stools, the inflammatory changes in the bowel, and the diarrhea noted clinically cannot be established. Bronchiolifts and emphysema, with an infiltrate of lymphoeytes in the walls of t h e bronchioles, were present in both infants and suggest the possibility that a viral agent might have been responsible for both the pulmonary and intestinal lesions; again, however, proof of this is lacking. In one infant the inflammatory infiltrate in the walls of the bronehioles also involved the interalveolar septa, and neutrophils were present within a number of alveoli; in this infant the possibility of a parenteral diarrhea secondary to bronehopnenmonia cannot be excluded. In any event, death probably occurred as a result of metabolic disturbances secondary to diarrhea. The inclusion of these infants among those who died as a result of an infectious process appears to be justified, and they are
rather arbitrarily considered as examples of acute enteritis of undetermined etiology.
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Isolated examples of staphylococcal pulmonary abscess, interstitial myocarditis, rheumatic earditis, postinfeetious (measles) encephalitis, chronic aspiration pneumonia, and chronic interstitial pneumonia were also included in the group of patients dying as the result of infections. The chronic aspiration pneumonia occurred in a Negro female infant 2 ~ years old with microcephaly, congenital panhypopituitarism, and congenital heart disease, who had had symptoms referable to the congenital malformations since birth. She had been hospitalized on several occasions prior to her final admission, at which time she wasdead at the time of arrival. The chronic interstitial pneumonia occurred in association with an organizing pneumonia in a small, premature infant 1 month of age who had been hospitalized elsewhere since birth; she died while being transferred to St. Christopher's Hospital for Children. The interstitial myoearditis occurred in an infant 7 89 months of age in whom mild symptoms had been present for about two days, but who died shortly after admission to the hospital. At necropsy the heart was enlarged and there was endocardial sclerosis confined to the left atrium, ttistologically there was severe edema of the interstitial tissue of the myocardium, with focal and diffuse infiltrates of lymphocytes. The importance of examining multiple sections of the myoeardium in order to demonstrate the presence of "isolated myocarditis" has been emphasized by others and was well exemplified here, since the inflammatory infiltrate was entirely absent in some of the sections prepared.
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CONGENITAL MALFOI~MATIONS The t y p e s of congenital m a l f o r m a tions e n c o u n t e r e d are listed in Table IV. A m o n g the patients w i t h congenital h e a r t disease, exclusive of the instances of endocardial sclerosis, the ages r a n g e d f r o m 12 days to 6 years, only f o u r p a t i e n t s being older t h a n 6 months. F o r one p a t i e n t no record of the presence or absence of preexisting cardiac disease was available. I n two p a t i e n t s no cardiac disease had been recognized p r i o r to the t e r m i n a l illness, b u t the r e m a i n i n g ten p a t i e n t s were known to have congenital cardiac TABLE ~V.
age this was associated w i t h a widely p a t e n t ductus arteriosus. I n the second infant, 5 months of age, there was questionable c o a r e t a t i o n of the a o r t a in addition to a low i n t e r v e n t r i c u l a r septai defect. The possibility t h a t the so-called " c o a r e t a t i o n " of the a o r t a r e p r e s e n t e d only the n o r m a l physiologic n a r r o w i n g which is c o m m o n l y e n c o u n t e r e d in small i n f a n t s in the descending a o r t a b e t w e e n the left subclavian a r t e r y and the duetus a r t e r i o s u s could not be excluded. I n b o t h instances the h e a r t was over twice its n o r m a l size, a n d severe pul-
CONGENITAL MALFORMATIONS
Tetralogy of Fallot Transposition of great vessels with interventricular septal defect Endocardia] sclerosis Endocardial sclerosis with coarctatlon of aorta Atrioventrieularis communis with patent ostium secundum Atrioventricularis communis with pulmonary stenosis Atrioventricularis communis with anomalous pulmonary ,/enous return Anomalous pulmonary venous return (partial) with pulmonary hypertension Transposition with overriding pulmonary artery (Taussig-Bing) Cot bilocutare with pulmonary atresia Cot triloculare biatrlum with rudimentary left ventrieular outflow chamber Interventricular septal defect with patent ductus arterlosus Interventricular septal defect (with coarctation?) tIydranencephaly Diaphragmatic hernia Total malformations. Two patients with mongolism are included in this group of congenital malformations; a third child with mongolism and congenital h e a r t disease (Eisenmenger's complex) died as a result of severe bronehopneumonia and a fourth as a result of postinfectious encephalitis; these last two are therefore included in the group dying as a result of infections. No a t t e m p t will be made to discuss all of the congenital m a l f o r m a t i o n s of the h e a r t encountered. The two inf a n t s w i t h simple i n t e r v e n t r i c u l a r septal defects, however, deserve special mention. I n one i n f a n t 6 months of
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m o n a r y congestion was p r e s e n t histologically. I n the first i n f a n t increased p u l m o n a r y blood flow m a y have resulted f r o m the left-to-right s h u n t b r o u g h t about both b y the widely p a t e n t ductus arteriosus a n d b y the i n t e r v e n t r i e u l a r septal defect. I n the second i n f a n t the e x p l a n a t i o n of the cardiac h y p e r t r o p h y and p u l m o n a r y congestion is not as a p p a r e n t . The possibility t h a t these were l a r g e l y the result of the n a r r o w i n g of the a o r t a could not be excluded b u t seemed unlikely because of the m i n o r degree of this n a r r o w i n g . A l t h o u g h mild bronc h o p n c u m o n i a and r i g h t otitis media
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were also p r e s e n t in this infant, the findings i n d i c a t e d t h a t d e a t h occurred as a result of left-sided cardiac failure. I n both infants, then, the observations suggest t h a t i n t e r v e n t r i e u l a r septal defects, especially if associated with other lesions which m i g h t enhance the pressure in the left ventricle or m i g h t increase p u l m o n a r y blood flow, m a y not be the innocuous lesions t h a t t h e y are c o m m o n l y considered to be, a n d m a y even be lethal in e a r l y infancy.
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irritability, fever, cough, dyspnea, and eyanosis. P r i o r to d e m o n s t r a t i o n of the enlarged heart b y physical or roentgenologic examination these symptoms were u s u a l l y a t t r i b u t e d to a r e s p i r a t o r y infection. A t post-mortern e x a m i n a t i o n there was severe cardiac e n l a r g e m e n t , with thickening a n d opacity of the m u r a l e n d o e a r d i u m a n d increased p r o m i n e n c e of the columnae earneae at the apex of the left ventricle (Fig. 3). The v a l v u l a r
l~ig. 3 . - - E n d o c a r d i a l s c l e r o s i s in a n i n f a n t 6 ~ m o n t h s of a g e . N o t e t h e h y p e r t r o p h y of t h e m y o c a r d i u m of t h e l e f t v e n t r m l e , t h e t h i c k , o p a q u e m u r a l e n d o c a r d i u m a n d t h e p r o m i n e n t eolumnae carneae at the apex. T h e a o r t a is n a r r o w e d a t t h e l e v e l of t h e e n t r a n c e of t h e ductus arteriosus.
E n d o e a r d i a l sclerosis was responsible f o r the d e a t h of three infants, all b e t w e e n 6 a n d 7 m o n t h s of age. The d u r a t i o n of s y m p t o m s in one patient, in w h o m t h e r e was an associated e o a r e t a t i o n of the a o r t a is not recorded; s y m p t o m s w e r e of only two d a y s ' d u r a t i o n in the r e m a i n i n g two infants. The clinical m a n i f e s t a t i o n s were quite nonspeeifie, i.e., lassitude,
e n d o e a r d i u m was not involved and the changes were p r e d o m i n a n t l y in the left side of the heart. I n one p a t i e n t d e a t h was a t t r i b u t e d to h y d r a n e n e e p h M y , the e e r e b r a 1 hemispheres being v i r t u a l l y absent a n d the laterM ventricles covered b y a thin, delicate m e m b r a n e . A diagnosis of c y t o m e g a l i e inclusion disease h a d bean m a d e w i t h i n a few days
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a f t e r the birth of this infant, the characteristic inclusion bodies being present in the urine and subsequently in fluid obtained by " s u b d u r a l " ( p r o b a b l y ventricular) p u n e t u r e. D e a t h occurred at the age of 1 year. No inclusion bodies were noted in the r e m n a n t s of the brain at necropsy, but t h e y were present in the salivary glands, kidney, pylorus, and thyroid. One i n f a n t died at 1 day of age as a result of a left d i a p h r a g m a t i c hernia. A superficial tentorial tear, minimal bronchopneumonia, and " h y p o p l a s i a " of the left lung were also n o t e d at autopsy. MISCELLANEOUS CAUSES OF DEATH The miscellaneous causes of death are listed in Table V. TABLE V. MISCELLANEOUSCAUSESOF DEATZ4 Intestinal obstruction and/or perforation Poisoning Fibrocystic disease of the pancreas Pulmonary hyaline membranes Malignant lymphoma Acute glomerulonephritis Chronic glomerulonephritis Diabetes mellitus Renal tubular necrosis, severe Aplastic anemia with cerebral hemorrhage Galactosemia Erythroblastosls fetalis Fetal anoxia (580 gram premature infant) Total
6 5 2 2 2 1 1 1 1 1 1 1 1 25
Six patients died as a result of intestinal obstruction a n d / o r perforation. Their ages r a n g e d f r o m 6 89 weeks to 6 years, and only one was more t h a n 2 years of age. Clinical manifestations had been present for one a n d one-half to six days in all of the p a t i e n t s ; in only one was there a n y k n o w n pre-existing disease (anap h y l a c t o l d p u r p u r a ) . The types of lesions e n c o u n t e r e d are listed in Table VI.
