- Email: [email protected]
Fulminating meningococcemia with bilateral adrenal hemorrhage
FULMINATING MENINGOCOCCEMIA W I T H B I L A T E R A I , ADRENAL HEMORRHAGE ( W A T E R t t O U S E - F R I D E R I C H S E N SYNDROME) JACOB A. DANClGER, M.D. NEW YOR~:, N. Y. IXTRODUC~ION
syndrome now known as the Waterhouse-Friderichsen synT HIS drome was first recognized in 1901 by IAttle2 Since 1901 several reviews of the literature have been published describing the syruptomatology and pathology on the basis of sixty-four case reports (Waterhouse, ~ Frider~ehsen, ~ Bamatter, 4 Aegerter, ~ Sacks, Gand LevinsonT). Within the past two years nine more cases have been described, s-~3 Our own case brings the total number described to seventyfour.
Fig. 1 . - - M a s s i v e b i l a t e r a l a d r e n a l h e m o r r h a g e .
The symptomatology of the syndrome is strikingly uniform and classically demonstrated by our ease. Likewise, the pathology in all cases revealed massive bilateral adrenal hemorrhage (Fig. 1). The etiology, however, has been the subject of controversy." Many theories have been proposed, and the most acceptable is one of massive baeterial invasion of the blood stream. Until 1916 the number and variety of organisms cultured from the blood, adrenals, and skin lesions, including streptococcus, staphylococcus, pneumoeoceus, colon F r o m t h e P e d i a t r i c S e r v i c e of Dr. B61a Schick, C h i e f of Staff, M o u n t S i n a i H o s p i t a l . 495
496
THE JOURNAL OF PEDIATRICS
bacillus, Bacillus pyocyaneus, Friedl~nder's bacillus, etc., would lead one to assume t h a t the described syndrome m a y have been caused b y n u m e r o u s different organisms. Since 1916, when MeLagen and Cooke 1~ first isolated the meningococcus f r o m two cases, the literature almost universally implicates the meningococcus as the etiological agent. The w o r k of McLagen and Cooke, 1~ McLean and Caffey, 15 Bamatter, ~ and others leaves little doubt that the most frequent causative agent is the meningococcus. Of the seventy-four cases described, 70 per cent were due to massive blood stream invasion b y the meningoeoceu8.
This f u l m i n a n t syndrome usually runs its striking course to death within t w e n t y - f o u r hours or less. Seventy per cent of the patients were u n d e r the age of 2 years, and 95 per cent u n d e r the age of 6 years. This is the case of a 3-year-old male child of Italian extraction (V. G,). H i s family history was essentially negative, and his p a s t history revealed measles, pertussis, chicken pox, and tonsillectomy. The child had been p e r f e c t l y well until about 5:30 P.~. on Sept. 6, 1939, at which time, while playing outdoors~ he complained to his mother of feeling weak in the legs and having a pain in the right thigh. The mother noticed that the child limped. She took him into the house immediately. Shortly thereafter he had a shaking chill with spastic, somewhat convulsive movements. The mother took his temperature, and it was 103 ~ 1~. The family physician was culled and saw the patient about one and one-half hours after onset of the illness. He could find only u red throat. The child then began to have several more spastic seizures and also vomited several times. About midnight he became lethargic and stuporous and did not respond to the mother's questioning. As the temperature continued to rise, the child was brought to the hospital at about 2:30 A.~., i.e., nine hours after the onset of illness. At this time the temperature was found to be 107 ~ F. On examining the child we found him in a semicomatose s t a t e and unable to answer questions. I-Iis general appearance was that of a very well nourished and well developed m~le child who was practically moribund. There was present marked conjunctivitis; the left eardrum was reddened; the threat was quite red, and a thick mucoid secretion was found in the mouth and pharynx. There was no generalized glandular enlargement. There were no marked changes in the lungs except a few tales which could be heard in the right axilla and over the left lower lobe posteriorly. The heart sounds were very distant and of poor quality. The abdomen was negative except for slight spasticlty of the right upper quadrant. Rectal examination was negative. Neurologically, there was evidence of sluggish deep reflexes; abdominal reflexes were absent, cremasterlc reflexes sluggish, and t
DANCIGER :
]~ULMINATING MENINGOCOCCEMIA
497
