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The shwartzman phenomenon complicating acute meningococcemia with meningitis
Case Report THE SHWARTZMAN PHENOMENON COMPLICATING ACUTE MENINGOCOCCEMIA W I T H MENINGITIS S. 1)AwD STER~BEaG, M.D., BnN M. ZWEI~L~a, M.D., S~YMOUR GRUBEIr M.D., AND JACOB LICHTEIr M.D. BROOI~LYN, N. Y. HWARTZMAN, 1 in 1928, described
of local tissue reacStivity.a phenomenon In his excellent monograph,
Shwartzman3 describes the phenomenon of local skin reactivity to various microorganisms and its immunological, pathological, and clinical significance. The basic experiments consist of a preparatory intradermal injection of Bacillus typhosu~ culture filtrate in a rabbit, followed twenty-four hours later by a provocative intravenous injection of the same filtrate. A severe hemorrhagic necrosis occurs at the prepared skin site four hours following the intravenous injection. Grossly, the skin site is dark blue, edematous, and has a red periphery. Microscopically, there is disruption of the venules, extensive hemorrhage, thrombosis, and neerobiosis of all the cells. The reaction traverses through the superficial skin layers and the abdominal wall of the rabbits. Repeated skin injections, at twenty-iour-hour intervals, of the bacterial culture filtrate fail to produce the hemorrhagic, necrotic reaction. The second or provocative injection must be given intravenously. Shwartzman also elicited the phenomenon by provocative intravenous injections of bacterial filtrates. A generalized Shwartzman reaction, consisting principally of a bilateral cortical renal necrosis, is elicited by injection of the active principles, intravenously, twenty-four hours apart. Among the bacteria producing active principles of high potency for the phenomenon of local tissue reactivity are: meningoF r o m the D e p a r t m e n t of Pediatrics, Beth-E1 Hospital. 369
coccus, B. typhosus, B. paratyphosus, B. coli, B. friedliinder, B. dysenteriae, B. prodigiosus, B. lepisepr B. pestis, Hernophilus influenzae, H. pertussis, and Vibrio choIerae. Blaek-Sehaffer, tIiebert, and Kerby 3 experimentally confirmed the fact that twice-washed living or dead meningococci possess potent preparatory and provocatory substances which can produce the local Shwartzman phenomenon. These workers hypothesize that in meningoeoccemia in man, each cutaneous lesion is a miniature Shwartzman reaetion. Frequently, prior to the clinical onset of the disease, there is a focal infection of the upper respiratory tract, which feeds meningocoeci into the blood stream. The organisms and their products deposit in the skin and prepare it. The patient's reactivity and.the meningocoeeus strain are the factors affecting the length of time for the preparation of the skin. The purpurie lesions result from the provoeatory effeet of the bacteriemia. The extent of the cutaneous lesions is again dependent upon the patient's reactivity and the virulence of the meningococcus strain. The successive crops of peteehiae are due to the provocatory effect of foci that are established later in the course of the baateriemia. In discussing the clinical implications of the Shwartzman phenomenon, Black-Schaffer4 emphasizes that some patients with very fulminating meningoeoecemia succumb in spite of antibiotic therapy. He suggests that the development of an antiserum directed not only against the meningococci, but
370
THE
JOURNAL
against the S h w a r t z m a n toxin as well, would help eliminate fatalities due to Shwartzman-potent bacteria. The following ease r e p o r t is t h a t of a 7-month-old i n f a n t who developed a severe S h w a r t z m a n reaction early in the course of meningococcemia. CASE I~EPORT
M. tI., a 7-month-old white male, was ~tdmitted to the Beth-E1 HospitaI on Dec. 4, 1949, with the chief complaint of " h i g h f e v e r and blood spots u n d e r the s k i n . " The previous d a y the inf a n t was seen in the office of one of us for a routine check-up, a n d at t h a t t i m e was p e r f e c t l y well. H e received his first immunization injection of diphtheria, pertussis, tetanus combined vaccine (0.5 c.c.). Six hours later the inf a n t ' s t e m p e r a t u r e rose to 104 ~ F., rectally, and he was given aspirin, t i e continued to r u n f e v e r between 103 ~ and 104 ~ F. A n h o u r before admission, the mother noticed widespread " s p o t s of blood u n d e r the s k i n . " The family and past history are noncontributory. Physical examination on admission revealed a well-nourished 7-month-old male infant, weighing 21 pounds, 5 ounces, who a p p e a r e d acutely ill but was alert. The rectal t e m p e r a t u r e was 100.8 ~ F., the