PEDIATRICS
Certainly intestinal obstruction or p e r f o r a t i o n cannot be considered as a cause of u n e x p e c t e d death occurring w i t h o u t p r e m o n i t o r y symptoms, tIowever, the severity of the illness m a y not be appreciated b y the parents or physician, and death m a y occur as a result of p e r f o r a t i o n with peritonitis or imbalance of fluids and electrolytes. The present group of patients f u r t h e r emphasizes the importance of early recognition and t r e a t m e n t of such conditions. Five patients died as a result of poisoning. The youngest infant, 35 days old, had had boric acid packs applied to the buttocks because of the presence of excoriation of the skin of the scrotum and buttocks, pres u m a b l y the result of diarrhea. W h e n first seen he was in extremis, d y i n g while still in the outpatient department. He was severely dehydrated, the b u t t o c k s were wasted, and there was severe excoriation of the skin of the buttocks and scrotum, the latter a p p e a r i n g fiery red. Caked masses of boric acid were present over the buttocks and scrotum. Post-mortem examination revealed histologic evidence of acute enteritis, with an exudate of neutrophils in the glands at the base of the lamina p r o p r i a of the small intestine; there was a questionable increase of myeloid cells in the lamina p r o p r i a of the small intestine but no evidence of acute inflammation of the mesenteric l y m p h nodes. A n u m b e r of the acinar cells of the pancreas TABLE VI. INTESTINAL OBSTRUCTION AND/OR PERFORATION
Intussusception u Mesenteric hernia Acute appendicitis with perforation Perforation of rectosigmoid (glass?) Total
2 1 1 1 1 6
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Fig. 4 . - - C o s s junction f r o m a child 3 y e a r s of a g e w i t h no evidence of lead poisoning. T h e n o r m a l m e t a p h y s e a l z o n e silould be c o m p a r e d w i t h t h a t p r e s e n t in F i g 5. (• r e d u c e d 1~. )
Fig. 5 . - - C o s t o c h o n d r a l j u n c t i o n f r o m a c h i l d 2 y e a r s of a g e w i t h l e a d p o i s o n i n g , N o t e t h e b r o a d z o n e of c l o s e l y p a c k e d , p e r s i s t e n t c a r t i l a g i n o u s t r a b e c u l a e in t h e m e t a p h y s i s . I t is t h i s z o n e w h i c h is r e s p o n s i b l e f o r t h e d e n s e r a d i o p a q u e line v i s i b l e in t h e r o e n t g e n o g r a m s . (X15; r e d u c e d 1/~.)
534
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contained discrete cytoplasmic vacuoles, some of which contained spherical blue bodies. Specimens of liver, kidney, and brain were submitted to Dr. Russell S. Fisher, Chief Medical Examiner of the State of Maryland, for determination of their content of boric acid. The results were as follows: kidney: 100.1 rag. per cent as boric acid; liver: 71.0 rag. per cent; brain: 107.0 rag. per cent. The boron equivalents of these were 17.5, 12.4, and 18.7 rag. per cent, respectively, quantities of boron which were believed by Dr. Fisher to be of clinical significance. 1~ However, it was his impression that such quantities of boron were somewhat lower than those generally encountered in fatal boric acid poisoning, and that the boric acid poisoning merely served as a contributory factor to the death of the infant. Perhaps the combination of acute enteritis, dehydration, and boric acid poisoning should be considered as responsible for death. The changes in the pancreas are suggestive of those described in patients with boric acid poisoning. 16 One infant 22 months of age died as a result of severe pulmonary edema and bronchopneumonia approximately three and one-half hours after ingesti n g lighter fluid. Three children died as a result of lead enccphalopathy. They were 2, 2, and 3 years of age, respectively. Mild symptoms had been present from ten days to two months p r i o r to admission to the hospital; severe symptoms were from fifteen hours' to two and one-half days' duration. Postmortem examination revealed evidence of severe cerebral edema in all, the cerebral convolutions being broad ,and flat and the sulci shallow. Histo-
OF
PEDIATRIC8
logic examination of the costochondral junctions revealed persistence of the calcified cartilaginous trabeeulae at the line of ossification. 17 About the trabcculae were considerable numbers of multinucleated giant cells (Figs. 4 and 5). Intranuclear aeidophilic inclusion bodies were present in the kidney in all three patients2 s In one the inclusions stained positively with the Kinyoun stain for acid-fast structures. The importance of routine histologic examination of the costochondral junctions was emphasized by the observations in these patients dying as a result of lead encephalopathy. In one instance the diagnosis was first suggested because of the abnormal persistence of calcified cartilaginous
Fig. 6.--Roentgenograms of eostochondral junctions a f t e r f i x a t i o n i n 10 p e r c e n t f o r malin. The specimen on the left is from a child 3 years of age with no evidence of lead poisoning. That on the right is from a child 3 years of age with lead poisoning. Note the broad radiopaque metaphyseal zone in the latter.
trabeculae at the line of ossification of the ribs. Subsequently, roentgen films of excised ribs which had been preserved in 10 per cent formalin revealed abnormally wide densities at the costochondral junctions (Fig. 6), and correlation of the clinical record with the macroscopic and histologic findings of the post-mortem examination established the diagnosis beyond reasonable doubt.
AREY
AND SOTOS:
UNEXPECTED
Two patients died as a result of fibroeystie disease of the pancreas. One of these, a n e w b o r n infant 18 hours of age, died as a result of meconium peritonitis following perforation of the colon; histologie examination confirmed the diagnosis of fibroeystie disease of the pancreas. The second infant, 61/2 months of age, had had mild fever, vomiting, and diarrhea for a period of about four days, followed b y evidence of severe
DEATH
IN EARLY
LIFE
535
Langerhans, and increased amounts of interstitial connective tissue (Fig. 7). The lungs were somewhat emphysematous; the changes commonly associated with fibrocystie disease of the pancreas were also a p p a r e n t in Brunn e r ' s glands, the intestinal glands, and in the glands of the trachea and bronchi. Since this i n f a n t died during a period of excessive heat in August, it seemed highly probable t h a t death had occurred as a result
F i g . 7 . - - l W i b r o e y s t i e d i s e a s e of t h e p a n c r e a s . N o t e t h e d i l a t e d a c i n l filled w i t h s e c r e t i o n a n d the increase of connective tissue. A p o r t i o n of a n o r m a l i s l a n d o f L a n g e r h a n s is p r e s e n t in the lower right-hand corner. (• r e d u c e d ~/~.)
d e h y d r a t i o n for only five and onehalf hours prior to death. No clinical manifestations suggestive of fibrocystic disease of the pancreas had been noted. Post-mortem examination revealed evidence of severe dehydration, but no explanation for this was apparent until histologie preparations of the pancreas were examined. These revealed well-advanced dilatation of the pancreatic aeini with "inspissat i o n " of secretion, disappearance of many aeini, r e t e n t i o n of islets of
of the excessive loss of sodium, such as is k n o w n to occur in patients with fibrocystie disease of the pancreas29, 20 No a t t e m p t will be made to discuss the remaining patients, whose deaths were a t t r i b u t e d to a v a r i e t y of causes. However, some mention should be made of the eighteen infants and children (17 per cent) in whom no obvious cause of d e a t h was a p p a r e n t a f t e r completion of the post-mortem examination (Table V I I ) . Their ages varied from 24 hours to 31/2 y e a r s ;