At about 4:30 a.~., eleven hours after the onset of the illness, the child became very cyanotic and dyspneic. A continuous intravenous injection of 250 c.c. normM saline was given, followed by a blood transfusion of 300 c.e. The impression was that we were dealing with a fulminating septicemia of unknown type. We had no evidence of meningitis nor of a pneumonia. The smear from the spinal fluid revealed no organisms. The child went into deep coma and became more cyanotic. The pulse became much faster and threadle~ and the respirations, which had been between 50 and 60 per minute, now became very shallow and rapidly developed Chey~te-Stokes character. The skin lesions, which before were maeular and erythematous in appearance, now took on a hemorrhagic character which became more conspicuous as the cyanosis deepened. The cyanosis quickly took on a heliotrope color and looked splotchy, just as is semi a f t e r death. The heart action became poorer. Cardiac stimulants were given, but the child continued to go downhill very rapidly and died at approximately 8:00 A.~., or fourteen and one-half hours after the onset of illness. The laboratory reports were as follows: The sputum revealed pneumocoecus Type X I X . The blood culture was positive for meningocoeeus (30 colonies per cubic centimeter). The spinal fluid culture was negative. The spinal fluid chemistry revealed chlorides, 770 rag. per cent; t~)tal protein, 25 rag. per cent; sugar 55 rag. per cent. The t r y p t o p h a n e test was negative; blood serology was negative. Stool culture revealed B. co~i. Permission for autopsy was obtained, and prior to the post-mortem examination, a smear was made from one of the pnrpuric spots which did ~ot reveal the presence of ~nenlngococci. Pathologic findings were as follows: Gross findings revealed congestion of lungs, h y p e r t r o p h y of mesenterie lymph nodes, and P e y e r ' s patches. The adrenals exhibited the most i m p o r t a n t pathologic findings. They were bluish in color and not enlarged. O n cut section there was seen gross hemorrhage of the medulla and innermost layer of the cortex. Also some blood was seen in the outer corti6al ]ayer.s. The brain was grossly negative. Microscopically, the adrenals showed complete destruction by hemorrhage of the entire medulla and the zona reticularis, so that no pigmentation was seen. Only a few scattered parenchymal cells persisted. Some areas of the cortex were not involved. The lungs and liver showed only marked congestion and edema. The hyperplasia of the mesenteric lymph nodes and Peyer's patches were confirmed by microscopic examination. Small areas of hemorrhage were seen in the kidneys and one testis. The skin hemorrhages were located in the fatty layer of the epidermis. No bacteria were found in the purpuric areas. Microscopic examination of the brain revealed no abnormalities in the leptomeninges. Special stains showed gram-negatlve diploeocci within the leucocytes contained in the meningeal vessels. COMMENT
The diagnosis of this syndrome should be considered in all infants and young children who become suddenly ill with vomiting, diarrhea, and collapse, particularly if the illness is associated with high fever, purpura, and cyanosis. It must be differentiated from other causes of adrenal hemorrhage, such as hemorrhage of the adrenal occurring in the newborn infant, or traumatic adrenal hemorrhage, which are usually not associated with purpura. There should b e l i t t l e difficulty in differentiating the syndrome from such conditions which have been
498
THE
JOURNAL
OF PEDIATR~C~
known to cause adrenal hemorrhage, such as diphtheria, scarlet fever, smallpox, and, occasionally, measles and pneumonia. Massive hemorrhage in the adrenals occurs in guinea pigs after injection of diphtheria toxin. This form of massive adrenal hemorrhage is not seen in diphtheria of the human being. However, the adrenals do show definite pathology. Greater difficulty in diagnosis may be encountered in districts where violent toxic scarlet fever or hemorrhagic smallpox occurs, for these diseases may produce a picture similar to this syndrome. The presence of meningococci in the smear of the purpuric spots (Fig. 2), as pointed out by McLean and Caffey, will certainly facilitate the diagnosis.
F i g . 2 . - - S e c t i o n t h r o u g h p u r p u r i c s p o t s h o w i n g d i l a t a t i o n of b l o o d v e s s e l s a n d p r e s e n c e of m e n i n g o c o c c i w i t h i n t h e s e v e s s e l s .
Up to the present time, the prognosis is fatal. Because of the very fulminant course of the syndrome, the therapy has been, to a great extent, based upon theoretical grounds. There is hope, however, that some of these cases may be saved if the diagnosis is made early enough, Sulfanilamide, intravenous antimeningococeus serum, intravenous saline, transfusions, adrenalin, and cortical extract should be used before the laboratory corroborates the suspected diagnosis. SU1KMA_RY
A case of a patient with the Waterhouse-Frideriehsen syndrome has been described. Seventy-four such cases have been described in the literature. Ninety-five per cent of the patients have been under 6 years of age.