pulse rate 140 p e r minute, r e s p i r a t o r y rate 32 p e r minute. The blood pressure was 80/40. A generalized petechial a n d p u r p u r i c eruption was present over the face, trunk, and extremities. The skin o v e r the buttocks a n d thighs was one coalescent ecchymotic area. Both e a r d r u m s were red. The p h a r y n x and nose were inflamed. No clinical signs referable to the central nervous system were present. A complete blood count, blood culture, nose a n d t h r o a t culture, urinalysis, a n d urine culture were done. A direct smear f r o m the p u r p u r i c areas was made. The i n f a n t was placed in an oxygen hood, a n d penicillin 100,000 units i n t r a m u s c u l a r l y every three hours, sulfadiazine 1.0 Gin. initially and 0.4 Gm. every f o u r hours orally, and aureomycin 125 mg. orally were
OF P E D I A T R I C S
given. Vitamin K, 4.8 mg., was given intramuscularly. Fluids were forced. The petechial smear revealed m a n y gram-negative intrace]lular and extracellular diploeocci. The admission h e m o g r a m was: red blood count 3.58 million per cubic millimeter, hemoglobin 55 p e r cent, white blood count 7,400 per cubic millimeter, with a different i m count of 35 per cent staff cells, 44 p e r cent segmented cells, 19 p e r cent lymphocytes, a n d 2 p e r cent monocytes, a n d plate]ets 290,000 p e r cubic millimeter. Urinalysis was negative except for a faint trace of albmnin. The infant appeared to be responding well to therapy when suddenly, six hours after admission, a generalized convulsion occurred. The rectal temperature was 101 ~ F. The convulsion was terminated with the administration of phenobarbital sodium intramuscularly and ether by open drop. A spinal tap was done and revealed cloudy fluid u n d e r increased pressure. There were 6,000 white blood cells per cubic millimeter, p r e d o m i n a n t l y polynuclears. A g r a m stain of the sediment revealed gram-negative diplococci. A cut-down was p e r f o r m e d on the right saphenous vein and patent e r m fluids administered. Sodium sulfadiazine, 1.0 Gm. initially, and 0.33 Gm. every f o u r hours, was started, intravenously. Penicillin dosage was increased to 1 million units every three hours. Ten cubic centimeters of adrenal cortical extract was given intravenously. A rectal tube was inserted to help relieve the abdominal distention. Eighteen hours a f t e r admission, it was evident t h a t the response to thera p y was excellent. The rectal temperature was 100 ~ F. The i n f a n t was alert, taking fluids b y mouth avariciously, a n d u r i n a t i n g well. There were no meningeal signs. There was a m a r k e d generalized p u r p u r a which was very p r o m i n e n t over the buttocks and thighs and the possibility of a slough was suspected (Fig. 1). The tip of the spleen was palpable, and a systolic m u r m u r was h e a r d at the apex. An electrocardiogram at this time, however, was normal except f o r a sinus
STERNBERG
ET
AL. :
SHWARTZMAN
371
PHENOMENON
]Fig. 1.
Fig.
2.
]~'ig. 3.
Fig. 1.--The marked, confluent purpura that occurred early over the buttocks and upper is readily seen. Fig. 2.--The areas of purpura seen in Fig. 1 now exhibit necrotic changes and are shown having an escharlike appearance, with beginning undermining slough at the periphery. Fig. 3.--The whole area has sloughed, and granulations with epithelization are seen. tidghs
372
THE
J O U R N A L OF P E D I A T R I C S
taehycardia. Intravenous fluids were were superficially infected. Small discontinued. Penicillin dosage was re- doses of ultraviolet irradiation were duced to 100,000 units intramuscularly started and aureomycin therapy given. every three hours, aureomycin therapy On the twenty-first day, the infant bewas stopped, and sulfadiazine was came afebrile and remained so for the given by mouth. remainder of his hospital stay. By the twenty-fouI~h day, the necrotic skin On the third hospital day, the temperature began to spike between 100 ~ over the buttocks and thighs had comand 103 ~ F., but the infant was alert pletely sloughed and relatively clean and the only new physical findings granulations were forming. On the thirty-fourth hospital day, were erosion of skin and blister formation in certain of the ecehymotic areas, the infant's general condition was good especially over the buttocks. The tem- and the buttocks were epithelializing Therapy w a s perature rise was ascribeable to the from the periphery. start of necrosis and gangrene of the limited to aureomycin, ultraviolet irskin and abso~:ption of blood from the radiation, and supportive therapy with blood and irradiated plasma transfuextensive