536 TABLE VII.
THE JOURNAL OF PEDIATRICS PATIENTS WITtt NO ANATOMIC CAUSE Ot~ ])EATIt
Cerebral damage Bronehopneumonia, mild Interventrieular sepia] defect Chondrodystrophy Bilateral tentorial tears Anemia, severe (abruptio placentae) No significant lesions Total
6 2 1 1 1 1 6 18
twelve were less than 6 months of age. In four of these patients the death may be considered as sudden, occurring in previously healthy infants. Five patients in whom no immediate cause of death was apparent were known clinically to have cerebral lesions of some type, as manifested by spastic quadriplegia, hypotonic cerebral palsy, microcephaly, and failure of development. Since the lesions encountered at autopsy in the central nervous systems of these patients appeared to have been of some duration, probably having had their onset at or before birth, these patients are arbitrarily included in the group in whom the cause of death was undetermined. In still a sixth patient included in this group, in whom realnourishment had been a prominent clinical manifestation since shortly after birth, there were bilateral encapsulated subdural hydromas demonstrated at the post-mortem examination. Again, because of the apparent chronicity of these lesions they are not considered as affording an adequate explanation for the death of the infant at the time it occurred. Nevertheless, in all these six patients it must be admitted that death may well have been in some way related to the cerebral damage, even though this had been compatible with existence for a considerable period of time, and
the decision to include them in the group of patients in whom no cause of death was demonstrated is a purely arbitrary one. In two of these six patients mild bronchopneumonia was present but was considered insufficient to be responsible for death. In a third patient there was clinical evidence of dehydration. Thus, it seems probable that infants and children with severe damage to the central nervous system may die as the result of relatively minor illnesses which would not be fatal to an otherwise normal child. DISCUSSION
Unexpected or unanticipated deaths include: (1) those occurring after a brief and apparently mild illness, and (2) sudden deaths occurring in apparently healthy infants and children. Such an arbitrary division is not always a valid one, however, and is dependent in part upon the accuracy of clinical observations in the period preceding death. The present discussion is concerned primarily with the former group of patients, only ten of the 103 patients actually dying suddenly and unexpectedly while in apparent good health. Septicemia was responsible for six of the ten sudden deaths and for ten of the ninety-three deaths occurring during the course of a recognized illness. An attempt has been made to inelude as causes of death only those lesions which might be accepted by the majority of pathologists, and to abstain from attributing death to lesions of doubtful significance. Thus, although mild or questionable degrees of cellular infiltrates were occasionally encountered in the interalveolar septa in these patients, they were not
AREY A N D SOTOS:
UNEXPECTED DEATH IN EARLY LIFE
accepted as an adequate anatomical cause of death. Comparable changes m a y be f o u n d in infants dying of a v a r i e t y of causes, and m a y also be observed in some surgically removed specimens of lung. Such morphologic changes have been a t t r i b u t e d to a viral infection TM 22 but, with few exceptions, careful a t t e m p t s to isolate a virus have been unsuccessful.", 23 F u r t h e r m o r e , evaluation of the presence or absence of slight thickening and mild inflammatory infiltration of the interalveolar septa is often difficult in small infants because of approximation of adjoining alveolar septa and because of the relatively wide septa n o r m a l l y present in the lungs of y o u n g infants, especially those b o r n p r e m a t u r e l y . As a result, the diagnosis of mild interstitial pneumonitis has often been an equivocal one and does not a p p e a r t o explain the deaths of these infants on an anatomical basis. Such a diagnosis has often been used to indicate the presence of an overwhelming infection,24, 25 but in the absence of positive cultures of bacteria f r o m the blood stream the presence of a mild interstitial pneumonitis does not appear sufficient to substantiate the occurrence of an overwhelming septicemia. There is no i n t e n t to deny the occurrence of inflammatory processes wholly or in large p a r t confined to the interstitial tissue of the lung. The occurrence of such lesions in association with atypical pneumonia, pertussis, plasma cell pneumonia, and the like, is too well recognized to necessitate f u r t h e r mention. However, the lesions usually described as interstitial pneumonia in infants dying suddenly are h a r d l y comparable to
537
these more generally accepted entities, and do not appear to be an adequate cause of death. A s p i r a t e d gastric contents, e.g., curdled milk, are commonly encountered in the t r a c h e a of infants dying of a v a r i e t y of causes. In the absence of other findings d e a t h is often att r i b u t e d to suffocation secondary to aspiration of Vomitus. In the presence of some well-recognized disease process, however, such aspiration is usually considered only as an incidental, inconsequential finding. In either event, it seems more logical to consider the aspiration of vomitus as an agonal occurrence and not .as a p r i m a r y cause of death. Massive aspiration of gastric contents should not occur in otherwise h e a l t h y infants with intact cough reflexes, and in the absence of definite evidence of obstruction, as b y a bolus of food lodged in the larynx, death should not be a t t r i b u t e d to this cause. Much has been w r i t t e n concerning the occurrence of accidental suffocation b y bedclothes as a cause of death in a p p a r e n t l y h e a l t h y infants, but no substantial evidence of the occurrence of such a process is available. 2" The diagnosis of suffocation should not be made simply because an infant is f o u n d dead face down in bed, nor is such a diagnosis justified m e r e l y because significant lesions are absent at the time of autopsy. Complete postm o r t e m examinations, including bacteriologic studies, will reveal infections as the cause of most such deaths, b u t in some no adequate cause of death can be demonstrated. In the absence of an unequivocal history of suffocation, e.g., homicidal suffocation or accidental s t r a n g u l a t i o n by hanging, such deaths should not be attrib-
538
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uted to suffocation and tile family should be made to u n d e r s t a n d that Lhey were in no way responsible for the death of their child. The pathologist can p e r f o r m a real service to the f a m i l y b y establishing the actual cause of death, and b y his refusal to incriminate the family on inadequate evidence. Failure to recognize the r a p i d i t y with which thymic involution may occur in association with a v a r i e t y of illnesses has led to an erroneous conception of the size of the normal thymus in infants and children. Since the m a j o r i t y of deaths in early life are p r e c e d e d by an illness of at least a few days' duration, a normal (or relatively large) thymus is the exception r a t h e r than the rule in any routine post-mortem series. Moreover, the relatively large size of the lymph nodes and lymphoid aggregates usually e n c o u n t e r e d at autopsies in children is not generally appreciated. As a result, the concomitant occurrence of p r o m i n e n t lymph nodes and lymphoid aggregates and an " e n l a r g e d " thymus in infants and children dying suddenly while in a p p a r e n t good health, or following anesthesia, minimal infections, or other trivial causes, has led to the t h e o r y of lymphatism or status thymieolymphaticus. These so-called thymic deaths have been a t t r i b u t e d to a v a r i e t y of vague and u n p r o v e d causes, including suffocation b y t r a c h e a l compression, anaphylaxis, the liberation of " t h y m i c l y m p h t o x i n " and adrenal insufficiency. That some such deaths m a y result from adrenal insufficiency has been neither p r o v e d nor disproved, but there is no conclusive evidence t h a t the t h y m u s per se is in any way responsible for these deaths, and the
t e r m "status t h y m i c o l y m p h a t i e u s " might b e t t e r be omitted from medical writings. SUMMARY
An adequate cause of death has been d e m o n s t r a t e d in eighty-five of 103 infants and children who either were dead at the time of arrival in the hospital or died within twentyf o u r hours after admission; only ten in the entire group can be considered as sudden, u n e x p e c t e d deaths occurring in previously healthy infants. Infections were the leading cause of death, being responsible for fortytwo of the 103 deaths; minor infections, such as otitis media or mini: real pneumonie processes, were not considered an adequate explanation of the death of an i n f a n t or child. The i m p o r t a n c e of obtaining post-mortem cultures of the blood of infants who die suddenly and u n e x p e c t e d l y is emphasized, and the significance of the presence of different types of microorganisms in post-mortem cultures of the blood is discussed. Congenital malformations, involving especially the heart, were responsible for eighteen of the 103 deaths. In over one-half of these patients the presence of a congenital malformation had been recognized for some time p r i o r to death. Mild cellular infiltrates in the interalveolar septa were not included as a cause of death, nor was aspiration of gastric contents into the trachea. There was no evidence that any of the infants died as a result of suffocation. It is suggested that the term "s t atus t h y m i c o l y m p h a t i c u s " might b e t t e r be omitted from medical writings.