DANCIGER :
FULMINATINGMENINGOCOCCEMIA
499
T h e e t i o l o g y h a s b e e n s h o w n to be the m e n i n g o e o c e u s i n 70 p e r c e n t of t h e cases. S y m p t o m a t o l o g y is s t r i k i n g l y u n i f o r m , w i t h s u d d e n onset, restlessness, a n d g a s t r o i n t e s t i n a l s y m p t o m s , f o l l o w e d s h o r t l y b y cyanosis, p u r p u r a , l e t h a r g y , coma, h i g h fever, a n d d e a t h . Death occurred w i t h i n t w e n t y - f o u r h o u r s or less i n t h e m a j o r i t y of cases. 1Ylassive b i l a t e r a l a d r e n a l h e m o r r h a g e is the m o s t c o m m o n a u t o p s y finding. S u g g e s t e d t h e r a p y i n c l u d e s s u l f a n i l a m i d e , a n t i m e n i n g o e o c c u s serum, i n t r a v e n o u s saline, t r a n s f u s i o n s , a d r e n a l i n , a n d c o r t i c a l e x t r a c t . REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Little, E. G.: Brit. J. Dermat. 13: 445, 1901. Waterhouse, R.: Lancet 1: 576, 191]. Friderichsen, C.: Jahrb. f. Kinderh. 87: 109, 1918. Bamatter, F.: Jahrb. f. Kinderh. 152: 129, 1934. Aegcrtcr, E. •.: J . A . IV[. A. 106: 1715, 1936. Sacks, IV[. S.: Ann. Int. ]Ked. 10: 1105~ 1936-37. Levinson, S.A.: J. PED~AT. 14: 506, ]939. Weingart, J.S.: J. Iowa IV[. Soc. 28: 5~ 1938. ]Y[cNamara, F. P., and Cornell~ W. J.: J. Iowa 1VL Sot. 28: 197, 1938. Crastcr, C. V, and Simon, It.: J . A . 1VLs 110: 1009, 1938. Usher, S . J . : Canad. ]W. A. J. 38: 232, 1938. Kamber, A.: Monatschr. f. Kinderh. 71: 351, 1937. Biddau~ I.: Pediatria 46: 598, 1938. 1VIcLagen, P. W., and Cooke, W . E . : Lancet 2: 1054, 1916. McLean, S., and Caffey, J.: Am. J. Dis. Child. 42: 1053, 1931.
syndrome now known as the Waterhouse-Friderichsen synT HIS drome was first recognized in 1901 by IAttle2 Since 1901 several reviews of the literature have been published describing the syruptomatology and pathology on the basis of sixty-four case reports (Waterhouse, ~ Frider~ehsen, ~ Bamatter, 4 Aegerter, ~ Sacks, Gand LevinsonT). Within the past two years nine more cases have been described, s-~3 Our own case brings the total number described to seventyfour.
Fig. 1 . - - M a s s i v e b i l a t e r a l a d r e n a l h e m o r r h a g e .
The symptomatology of the syndrome is strikingly uniform and classically demonstrated by our ease. Likewise, the pathology in all cases revealed massive bilateral adrenal hemorrhage (Fig. 1). The etiology, however, has been the subject of controversy." Many theories have been proposed, and the most acceptable is one of massive baeterial invasion of the blood stream. Until 1916 the number and variety of organisms cultured from the blood, adrenals, and skin lesions, including streptococcus, staphylococcus, pneumoeoceus, colon F r o m t h e P e d i a t r i c S e r v i c e of Dr. B61a Schick, C h i e f of Staff, M o u n t S i n a i H o s p i t a l . 495
496
THE JOURNAL OF PEDIATRICS
bacillus, Bacillus pyocyaneus, Friedl~nder's bacillus, etc., would lead one to assume t h a t the described syndrome m a y have been caused b y n u m e r o u s different organisms. Since 1916, when MeLagen and Cooke 1~ first isolated the meningococcus f r o m two cases, the literature almost universally implicates the meningococcus as the etiological agent. The w o r k of McLagen and Cooke, 1~ McLean and Caffey, 15 Bamatter, ~ and others leaves little doubt that the most frequent causative agent is the meningococcus. Of the seventy-four cases described, 70 per cent were due to massive blood stream invasion b y the meningoeoceu8.