purpnra. sions. At this stage, surgery did not The next day the infant's clinical appear to be indicated, although the condition appeared good but the fever possibility that skin grafting might bepersisted. AureoInyein 100 rag. every come necessary was considered. On the four hours by mouth was instituted. forty-seventh hospital day, the patient A repeated spinal tap revealed fluid was discharged from the hospital. At that was faintly cloudy, with 220 white this time his buttocks were healing so blood cells, 75 per cent polynuclear. well that no further treatment was inThe spinal fluid culture was negative. dicated (F~g. 3). I t was apparent that the primary Specimens of blood taken from the therapeutic problem at this time was patient on Dee. 31, 1949, and Jan. 13, the care of the infant's skin. The pa- 1950, revealed that his serum was agtient was placed on his abdomen and glutinated with type specific monovacovered with a heat cradle that sap- lent meningocoecie antigen of Group ported sterile bed linens. For the sec- 1-3 in a titer of 1:1,600. ondary anemia and the skin condition, blood transfusions of 125 e.c. each were COMMENT given for the next three days. The De Fuceio and Dresner .5 recently retemperature continued to range between 100 ~ and 102.4 ~ F. until the ported a case of meningococcemia with eighth hospital day, when the infant meningococeal meningitis in a 7-yearbecame afebrile. Meanwhile the pur- old Negro male, that was complicated parle spots were fading except for an by gangrene of the lower extremities, area 1.5 era. in circumference on the necessitating amputation of the lower right cheek, and the buttocks and up- third of both legs. These authors do per posterior region of the thighs not mention the possible role of the phenomenon in the etiwhich had a black eschar that started Shwartzman sloughing along the periphery (Fig. 2). ology of the complication of gangrene By the thirteenth day, the Iesion on the in their case. cheek had sloughed, leavihg a clean, Hill and Kinney, 6 in a study of deep, granulating ulcer. Sulfadiazine twenty-five autopsied cases, presented and aureomycin therapy was stopped the clinical and pathological features but penicillin was continued. On the of the skin lesions in acute meningosixteenth hospital day, the infant had coccemia. Most of their cases presented a temperature of 100 ~ to 101.6 ~ F. The varied cutaneous lesions, including erychild was well except for the skin, thematous macules, papules, nodules, which showed sloughing of the but- vesicles, petechiae, and purpura. Mactocks with deep ulcers, some of which ales over the trunk and lower extremi-
STERNBERG ET AL. :
SHWARTZMAN
ties appeared first. Many petechiae coalesced to form larger p u r p u r i e lesions, some of which even enveloped an entire segment of the b o d y . The extremities were the commonest site for the skin lesions but other areas subjeet to pressure and friction were frequently involved. Peteehiae were commonest over the joints while p u r p u r a showed a predilection for the extremities and back. The skin lesions generally appeared twelve to thirty-six hours after the institution of chemotherapy, the maculopapular lesions usually faded, but hemorrhagic lesions were not affected. Two surviving patients presented necrosis and sloughing of the p u r p u r i c lesions, with complicating gangrene of the extremities. One of these patients required amputation of the toes, and both underwent a long period of hospitalization. In discussing the pathology of the cutaneous lesions in acute meningocoecemia, Hill and Kinrmy ~ emphasize that the fundamental lesion is one of diffuse vascular damage featured by a d i l a t a t i o n and engorgement of the blood vessels. Smaller blood vessels and capillaries have a swelling of the endothelial cells. Platelet thrombi are present in many blood vessels. The authors feel that the presence of the meningoeocei causes the vascular damage. The organisms localize in the endothelium, resulting in endothelial changes and inflammation of the vessel wails, with subsequent necrosis and thrombosis. The hemorrhagic tesions are caused by the extravasation of red blood cells from the damaged vessels. Vascular thrombi account for the late complication of gangrene. A p p a r e n t l y the control of the bacteriemia did not prevent the occurrence of gangrene in the authors' two cited cases. Dehydration, loss of vascular tone, and stasis promote the continued propagation of the thrombi, and account for the eventual gangrene. The authors feel that as modern chemotherapy helps more patients survive the initial baeteriemia, the skin complications will become more apparent.