AREY AND SOTOS:
UNEXPECTED DEATH IN EARLY LIFE
REFERENCES 1. Farber, S.: U n e x p e c t e d Death in E a r l y Life, New E n g l a n d J. Med. 219: 836, 1938. 2. Werne, J., and Garrow, I.: Sudden Deaths of I n f a n t s Allegedly Due to Mechanical Suffocation, Am. J. Pub. I t e a l t h 37: 675, 1947. 3. Werne, J., a n d Garrow, I.: Sudden A p p a r e n t l y U n e x p l a i n e d D e a t h During I n f a n c y . I. P a t h o l o g i c F i n d i n g s in Inf a n t s F o u n d Dead, Am. J. P a t h . 29: 633, 1953. II. P a t h o l o g i c F i n d i n g s in I n f a n t s Observed to Die Suddenly, Am. J. P a t h . 29: 817, 1953. III. Pathologic F i n d i n g s in I n f a n t s D y i n g I m m e d i a t e l y A f t e r Violence, C o n t r a s t e d W i t h Those A f t e r Sudden A p p a r e n t l y Unexplained Death, Am. J. P a t h . 29: 833, 1953. 4. Carroll, G. J.: Sudden D e a t h in I n f a n t s , J. PEDIAT. 45: 401, 1954. 5. Bowden, K.: Sudden D e a t h or Alleged Accidental Suffocation in Babies, M. J. A u s t r a l i a 1: 65, 1950. 6. Adelson, L.: No A n a t o m i c Cause of Death. The E n i g m a of the Forensic Pathologist, Connecticut 1VL J. 18: 732, 1954. 7. Lanman, J. T.: A d r e n a l Steroids in Meningococcemia, J. PEDIAT. 46: 724, 1955. 8. Klein, R.: A d r e n a l F u n c t i o n in I n f a n t s and Children, T h i r t e e n t h M & R Pedia t r i c Research Conference, Nov., 1954, p. 36. 9. Kelley, u C.: A d r e n a l F u n c t i o n in Infants and Children, T h i r t e e n t h M & R P e d i a t r i c Research Conference, Nov., 1954, p. 95. 10. Rich, A. R.: A P e c u l i a r Type of Adrenal Cortical Damage Associated W i t h Acute Infections, and I t s Possible Relation to Circulatory Collapse~ Bull. J o h n s Hopkins Hosp. 74: 1, 1944. 11. Spain, D. 1VL, Bradess, V. A., and Greenblurt, I. J.: Possible F a c t o r in Sudden and Unexpected D e a t h During I n f a n c y , J. A. M. A. 156: 246, 1954. 12. Donohue, W . L . : Alymphoeytosis, Pediatrics 11: 129, 1953. 13. Keidan, S. E., McCarthy, K., and I-Iaworth, J. C.: F a t a l Generalized Vac-
14.
15. 16. 17.
18.
19.
20.
21.
22. 23.
24.
25. 26.
539
cinia W i t h Failure of A n t i b o d y Production and Absence of Serum Gamma Globulin, Arch. Dis. Childhood 28: 110, 1953. Craig, J. M., Gitlin, D., and J e w e t t , T. C.: The Response of Lymph Nodes of Normal and Congenitally Agammaglobulinemie Children to Antigenic Stimuli, Am. J. Dis. Child. 88: 626, 1954. Fisher, R. S.: P e r s o n a l communication. Fisher, B. S.: I n t r a e y t o p l a s m i c Inclusions in the P a n c r e a s Due to Boric Acid Poisoning, Am. J. P a t h . 27: 745, 1951. Park, E. A., J a c k s o n , D., and Kajdi, L.: Shadows Produced b y Lead in the X-ray P i c t u r e s of t h e Growing Skeleton, Am. J. Dis. Child. 41: 485, 1931. Blaekman, S. S., Jr.: I n t r a n u c l e a r Inclusion Bodies in the Kidney and Liver Caused by L e a d Poisoning, Bull. J o h n s Hopkins Hosp. 58: 384, 1936. Kessler, W. B., a n d Andersen, D. H.: H e a t P r o s t r a t i o n in Fibrocystic Disease of the P a n c r e a s a n d Other Conditions, P e d i a t r i c s 8: 648, 1951. DiSant'Agnese, P. A., Darling, R.' C., Perera, G. A., and Shea, E.: Abnormal Electrolyte Composition of Sweat in Cystic Fibrosis of the Pancreas. Cllnlcal Significance and Relationship to the Disease, P e d i a t r i c s 12: 549, 1953. Gruenwald, P., and Jaeobi, M.: Mononuclear P n e u m o n i a in Sudden Death or Rapidly F a t a l Illness in I n f a n t s , J. PEDIAT. 39: 650, 1951. Adams, J. M.: Sudden Death in I n f a n t s Due to Pneumonia, J. PEDIAT. 23: 189, 1943. Bowden, K. M., and French, E. L.: Unexpected D e a t h in I n f a n t s and Young Children: Second Series, M. J. A u s t r a l i a 1: 925, 1951. Farber, S.: F u l m i n a t i n g Streptococcus I n f e c t i o n s in I n f a n c y as a Cause of Sudden Death, New E n g l a n d J. 1V[ed. 9.11: 154, 1934. Goldbloom~ A., and Wiglesworth, F. W.: Sudden D e a t h in I n f a n c y , Canad. M. A. J. 38: 119, 1938. Woolley, P. V., Jr.: ~r Suffocation During I n f a n c y . A Comment on I t s Relation to the Total Problem of Sudden Death, J. PEDIAT. 26: 572, 1945.
F den,
F r o m St. C h r i s t o p h e r ' s H o s p i t a l f o r Child r e n a n d t h e D e p a r t m e n t s of P e d i a t r i c s a n d P a t h o l o g y , T e m p l e U n i v e r s i t y School of M e d i cine. *Present address : Children's Hospital, C o l u m b u s , Ohio.
servations whenever these are available. During the six-year period, 1949 to 1954 inclusive, there were 95,195 new admissions to the outpatient department of St. Christopher's Hospital for Children, and 18,366 infants and children were admitted to the hospital. Thirty-three patients were dead at the time of arrival, ten died in the outpatient department and seventy-one died within twenty-four hours after admission to the hospital. This represents a mortality of 1.0 per 1,000 total admissions. The over-M1 mortality for patients admitted to the hospitat during this same period was 17.9 per 1,000. Autopsies were performed on 103 of these 114 patients (90 per cent); this represents 31 per cent of all autopsies conducted by the hospital during this period of time. Seventy-six of the 114 patients died during the first year of life. The greatest frequency was during the first two months of life, this period accounting for thirty-five of the 114 deaths. Eighteen patients were between 1 and 2 years of age, and only twenty were older than 2 years. Eighty-five deaths occurred during the months September through April and twenty-nine occurred during the four remaining months. Males and femMes were approximate]y equally represented. Seventy-eight patients were
5~3
524
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Eleven of t h e sixteen patients in white and thirty-six were Negro; this racial distribution is comparable to whom septicemia was considered to be that of the general admissions to the TABLE I. CAUSES OF DEATH hospital. 42 Before any discussion of the vari- Infections Congenital malformations 18 ous lesions encountered at post-mor- Miscellaneous 25 tern examination of these patients is U n d e t e r m i n e d 18 Total 103 begun, certain differences between this material and that commonly reported TABLE I~. :INFECTIONS AS A CAUSE OF DEATH in the literature as " s u d d e n d e a t h " in infants and children should be Septicemia 16 Bronchopneumonia 6 noted. F o r the most part the present Leptomeningitls 6 series consists of infants and children Acute epiglottitis, laryngotracheitis or trueheobronchitis 3 in whom clinical manifestations of Ecthyma gangrenosum 3 illness were present for a variable but Miscellaneous 8 Total 42 usually short period of time prior to death, but in whom for various reasons the severity of the illness was t h e primary cause of death were innot appreciated. Moreover, all pa- fants 6 months or less of age, one of tients dying within twenty-four hours whom died during the neonatal period. after admission to the hospital are in- Only two patients in this group were cluded, regardless of the presence or over 2 years of age. One child, aged absence of previous hospital admis- 2 years 9 months, in whom symptoms sions. Therefore, in approximately had been apparent for only two days, one-third of the 103 patients upon died as a result of staphylococcal pyewhom autopsies were performed a mia secondary to an acute osteomyewell-recognized pre-existing disease, litis of the fibula; multiple abscesses often of a serious nature, was known were present in the heart, kidneys, to have been present for some time and lungs. prior to death. The present material In three patients death was attributis thus not entirely comparable with ed to the presence of bilateral adrenal that often reported as "sudden death" hemorrhages associated with purpura in previously healthy infants and (Waterhouse-Friderichsen syndrome) children and, instead, is more indica(Fig. 1). The infants were 5, 11, and tive of the disease processes respon- 20 months of age. In one of these insible for death following brief and fants symptoms were of twenty-four apparently mild illnesses. hours' duration; in the remaining two, The causes of death among the 103 mild symptoms were present for several patients upon whom post-mortem ex- days, followed by a severe illness of aminations were performed are listed six and one-half and twenty-four hours, in Table I. As with most reported respectively. IIistologic evidence of series of unexpected deaths, infections meningitis, although minimal, was were the leading cause of death, 2-G present in all these infants; in one it accounting for forty-two of the 103 was confined to the spinal leptodeaths. These are tabulated in Table meninges; the meningitis was not II. recognized macroscopically. Neisseria
A R E Y A N D SOTOS:
UiNEXPECTED DEATH I N EARLY LIFE
meningitidi microorganisms were isolated from the blood, cerebrospinal fluid, and nasopharynx of one infant during life, but cultures of the blood and cerebrospinal fluid obtained post mortem were sterile. An atypical meningococcus was isolated from the blood stream of one infant, but blood cultures in the third infant revealed no growth. Nevertheless, because of
Fig. 1.---Bilateral
adrenal
the blood been reportedJ -9 That a comparable clinical picture may occur in the absence of massive adrenal hemorrhage has been demonstrated by Rich, 1~ who described degenerative changes in the adrenal cortex in association with severe acute infections. Blood cultures obtained either during life, immediately post mortem, or at the time of autopsy grew pneu-
hemorrhage. The resDonsible o r g a n i s m d u r i n g life o r a t t h e t i m e of a u t o p s y .