This f u l m i n a n t syndrome usually runs its striking course to death within t w e n t y - f o u r hours or less. Seventy per cent of the patients were u n d e r the age of 2 years, and 95 per cent u n d e r the age of 6 years. This is the case of a 3-year-old male child of Italian extraction (V. G,). H i s family history was essentially negative, and his p a s t history revealed measles, pertussis, chicken pox, and tonsillectomy. The child had been p e r f e c t l y well until about 5:30 P.~. on Sept. 6, 1939, at which time, while playing outdoors~ he complained to his mother of feeling weak in the legs and having a pain in the right thigh. The mother noticed that the child limped. She took him into the house immediately. Shortly thereafter he had a shaking chill with spastic, somewhat convulsive movements. The mother took his temperature, and it was 103 ~ 1~. The family physician was culled and saw the patient about one and one-half hours after onset of the illness. He could find only u red throat. The child then began to have several more spastic seizures and also vomited several times. About midnight he became lethargic and stuporous and did not respond to the mother's questioning. As the temperature continued to rise, the child was brought to the hospital at about 2:30 A.~., i.e., nine hours after the onset of illness. At this time the temperature was found to be 107 ~ F. On examining the child we found him in a semicomatose s t a t e and unable to answer questions. I-Iis general appearance was that of a very well nourished and well developed m~le child who was practically moribund. There was present marked conjunctivitis; the left eardrum was reddened; the threat was quite red, and a thick mucoid secretion was found in the mouth and pharynx. There was no generalized glandular enlargement. There were no marked changes in the lungs except a few tales which could be heard in the right axilla and over the left lower lobe posteriorly. The heart sounds were very distant and of poor quality. The abdomen was negative except for slight spasticlty of the right upper quadrant. Rectal examination was negative. Neurologically, there was evidence of sluggish deep reflexes; abdominal reflexes were absent, cremasterlc reflexes sluggish, and t
DANCIGER :
]~ULMINATING MENINGOCOCCEMIA
497
At about 4:30 a.~., eleven hours after the onset of the illness, the child became very cyanotic and dyspneic. A continuous intravenous injection of 250 c.c. normM saline was given, followed by a blood transfusion of 300 c.e. The impression was that we were dealing with a fulminating septicemia of unknown type. We had no evidence of meningitis nor of a pneumonia. The smear from the spinal fluid revealed no organisms. The child went into deep coma and became more cyanotic. The pulse became much faster and threadle~ and the respirations, which had been between 50 and 60 per minute, now became very shallow and rapidly developed Chey~te-Stokes character. The skin lesions, which before were maeular and erythematous in appearance, now took on a hemorrhagic character which became more conspicuous as the cyanosis deepened. The cyanosis quickly took on a heliotrope color and looked splotchy, just as is semi a f t e r death. The heart action became poorer. Cardiac stimulants were given, but the child continued to go downhill very rapidly and died at approximately 8:00 A.~., or fourteen and one-half hours after the onset of illness. The laboratory reports were as follows: The sputum revealed pneumocoecus Type X I X . The blood culture was positive for meningocoeeus (30 colonies per cubic centimeter). The spinal fluid culture was negative. The spinal fluid chemistry revealed chlorides, 770 rag. per cent; t~)tal protein, 25 rag. per cent; sugar 55 rag. per cent. The t r y p t o p h a n e test was negative; blood serology was negative. Stool culture revealed B. co~i. Permission for autopsy was obtained, and prior to the post-mortem examination, a smear was made from one of the pnrpuric spots which did ~ot reveal the presence of ~nenlngococci. Pathologic findings were as follows: Gross findings revealed congestion of lungs, h y p e r t r o p h y of mesenterie lymph nodes, and P e y e r ' s patches. The adrenals exhibited the most i m p o r t a n t pathologic findings. They were bluish in color and not enlarged. O n cut section there was seen gross hemorrhage of the medulla and innermost layer of the cortex. Also some blood was seen in the outer corti6al ]ayer.s. The brain was grossly negative. Microscopically, the adrenals showed complete destruction by hemorrhage of the entire medulla and the zona reticularis, so that no pigmentation was seen. Only a few scattered parenchymal cells persisted. Some areas of the cortex were not involved. The lungs and liver showed only marked congestion and edema. The hyperplasia of the mesenteric lymph nodes and Peyer's patches were confirmed by microscopic examination. Small areas of hemorrhage were seen in the kidneys and one testis. The skin hemorrhages were located in the fatty layer of the epidermis. No bacteria were found in the purpuric areas. Microscopic examination of the brain revealed no abnormalities in the leptomeninges. Special stains showed gram-negatlve diploeocci within the leucocytes contained in the meningeal vessels. COMMENT
The diagnosis of this syndrome should be considered in all infants and young children who become suddenly ill with vomiting, diarrhea, and collapse, particularly if the illness is associated with high fever, purpura, and cyanosis. It must be differentiated from other causes of adrenal hemorrhage, such as hemorrhage of the adrenal occurring in the newborn infant, or traumatic adrenal hemorrhage, which are usually not associated with purpura. There should b e l i t t l e difficulty in differentiating the syndrome from such conditions which have been
498
THE
JOURNAL
OF PEDIATR~C~
known to cause adrenal hemorrhage, such as diphtheria, scarlet fever, smallpox, and, occasionally, measles and pneumonia. Massive hemorrhage in the adrenals occurs in guinea pigs after injection of diphtheria toxin. This form of massive adrenal hemorrhage is not seen in diphtheria of the human being. However, the adrenals do show definite pathology. Greater difficulty in diagnosis may be encountered in districts where violent toxic scarlet fever or hemorrhagic smallpox occurs, for these diseases may produce a picture similar to this syndrome. The presence of meningococci in the smear of the purpuric spots (Fig. 2), as pointed out by McLean and Caffey, will certainly facilitate the diagnosis.