PHENOMENON
373
The Waterhouse-Friderichsen syndrome, which is at times a dramatic complication of meningococcemia, is a p p a r e n t l y not part of the Shwartzman phenomenon. Black~Sehaffer, Hiebert, and K e r b y 3 point out that since only a small number of patients with p u r p u r i c meningocoeeemia develop adrenal necrosis that p u r p u r i c meningococcemia is not synonymous with the Waterhouse-Frideriehsen syndrome. Experimentally, a single intravenous inoculation of potent bacterial filtrate can produce adrenal necrosis. However, t h e Sehwartzman phenomenon m a y be elicited only by first preparing the site and then provoking the response by an intravenous inoculation. Therefore, they feel that the adrenal necrosis may not be considered part of the Shwartzman phenomenon. The adrenal lesions are a byproduct of a general toxemia and not a result of the Shwartzman phenomenon. The excellent pathological descriptions of Hill and Kinney s bear a striking resemblanee to the gross and mieroseopie descriptions of the Shwartzman phenomenon, tIowever, Hill and Kinney s do not consider, nor mention this simi]arity. We feel that the work of Shwartzman and Black-Schaffer and his co-workers represents strong experimental evidence for the incrimination of the Shwartzman phenomenon as an underlying cause for the complicating cutaneous lesions in acute meningococcemia. Therefore, .we consider our patient as a ease os acute meningococcemia with meningitis, complicated by the appearance of the Shwartzman phenomenon. " I n terms of the phenomenon the obvious mechanism is as follows: the toxic products of meningocoeei lodged in the capillaries of the skin may serve as the p r e p a r a t o r y factor, while the meningoeocci or their toxic products circulating in the btood stream may serve as the provocative factor. ' ,7 SUMMARY
1. A ease of acute meningoeoeeemia with meningitis complicated by the
374
THE
JOURNAL
Shwartzman phenomenon in a 7-monthold white male infant is reported. 2. The Shwartzman phenomenon is briefly described and the etiological and pathological aspects of the cutaneous complications of acute meningocoecemia are reviewed. 3. The role of the Shwartzman phenomenon in causing cutaneous lesions in acute meningococeemia is emphasized. We wish to express our deep g r a t i t u d e to Dr. Bela Schiek, of the Department of Pediatrics of the Beth-E1 Hospital, for his encouragement and assistance in the preparation of this paper. We wish also to thank :Dr. Gregory Shwartzman for reviewing this paper and for pointing out to us the mechanism
of the Shwarizman phenomenon in the case we have reported.
OF
PEDIATRICS
REFERENCES 1. Shwartzman, G.: Studies on Bacillus Typhosus Toxic Substances: I. Phenomenon of Local Skin Reactivity to B. Typhosus Culture Filtrate, J. Exper. Med. 48: 247, 1928. 2. Shwartzman, G.: Phenomenon of Local Tissue Reactivity. New York, 1937, Paul B. tIoeber, Inc. 3. Black-Schaffer, B., Hiebert, T. G., and Kerby, G. P . : Experimental Study of Purpuric Meningococcemia in Relation to the Shwartzman Phenomenon, Arch. Path. 43: 28, 1947. 4. Black-Sehaffer, B. : The Clinical Implications of the Shwartzman Phenomenon, J. Mt. s i n a i Hosp. 16: 207~ 1949. 5. De Fuecio, C. P., a n d Dresner, E v e l y n : Meningococcemia With Meningitis Accompanied by Bilateral Gangrene of the Lower Extremities, Pediatrics 3: 837, :I949. 6. Hil% W. 1%., and Kinney, T. D.: Tile Cutaneous Lesions in Acute M eningococcemia, J. A. M. A. 134: 513, 1947. 7. Shwartzman, G.: Personal eommunlcation, New York. June, 1950.