the clinical and pathologic findings these last two infants are included in this group. The mechanism responsible for death in patients with the WaterhouseFriderichsen syndrome is unknown. Conflicting evidence regarding the role of adrenal insufficiency has appeared, and only rarely have low levels of 17-hydroxyeorticosteroids in
525
was
not
identified either
mococci in eight instances and beta hemolytic streptococci in four. In five of these patients the positive blood culture was the only significant finding, no apparent portal of entry being demonstrable at autopsy. In the remaining seven patients, however, the positive blood culture was associated with other evidences of inf e c t i o n which were demonstrable at
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n e c r o p s y ; in two patients there was an associated dermatitis and in one patient each there were pneumonia, necrotizing bronchiolitis, bilateral otitis media, acute omphalitis, and pneumococcal peritonitis associated with lipoid nephrosis. In the entire series of 103 patients there were ten in whom death m a y be considered as having occurred suddenly and u n e x p e c t e d l y in a previously healthy infant. The ages of these ten patients varied from 5 weeks to 4 months. In four of these, death was~ attributed to pneumocoecal septicemia, in two, to beta hemolytic streptococcal septicemia, and in four no cause of death was demonstrated (Table III). In one of these infants dying with septicemia a mild scrotal dermatitis was present, another had bilateral otitis media, and in the remaining four no significant findings were present other t h a n the positive blood culture. TABLE I I I . CAUSES OF SUDDEN, UNEXPECTED DEATHS IN PREVIOUSLY I{EALTtIY INFANTS
Pneumoeoeea] septicemia Beta hemolytic streptococcal septicemia Undetermined Total
4 2 4 10
The significance of positive blood cultures obtained during the agonal period or after death is difficult to evaluate, and the importance of even pathogenic organisms in post-mortem blood cultures is questioned b y some investigators, s In general, however, positive blood cultures of pneumococci, beta h e m o 1 y t i c streptococci, meningococei, or Hemophilus influenzae are obtained at post-mortem examination only from patients in whom other evidences of infection are apparent, or those in whom death
PEDIATRICS
occurs u n e x p e c t e d l y and in whom no other cause of death is a p p a r e n t a f t e r a complete post-mortem examination. The presence of gram-negative bacilli
(Pseudomonas aeruginosa, Proteus vulgaris, and Eseherichia colt) or enterococci in agonal or post-mortem blood cultures is usually of little or no significance ; occasionally, however, when an a p p a r e n t p o r t a l of e n t r y is present, such as ulcerative lesions in the colon and skin associated with ecthyma gangrenosum, their presence in the blood stream m a y be indicative of an actual septicemia. Staphylococci are usually considered as contaminants unless associated with obvious evideuces of infection p r o d u c e d b y these organisms, e.g., metastatic abscesses. The varied significance of different types of organisms in the blood agonally or after death is not entirely clear. It seems possible, however, t h a t the facility with which different organisms m a y invade the blood stream at this time may be as dependent upon t h e i r location and nmnbers within the b o d y as upon intrinsic differences in the bacteria themselves. Thus, the n o r m a l inhabitants of the gastrointestinal tract, usually present in large numbers, are r a t h e r commonly present in the blood stream a f t e r death, but t h e i r presence is usually of little or no significance. Other organisms, such as pneumococci, beta hemolytic streptococci, and H. influenzae, do not usually attain sufficient numbers in the b o d y to be demonstrated in postm o r t e m cultures unless an associated infection produced b y them is also apparent, or unless t h e y occur as p a r t of an overwhelming infection in infants dying suddenly and unexpectedly.
AREY A N D SOTOS:
UNEXPECTED DEATH IN EARLY LIFE
The mechanism responsible for death in this group of patients is certainly not clear. In certain instances the septicemia was merely a part of clearly demonstrable infectious processes within the body, e.g., pneumoeoccal peritonitis or leptomeningitis. In one instance the septicemia was present in association with a widespread pnemnonie process and the clinical manifestations were predominantly those of severe diarrhea with associated hyperelectrolytemia; in this patient the metabolic disturbances may well have been the major factor responsible for death. In still other instances, however, the septicemia was present in association with relatively localized infectious processes, such as otitis m e d i a; or no demonstrable loeaIized infection was present. In such instances, when organisms commonly considered as pathogenic are isolated from the blood stream, death is arbitrarily attributed to septicemia, but it must be recognized that this is only an arbitrary and admittedly unsatisfactory explanation of death. Baeteremia per se is probably of relatively frequent occurrence, and many patients with septicemia recover or die only after manifesting signs and symptoms of an infection for some time. In the present group of patients, however, evidences of severe illness were present for twenty-four hours or less in thirteen of the sixteen patients, and in six of these death occurred suddenly and unexpectedly. Since baeteremia cannot be differentiated from septicemia by isolated cultures of the blood, and since the usual clinical manifestations of sepsis were not apparent, it is obviously impossible to prove that death actually was caused by septicemia. It seems highly
527
probable that their deaths are in ~ way related to infection, but the exact mechanism must, for the present, remain unexplained. Perhaps an inability to respond to infection, assoelated with diminished levels of gamma globulin, 11 may be important, but preliminary studies in our laboratory have failed to demonstrate any apparent relationship between the levels of gamma globulin demonstrable in blood obrained at autopsy and the occurrence of sudden, unexpected death. F u r t h e r work concerning this aspect of the problem is certainly indicated and is currently being conducted. In six patients death was attributed to bronchopneumonia. In no instance was the presence of only a few neutrophils in the alveoli considered adequate to explain the death of an infant or child; all six patients had histologic evidence of a moderate to severe acute inflammatory process in the pulmonary alveoli. Their ages varied from 16 hours to 21/2 years; two were less than 1 month of age. In one patient each the pneumonia was associated with congenital heart disease and otitis media, bilateral otitis media and acute tonsillitis, bilateral otitis media, fetal anoxia, acute omphalitis, and with thromboses of the dural sinuses with infarction of the braitl; in the last patient death may well have occurred as a result of the cerebral changes, but the pneumonia was believed to have antedated the im farction of the brain. In two of the patients in whom death was attributed to pneumonia death occurred after an acute, severe illness of apparently only a few hours' duration. Although mild symptoms were present for some time in several patients, in only one did the acute,
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severe illness exceed twenty-four hours in duration. Leptomeningitis was responsible for the d e a t h of six patients, whose ages r a n g e d f r o m 3 weeks to 2 8 9 years. I n one i n f a n t 22 days old the meningitis was caused b y Proteus morganii and was secondary to a myelomeningocele. I n the r e m a i n i n g p a t i e n t s the responsible organisms were H. influenzae in two, and Mycobacterium tuberculosis, pneumococci, and coliform organisms in one each. The d u r a t i o n of s y m p t o m s in these p a t i e n t s v a r i e d f r o m one a n d one-half days to one week. T h r e e p a t i e n t s died as a result of acute infections of the epiglottis,
three infants whose ages r a n g e d f r o m 2 weeks to 8 months. D i a r r h e a lasting f r o m one to several weeks h a d been present in two and possibly in the t h i r d i n f a n t ; in all there were u l c e r a t i v e lesions of the s c r o t u m and of the p e r i n e u m or buttocks. Ps. aeruginosa microorganisms were obtained in cultures f r o m the stool of one infant. I n the other two, cultures of the blood at the time of p o s t - m o r t e m e x a m i n a t i o n were positive for t h e ' same organism. I n one i n f a n t there were multiple large punched-out ulcers distributed throughout the colon (Fig. 2) ; in another only a mild acute enterocolitis was noted histologically. I n the ~hird infant, 2 months of age, the
Fig. 2.--]V[ultiple u l c e r s of colon. P s e u d o m o n a s aeruginosc4 Streptococcus faeealis, a n d c o l i f o r m o r g a n i s m s w e r e i s o l a t e d f r o m t h e s e lesions, D i a r r h e a h a d b e e n p r e s e n t f o r s e v e r a l w e e k s .