F i g . 2 . - - S e c t i o n t h r o u g h p u r p u r i c s p o t s h o w i n g d i l a t a t i o n of b l o o d v e s s e l s a n d p r e s e n c e of m e n i n g o c o c c i w i t h i n t h e s e v e s s e l s .
Up to the present time, the prognosis is fatal. Because of the very fulminant course of the syndrome, the therapy has been, to a great extent, based upon theoretical grounds. There is hope, however, that some of these cases may be saved if the diagnosis is made early enough, Sulfanilamide, intravenous antimeningococeus serum, intravenous saline, transfusions, adrenalin, and cortical extract should be used before the laboratory corroborates the suspected diagnosis. SU1KMA_RY
A case of a patient with the Waterhouse-Frideriehsen syndrome has been described. Seventy-four such cases have been described in the literature. Ninety-five per cent of the patients have been under 6 years of age.
DANCIGER :
FULMINATINGMENINGOCOCCEMIA
499
T h e e t i o l o g y h a s b e e n s h o w n to be the m e n i n g o e o c e u s i n 70 p e r c e n t of t h e cases. S y m p t o m a t o l o g y is s t r i k i n g l y u n i f o r m , w i t h s u d d e n onset, restlessness, a n d g a s t r o i n t e s t i n a l s y m p t o m s , f o l l o w e d s h o r t l y b y cyanosis, p u r p u r a , l e t h a r g y , coma, h i g h fever, a n d d e a t h . Death occurred w i t h i n t w e n t y - f o u r h o u r s or less i n t h e m a j o r i t y of cases. 1Ylassive b i l a t e r a l a d r e n a l h e m o r r h a g e is the m o s t c o m m o n a u t o p s y finding. S u g g e s t e d t h e r a p y i n c l u d e s s u l f a n i l a m i d e , a n t i m e n i n g o e o c c u s serum, i n t r a v e n o u s saline, t r a n s f u s i o n s , a d r e n a l i n , a n d c o r t i c a l e x t r a c t . REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Little, E. G.: Brit. J. Dermat. 13: 445, 1901. Waterhouse, R.: Lancet 1: 576, 191]. Friderichsen, C.: Jahrb. f. Kinderh. 87: 109, 1918. Bamatter, F.: Jahrb. f. Kinderh. 152: 129, 1934. Aegcrtcr, E. •.: J . A . IV[. A. 106: 1715, 1936. Sacks, IV[. S.: Ann. Int. ]Ked. 10: 1105~ 1936-37. Levinson, S.A.: J. PED~AT. 14: 506, ]939. Weingart, J.S.: J. Iowa IV[. Soc. 28: 5~ 1938. ]Y[cNamara, F. P., and Cornell~ W. J.: J. Iowa 1VL Sot. 28: 197, 1938. Crastcr, C. V, and Simon, It.: J . A . 1VLs 110: 1009, 1938. Usher, S . J . : Canad. ]W. A. J. 38: 232, 1938. Kamber, A.: Monatschr. f. Kinderh. 71: 351, 1937. Biddau~ I.: Pediatria 46: 598, 1938. 1VIcLagen, P. W., and Cooke, W . E . : Lancet 2: 1054, 1916. McLean, S., and Caffey, J.: Am. J. Dis. Child. 42: 1053, 1931.