l a r y n x a n d / o r t r a c h e a and bronchi. T h e i r ages v a r i e d f r o m 9 m o n t h s to y e a r s ; only one was less t h a n 2 y e a r s of age. Cultures of the involved areas yielded H. influenzae in one, H. influenzae and pneumococci in one, and Staphylococcus aureus in one. Mild s y m p t o m s were p r e s e n t f r o m one to three d a y s in all of the patients, but the severe illness was as short as two hours p r i o r to the d e a t h of one child in w h o m t h e r e was occlusive swelling of the epiglottis and a r y e p i g l o t t i e folds. E c t h y m a g a n g r e n o s u m was considered responsible for the d e a t h of
l y m p h o i d a g g r e g a t e s of the small and l a r g e intestine were devoid of lymphocytes and were replaced b y a neutrophilic exudate. There was in addition a r e m a r k a b l e p a u c i t y of l y m p h o e y t e s in the mesenterie l y m p h nodes and in the 3/[alpighian corpuscles of the spleen. These findings are similar to those described in a child w i t h "alymphoeytosis, ''12 a n d are suggestive of those associated with a g a m m a g l o b u linemia.13, 14 U n f o r t u n a t e l y , electrop h o r e t i c studies were not available to p r o v e or disprove this diagnosis. I n none of the other p a t i e n t s in the entire series were c o m p a r a b l e evidences
AREY AND SOTOS:
UNEXPECTED
of lymphocytic depletion present to suggest this diagnosis on a morphologic basis. Death was attributed to acute enteritis in two infants 3 and 5 months of age, respectively. Diarrhea of two to five days' duration had been noted clinically. This was associated with dehydration and, in one infant, with severe acidosis. Pr. vulgaris and coliform organisms were isolated from the stools of both infants. Histologically, increased numbers of myeloid cells and nentrophils were present in the lamina propria of the small bowel and the mesenteric lymph nodes contained increased numbers of neutrophils. Certainly the causative relationship between the organisms isolated from the stools, the inflammatory changes in the bowel, and the diarrhea noted clinically cannot be established. Bronchiolifts and emphysema, with an infiltrate of lymphoeytes in the walls of t h e bronchioles, were present in both infants and suggest the possibility that a viral agent might have been responsible for both the pulmonary and intestinal lesions; again, however, proof of this is lacking. In one infant the inflammatory infiltrate in the walls of the bronehioles also involved the interalveolar septa, and neutrophils were present within a number of alveoli; in this infant the possibility of a parenteral diarrhea secondary to bronehopnenmonia cannot be excluded. In any event, death probably occurred as a result of metabolic disturbances secondary to diarrhea. The inclusion of these infants among those who died as a result of an infectious process appears to be justified, and they are
rather arbitrarily considered as examples of acute enteritis of undetermined etiology.
DEATH IN EARLY LIFE
529
Isolated examples of staphylococcal pulmonary abscess, interstitial myocarditis, rheumatic earditis, postinfeetious (measles) encephalitis, chronic aspiration pneumonia, and chronic interstitial pneumonia were also included in the group of patients dying as the result of infections. The chronic aspiration pneumonia occurred in a Negro female infant 2 ~ years old with microcephaly, congenital panhypopituitarism, and congenital heart disease, who had had symptoms referable to the congenital malformations since birth. She had been hospitalized on several occasions prior to her final admission, at which time she wasdead at the time of arrival. The chronic interstitial pneumonia occurred in association with an organizing pneumonia in a small, premature infant 1 month of age who had been hospitalized elsewhere since birth; she died while being transferred to St. Christopher's Hospital for Children. The interstitial myoearditis occurred in an infant 7 89 months of age in whom mild symptoms had been present for about two days, but who died shortly after admission to the hospital. At necropsy the heart was enlarged and there was endocardial sclerosis confined to the left atrium, ttistologically there was severe edema of the interstitial tissue of the myocardium, with focal and diffuse infiltrates of lymphocytes. The importance of examining multiple sections of the myoeardium in order to demonstrate the presence of "isolated myocarditis" has been emphasized by others and was well exemplified here, since the inflammatory infiltrate was entirely absent in some of the sections prepared.
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CONGENITAL MALFOI~MATIONS The t y p e s of congenital m a l f o r m a tions e n c o u n t e r e d are listed in Table IV. A m o n g the patients w i t h congenital h e a r t disease, exclusive of the instances of endocardial sclerosis, the ages r a n g e d f r o m 12 days to 6 years, only f o u r p a t i e n t s being older t h a n 6 months. F o r one p a t i e n t no record of the presence or absence of preexisting cardiac disease was available. I n two p a t i e n t s no cardiac disease had been recognized p r i o r to the t e r m i n a l illness, b u t the r e m a i n i n g ten p a t i e n t s were known to have congenital cardiac TABLE ~V.
age this was associated w i t h a widely p a t e n t ductus arteriosus. I n the second infant, 5 months of age, there was questionable c o a r e t a t i o n of the a o r t a in addition to a low i n t e r v e n t r i c u l a r septai defect. The possibility t h a t the so-called " c o a r e t a t i o n " of the a o r t a r e p r e s e n t e d only the n o r m a l physiologic n a r r o w i n g which is c o m m o n l y e n c o u n t e r e d in small i n f a n t s in the descending a o r t a b e t w e e n the left subclavian a r t e r y and the duetus a r t e r i o s u s could not be excluded. I n b o t h instances the h e a r t was over twice its n o r m a l size, a n d severe pul-
CONGENITAL MALFORMATIONS
Tetralogy of Fallot Transposition of great vessels with interventricular septal defect Endocardia] sclerosis Endocardial sclerosis with coarctatlon of aorta Atrioventrieularis communis with patent ostium secundum Atrioventricularis communis with pulmonary stenosis Atrioventricularis communis with anomalous pulmonary ,/enous return Anomalous pulmonary venous return (partial) with pulmonary hypertension Transposition with overriding pulmonary artery (Taussig-Bing) Cot bilocutare with pulmonary atresia Cot triloculare biatrlum with rudimentary left ventrieular outflow chamber Interventricular septal defect with patent ductus arterlosus Interventricular septal defect (with coarctation?) tIydranencephaly Diaphragmatic hernia Total malformations. Two patients with mongolism are included in this group of congenital malformations; a third child with mongolism and congenital h e a r t disease (Eisenmenger's complex) died as a result of severe bronehopneumonia and a fourth as a result of postinfectious encephalitis; these last two are therefore included in the group dying as a result of infections. No a t t e m p t will be made to discuss all of the congenital m a l f o r m a t i o n s of the h e a r t encountered. The two inf a n t s w i t h simple i n t e r v e n t r i c u l a r septal defects, however, deserve special mention. I n one i n f a n t 6 months of
18
m o n a r y congestion was p r e s e n t histologically. I n the first i n f a n t increased p u l m o n a r y blood flow m a y have resulted f r o m the left-to-right s h u n t b r o u g h t about both b y the widely p a t e n t ductus arteriosus a n d b y the i n t e r v e n t r i e u l a r septal defect. I n the second i n f a n t the e x p l a n a t i o n of the cardiac h y p e r t r o p h y and p u l m o n a r y congestion is not as a p p a r e n t . The possibility t h a t these were l a r g e l y the result of the n a r r o w i n g of the a o r t a could not be excluded b u t seemed unlikely because of the m i n o r degree of this n a r r o w i n g . A l t h o u g h mild bronc h o p n c u m o n i a and r i g h t otitis media
AREY A N D SOTOS:
UNEXPECTED DEATH IN EARLY LIFE
were also p r e s e n t in this infant, the findings i n d i c a t e d t h a t d e a t h occurred as a result of left-sided cardiac failure. I n both infants, then, the observations suggest t h a t i n t e r v e n t r i e u l a r septal defects, especially if associated with other lesions which m i g h t enhance the pressure in the left ventricle or m i g h t increase p u l m o n a r y blood flow, m a y not be the innocuous lesions t h a t t h e y are c o m m o n l y considered to be, a n d m a y even be lethal in e a r l y infancy.
53]
irritability, fever, cough, dyspnea, and eyanosis. P r i o r to d e m o n s t r a t i o n of the enlarged heart b y physical or roentgenologic examination these symptoms were u s u a l l y a t t r i b u t e d to a r e s p i r a t o r y infection. A t post-mortern e x a m i n a t i o n there was severe cardiac e n l a r g e m e n t , with thickening a n d opacity of the m u r a l e n d o e a r d i u m a n d increased p r o m i n e n c e of the columnae earneae at the apex of the left ventricle (Fig. 3). The v a l v u l a r
l~ig. 3 . - - E n d o c a r d i a l s c l e r o s i s in a n i n f a n t 6 ~ m o n t h s of a g e . N o t e t h e h y p e r t r o p h y of t h e m y o c a r d i u m of t h e l e f t v e n t r m l e , t h e t h i c k , o p a q u e m u r a l e n d o c a r d i u m a n d t h e p r o m i n e n t eolumnae carneae at the apex. T h e a o r t a is n a r r o w e d a t t h e l e v e l of t h e e n t r a n c e of t h e ductus arteriosus.
E n d o e a r d i a l sclerosis was responsible f o r the d e a t h of three infants, all b e t w e e n 6 a n d 7 m o n t h s of age. The d u r a t i o n of s y m p t o m s in one patient, in w h o m t h e r e was an associated e o a r e t a t i o n of the a o r t a is not recorded; s y m p t o m s w e r e of only two d a y s ' d u r a t i o n in the r e m a i n i n g two infants. The clinical m a n i f e s t a t i o n s were quite nonspeeifie, i.e., lassitude,
e n d o e a r d i u m was not involved and the changes were p r e d o m i n a n t l y in the left side of the heart. I n one p a t i e n t d e a t h was a t t r i b u t e d to h y d r a n e n e e p h M y , the e e r e b r a 1 hemispheres being v i r t u a l l y absent a n d the laterM ventricles covered b y a thin, delicate m e m b r a n e . A diagnosis of c y t o m e g a l i e inclusion disease h a d bean m a d e w i t h i n a few days
532
THE
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OF
a f t e r the birth of this infant, the characteristic inclusion bodies being present in the urine and subsequently in fluid obtained by " s u b d u r a l " ( p r o b a b l y ventricular) p u n e t u r e. D e a t h occurred at the age of 1 year. No inclusion bodies were noted in the r e m n a n t s of the brain at necropsy, but t h e y were present in the salivary glands, kidney, pylorus, and thyroid. One i n f a n t died at 1 day of age as a result of a left d i a p h r a g m a t i c hernia. A superficial tentorial tear, minimal bronchopneumonia, and " h y p o p l a s i a " of the left lung were also n o t e d at autopsy. MISCELLANEOUS CAUSES OF DEATH The miscellaneous causes of death are listed in Table V. TABLE V. MISCELLANEOUSCAUSESOF DEATZ4 Intestinal obstruction and/or perforation Poisoning Fibrocystic disease of the pancreas Pulmonary hyaline membranes Malignant lymphoma Acute glomerulonephritis Chronic glomerulonephritis Diabetes mellitus Renal tubular necrosis, severe Aplastic anemia with cerebral hemorrhage Galactosemia Erythroblastosls fetalis Fetal anoxia (580 gram premature infant) Total
6 5 2 2 2 1 1 1 1 1 1 1 1 25
Six patients died as a result of intestinal obstruction a n d / o r perforation. Their ages r a n g e d f r o m 6 89 weeks to 6 years, and only one was more t h a n 2 years of age. Clinical manifestations had been present for one a n d one-half to six days in all of the p a t i e n t s ; in only one was there a n y k n o w n pre-existing disease (anap h y l a c t o l d p u r p u r a ) . The types of lesions e n c o u n t e r e d are listed in Table VI.
PEDIATRICS
Certainly intestinal obstruction or p e r f o r a t i o n cannot be considered as a cause of u n e x p e c t e d death occurring w i t h o u t p r e m o n i t o r y symptoms, tIowever, the severity of the illness m a y not be appreciated b y the parents or physician, and death m a y occur as a result of p e r f o r a t i o n with peritonitis or imbalance of fluids and electrolytes. The present group of patients f u r t h e r emphasizes the importance of early recognition and t r e a t m e n t of such conditions. Five patients died as a result of poisoning. The youngest infant, 35 days old, had had boric acid packs applied to the buttocks because of the presence of excoriation of the skin of the scrotum and buttocks, pres u m a b l y the result of diarrhea. W h e n first seen he was in extremis, d y i n g while still in the outpatient department. He was severely dehydrated, the b u t t o c k s were wasted, and there was severe excoriation of the skin of the buttocks and scrotum, the latter a p p e a r i n g fiery red. Caked masses of boric acid were present over the buttocks and scrotum. Post-mortem examination revealed histologic evidence of acute enteritis, with an exudate of neutrophils in the glands at the base of the lamina p r o p r i a of the small intestine; there was a questionable increase of myeloid cells in the lamina p r o p r i a of the small intestine but no evidence of acute inflammation of the mesenteric l y m p h nodes. A n u m b e r of the acinar cells of the pancreas TABLE VI. INTESTINAL OBSTRUCTION AND/OR PERFORATION
Intussusception u Mesenteric hernia Acute appendicitis with perforation Perforation of rectosigmoid (glass?) Total
2 1 1 1 1 6
A R E Y A N D SOTOS:
UNEXPECTED DEATH IN EARLY LIFE
533
Fig. 4 . - - C o s s junction f r o m a child 3 y e a r s of a g e w i t h no evidence of lead poisoning. T h e n o r m a l m e t a p h y s e a l z o n e silould be c o m p a r e d w i t h t h a t p r e s e n t in F i g 5. (• r e d u c e d 1~. )
Fig. 5 . - - C o s t o c h o n d r a l j u n c t i o n f r o m a c h i l d 2 y e a r s of a g e w i t h l e a d p o i s o n i n g , N o t e t h e b r o a d z o n e of c l o s e l y p a c k e d , p e r s i s t e n t c a r t i l a g i n o u s t r a b e c u l a e in t h e m e t a p h y s i s . I t is t h i s z o n e w h i c h is r e s p o n s i b l e f o r t h e d e n s e r a d i o p a q u e line v i s i b l e in t h e r o e n t g e n o g r a m s . (X15; r e d u c e d 1/~.)
534
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contained discrete cytoplasmic vacuoles, some of which contained spherical blue bodies. Specimens of liver, kidney, and brain were submitted to Dr. Russell S. Fisher, Chief Medical Examiner of the State of Maryland, for determination of their content of boric acid. The results were as follows: kidney: 100.1 rag. per cent as boric acid; liver: 71.0 rag. per cent; brain: 107.0 rag. per cent. The boron equivalents of these were 17.5, 12.4, and 18.7 rag. per cent, respectively, quantities of boron which were believed by Dr. Fisher to be of clinical significance. 1~ However, it was his impression that such quantities of boron were somewhat lower than those generally encountered in fatal boric acid poisoning, and that the boric acid poisoning merely served as a contributory factor to the death of the infant. Perhaps the combination of acute enteritis, dehydration, and boric acid poisoning should be considered as responsible for death. The changes in the pancreas are suggestive of those described in patients with boric acid poisoning. 16 One infant 22 months of age died as a result of severe pulmonary edema and bronchopneumonia approximately three and one-half hours after ingesti n g lighter fluid. Three children died as a result of lead enccphalopathy. They were 2, 2, and 3 years of age, respectively. Mild symptoms had been present from ten days to two months p r i o r to admission to the hospital; severe symptoms were from fifteen hours' to two and one-half days' duration. Postmortem examination revealed evidence of severe cerebral edema in all, the cerebral convolutions being broad ,and flat and the sulci shallow. Histo-
OF
PEDIATRIC8
logic examination of the costochondral junctions revealed persistence of the calcified cartilaginous trabeeulae at the line of ossification. 17 About the trabcculae were considerable numbers of multinucleated giant cells (Figs. 4 and 5). Intranuclear aeidophilic inclusion bodies were present in the kidney in all three patients2 s In one the inclusions stained positively with the Kinyoun stain for acid-fast structures. The importance of routine histologic examination of the costochondral junctions was emphasized by the observations in these patients dying as a result of lead encephalopathy. In one instance the diagnosis was first suggested because of the abnormal persistence of calcified cartilaginous
Fig. 6.--Roentgenograms of eostochondral junctions a f t e r f i x a t i o n i n 10 p e r c e n t f o r malin. The specimen on the left is from a child 3 years of age with no evidence of lead poisoning. That on the right is from a child 3 years of age with lead poisoning. Note the broad radiopaque metaphyseal zone in the latter.
trabeculae at the line of ossification of the ribs. Subsequently, roentgen films of excised ribs which had been preserved in 10 per cent formalin revealed abnormally wide densities at the costochondral junctions (Fig. 6), and correlation of the clinical record with the macroscopic and histologic findings of the post-mortem examination established the diagnosis beyond reasonable doubt.
AREY
AND SOTOS:
UNEXPECTED
Two patients died as a result of fibroeystie disease of the pancreas. One of these, a n e w b o r n infant 18 hours of age, died as a result of meconium peritonitis following perforation of the colon; histologie examination confirmed the diagnosis of fibroeystie disease of the pancreas. The second infant, 61/2 months of age, had had mild fever, vomiting, and diarrhea for a period of about four days, followed b y evidence of severe
DEATH
IN EARLY
LIFE
535
Langerhans, and increased amounts of interstitial connective tissue (Fig. 7). The lungs were somewhat emphysematous; the changes commonly associated with fibrocystie disease of the pancreas were also a p p a r e n t in Brunn e r ' s glands, the intestinal glands, and in the glands of the trachea and bronchi. Since this i n f a n t died during a period of excessive heat in August, it seemed highly probable t h a t death had occurred as a result
F i g . 7 . - - l W i b r o e y s t i e d i s e a s e of t h e p a n c r e a s . N o t e t h e d i l a t e d a c i n l filled w i t h s e c r e t i o n a n d the increase of connective tissue. A p o r t i o n of a n o r m a l i s l a n d o f L a n g e r h a n s is p r e s e n t in the lower right-hand corner. (• r e d u c e d ~/~.)
d e h y d r a t i o n for only five and onehalf hours prior to death. No clinical manifestations suggestive of fibrocystic disease of the pancreas had been noted. Post-mortem examination revealed evidence of severe dehydration, but no explanation for this was apparent until histologie preparations of the pancreas were examined. These revealed well-advanced dilatation of the pancreatic aeini with "inspissat i o n " of secretion, disappearance of many aeini, r e t e n t i o n of islets of
of the excessive loss of sodium, such as is k n o w n to occur in patients with fibrocystie disease of the pancreas29, 20 No a t t e m p t will be made to discuss the remaining patients, whose deaths were a t t r i b u t e d to a v a r i e t y of causes. However, some mention should be made of the eighteen infants and children (17 per cent) in whom no obvious cause of d e a t h was a p p a r e n t a f t e r completion of the post-mortem examination (Table V I I ) . Their ages varied from 24 hours to 31/2 y e a r s ;
536 TABLE VII.
THE JOURNAL OF PEDIATRICS PATIENTS WITtt NO ANATOMIC CAUSE Ot~ ])EATIt
Cerebral damage Bronehopneumonia, mild Interventrieular sepia] defect Chondrodystrophy Bilateral tentorial tears Anemia, severe (abruptio placentae) No significant lesions Total
6 2 1 1 1 1 6 18
twelve were less than 6 months of age. In four of these patients the death may be considered as sudden, occurring in previously healthy infants. Five patients in whom no immediate cause of death was apparent were known clinically to have cerebral lesions of some type, as manifested by spastic quadriplegia, hypotonic cerebral palsy, microcephaly, and failure of development. Since the lesions encountered at autopsy in the central nervous systems of these patients appeared to have been of some duration, probably having had their onset at or before birth, these patients are arbitrarily included in the group in whom the cause of death was undetermined. In still a sixth patient included in this group, in whom realnourishment had been a prominent clinical manifestation since shortly after birth, there were bilateral encapsulated subdural hydromas demonstrated at the post-mortem examination. Again, because of the apparent chronicity of these lesions they are not considered as affording an adequate explanation for the death of the infant at the time it occurred. Nevertheless, in all these six patients it must be admitted that death may well have been in some way related to the cerebral damage, even though this had been compatible with existence for a considerable period of time, and
the decision to include them in the group of patients in whom no cause of death was demonstrated is a purely arbitrary one. In two of these six patients mild bronchopneumonia was present but was considered insufficient to be responsible for death. In a third patient there was clinical evidence of dehydration. Thus, it seems probable that infants and children with severe damage to the central nervous system may die as the result of relatively minor illnesses which would not be fatal to an otherwise normal child. DISCUSSION
Unexpected or unanticipated deaths include: (1) those occurring after a brief and apparently mild illness, and (2) sudden deaths occurring in apparently healthy infants and children. Such an arbitrary division is not always a valid one, however, and is dependent in part upon the accuracy of clinical observations in the period preceding death. The present discussion is concerned primarily with the former group of patients, only ten of the 103 patients actually dying suddenly and unexpectedly while in apparent good health. Septicemia was responsible for six of the ten sudden deaths and for ten of the ninety-three deaths occurring during the course of a recognized illness. An attempt has been made to inelude as causes of death only those lesions which might be accepted by the majority of pathologists, and to abstain from attributing death to lesions of doubtful significance. Thus, although mild or questionable degrees of cellular infiltrates were occasionally encountered in the interalveolar septa in these patients, they were not
AREY A N D SOTOS:
UNEXPECTED DEATH IN EARLY LIFE
accepted as an adequate anatomical cause of death. Comparable changes m a y be f o u n d in infants dying of a v a r i e t y of causes, and m a y also be observed in some surgically removed specimens of lung. Such morphologic changes have been a t t r i b u t e d to a viral infection TM 22 but, with few exceptions, careful a t t e m p t s to isolate a virus have been unsuccessful.", 23 F u r t h e r m o r e , evaluation of the presence or absence of slight thickening and mild inflammatory infiltration of the interalveolar septa is often difficult in small infants because of approximation of adjoining alveolar septa and because of the relatively wide septa n o r m a l l y present in the lungs of y o u n g infants, especially those b o r n p r e m a t u r e l y . As a result, the diagnosis of mild interstitial pneumonitis has often been an equivocal one and does not a p p e a r t o explain the deaths of these infants on an anatomical basis. Such a diagnosis has often been used to indicate the presence of an overwhelming infection,24, 25 but in the absence of positive cultures of bacteria f r o m the blood stream the presence of a mild interstitial pneumonitis does not appear sufficient to substantiate the occurrence of an overwhelming septicemia. There is no i n t e n t to deny the occurrence of inflammatory processes wholly or in large p a r t confined to the interstitial tissue of the lung. The occurrence of such lesions in association with atypical pneumonia, pertussis, plasma cell pneumonia, and the like, is too well recognized to necessitate f u r t h e r mention. However, the lesions usually described as interstitial pneumonia in infants dying suddenly are h a r d l y comparable to
537
these more generally accepted entities, and do not appear to be an adequate cause of death. A s p i r a t e d gastric contents, e.g., curdled milk, are commonly encountered in the t r a c h e a of infants dying of a v a r i e t y of causes. In the absence of other findings d e a t h is often att r i b u t e d to suffocation secondary to aspiration of Vomitus. In the presence of some well-recognized disease process, however, such aspiration is usually considered only as an incidental, inconsequential finding. In either event, it seems more logical to consider the aspiration of vomitus as an agonal occurrence and not .as a p r i m a r y cause of death. Massive aspiration of gastric contents should not occur in otherwise h e a l t h y infants with intact cough reflexes, and in the absence of definite evidence of obstruction, as b y a bolus of food lodged in the larynx, death should not be a t t r i b u t e d to this cause. Much has been w r i t t e n concerning the occurrence of accidental suffocation b y bedclothes as a cause of death in a p p a r e n t l y h e a l t h y infants, but no substantial evidence of the occurrence of such a process is available. 2" The diagnosis of suffocation should not be made simply because an infant is f o u n d dead face down in bed, nor is such a diagnosis justified m e r e l y because significant lesions are absent at the time of autopsy. Complete postm o r t e m examinations, including bacteriologic studies, will reveal infections as the cause of most such deaths, b u t in some no adequate cause of death can be demonstrated. In the absence of an unequivocal history of suffocation, e.g., homicidal suffocation or accidental s t r a n g u l a t i o n by hanging, such deaths should not be attrib-
538
THE
J O U R N A L OF P E D I A T R I C S
uted to suffocation and tile family should be made to u n d e r s t a n d that Lhey were in no way responsible for the death of their child. The pathologist can p e r f o r m a real service to the f a m i l y b y establishing the actual cause of death, and b y his refusal to incriminate the family on inadequate evidence. Failure to recognize the r a p i d i t y with which thymic involution may occur in association with a v a r i e t y of illnesses has led to an erroneous conception of the size of the normal thymus in infants and children. Since the m a j o r i t y of deaths in early life are p r e c e d e d by an illness of at least a few days' duration, a normal (or relatively large) thymus is the exception r a t h e r than the rule in any routine post-mortem series. Moreover, the relatively large size of the lymph nodes and lymphoid aggregates usually e n c o u n t e r e d at autopsies in children is not generally appreciated. As a result, the concomitant occurrence of p r o m i n e n t lymph nodes and lymphoid aggregates and an " e n l a r g e d " thymus in infants and children dying suddenly while in a p p a r e n t good health, or following anesthesia, minimal infections, or other trivial causes, has led to the t h e o r y of lymphatism or status thymieolymphaticus. These so-called thymic deaths have been a t t r i b u t e d to a v a r i e t y of vague and u n p r o v e d causes, including suffocation b y t r a c h e a l compression, anaphylaxis, the liberation of " t h y m i c l y m p h t o x i n " and adrenal insufficiency. That some such deaths m a y result from adrenal insufficiency has been neither p r o v e d nor disproved, but there is no conclusive evidence t h a t the t h y m u s per se is in any way responsible for these deaths, and the
t e r m "status t h y m i c o l y m p h a t i e u s " might b e t t e r be omitted from medical writings. SUMMARY
An adequate cause of death has been d e m o n s t r a t e d in eighty-five of 103 infants and children who either were dead at the time of arrival in the hospital or died within twentyf o u r hours after admission; only ten in the entire group can be considered as sudden, u n e x p e c t e d deaths occurring in previously healthy infants. Infections were the leading cause of death, being responsible for fortytwo of the 103 deaths; minor infections, such as otitis media or mini: real pneumonie processes, were not considered an adequate explanation of the death of an i n f a n t or child. The i m p o r t a n c e of obtaining post-mortem cultures of the blood of infants who die suddenly and u n e x p e c t e d l y is emphasized, and the significance of the presence of different types of microorganisms in post-mortem cultures of the blood is discussed. Congenital malformations, involving especially the heart, were responsible for eighteen of the 103 deaths. In over one-half of these patients the presence of a congenital malformation had been recognized for some time p r i o r to death. Mild cellular infiltrates in the interalveolar septa were not included as a cause of death, nor was aspiration of gastric contents into the trachea. There was no evidence that any of the infants died as a result of suffocation. It is suggested that the term "s t atus t h y m i c o l y m p h a t i c u s " might b e t t e r be omitted from medical writings.
AREY AND SOTOS:
UNEXPECTED DEATH IN EARLY LIFE
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