of local tissue reacStivity.a phenomenon In his excellent monograph,
Shwartzman3 describes the phenomenon of local skin reactivity to various microorganisms and its immunological, pathological, and clinical significance. The basic experiments consist of a preparatory intradermal injection of Bacillus typhosu~ culture filtrate in a rabbit, followed twenty-four hours later by a provocative intravenous injection of the same filtrate. A severe hemorrhagic necrosis occurs at the prepared skin site four hours following the intravenous injection. Grossly, the skin site is dark blue, edematous, and has a red periphery. Microscopically, there is disruption of the venules, extensive hemorrhage, thrombosis, and neerobiosis of all the cells. The reaction traverses through the superficial skin layers and the abdominal wall of the rabbits. Repeated skin injections, at twenty-iour-hour intervals, of the bacterial culture filtrate fail to produce the hemorrhagic, necrotic reaction. The second or provocative injection must be given intravenously. Shwartzman also elicited the phenomenon by provocative intravenous injections of bacterial filtrates. A generalized Shwartzman reaction, consisting principally of a bilateral cortical renal necrosis, is elicited by injection of the active principles, intravenously, twenty-four hours apart. Among the bacteria producing active principles of high potency for the phenomenon of local tissue reactivity are: meningoF r o m the D e p a r t m e n t of Pediatrics, Beth-E1 Hospital. 369
coccus, B. typhosus, B. paratyphosus, B. coli, B. friedliinder, B. dysenteriae, B. prodigiosus, B. lepisepr B. pestis, Hernophilus influenzae, H. pertussis, and Vibrio choIerae. Blaek-Sehaffer, tIiebert, and Kerby 3 experimentally confirmed the fact that twice-washed living or dead meningococci possess potent preparatory and provocatory substances which can produce the local Shwartzman phenomenon. These workers hypothesize that in meningoeoccemia in man, each cutaneous lesion is a miniature Shwartzman reaetion. Frequently, prior to the clinical onset of the disease, there is a focal infection of the upper respiratory tract, which feeds meningocoeci into the blood stream. The organisms and their products deposit in the skin and prepare it. The patient's reactivity and.the meningocoeeus strain are the factors affecting the length of time for the preparation of the skin. The purpurie lesions result from the provoeatory effeet of the bacteriemia. The extent of the cutaneous lesions is again dependent upon the patient's reactivity and the virulence of the meningococcus strain. The successive crops of peteehiae are due to the provocatory effect of foci that are established later in the course of the baateriemia. In discussing the clinical implications of the Shwartzman phenomenon, Black-Schaffer4 emphasizes that some patients with very fulminating meningoeoecemia succumb in spite of antibiotic therapy. He suggests that the development of an antiserum directed not only against the meningococci, but
370
THE
JOURNAL
against the S h w a r t z m a n toxin as well, would help eliminate fatalities due to Shwartzman-potent bacteria. The following ease r e p o r t is t h a t of a 7-month-old i n f a n t who developed a severe S h w a r t z m a n reaction early in the course of meningococcemia. CASE I~EPORT
M. tI., a 7-month-old white male, was ~tdmitted to the Beth-E1 HospitaI on Dec. 4, 1949, with the chief complaint of " h i g h f e v e r and blood spots u n d e r the s k i n . " The previous d a y the inf a n t was seen in the office of one of us for a routine check-up, a n d at t h a t t i m e was p e r f e c t l y well. H e received his first immunization injection of diphtheria, pertussis, tetanus combined vaccine (0.5 c.c.). Six hours later the inf a n t ' s t e m p e r a t u r e rose to 104 ~ F., rectally, and he was given aspirin, t i e continued to r u n f e v e r between 103 ~ and 104 ~ F. A n h o u r before admission, the mother noticed widespread " s p o t s of blood u n d e r the s k i n . " The family and past history are noncontributory. Physical examination on admission revealed a well-nourished 7-month-old male infant, weighing 21 pounds, 5 ounces, who a p p e a r e d acutely ill but was alert. The rectal t e m p e r a t u r e was 100.8 ~ F., the pulse rate 140 p e r minute, r e s p i r a t o r y rate 32 p e r minute. The blood pressure was 80/40. A generalized petechial a n d p u r p u r i c eruption was present over the face, trunk, and extremities. The skin o v e r the buttocks a n d thighs was one coalescent ecchymotic area. Both e a r d r u m s were red. The p h a r y n x and nose were inflamed. No clinical signs referable to the central nervous system were present. A complete blood count, blood culture, nose a n d t h r o a t culture, urinalysis, a n d urine culture were done. A direct smear f r o m the p u r p u r i c areas was made. The i n f a n t was placed in an oxygen hood, a n d penicillin 100,000 units i n t r a m u s c u l a r l y every three hours, sulfadiazine 1.0 Gin. initially and 0.4 Gm. every f o u r hours orally, and aureomycin 125 mg. orally were
OF P E D I A T R I C S
given. Vitamin K, 4.8 mg., was given intramuscularly. Fluids were forced. The petechial smear revealed m a n y gram-negative intrace]lular and extracellular diploeocci. The admission h e m o g r a m was: red blood count 3.58 million per cubic millimeter, hemoglobin 55 p e r cent, white blood count 7,400 per cubic millimeter, with a different i m count of 35 per cent staff cells, 44 p e r cent segmented cells, 19 p e r cent lymphocytes, a n d 2 p e r cent monocytes, a n d plate]ets 290,000 p e r cubic millimeter. Urinalysis was negative except for a faint trace of albmnin. The infant appeared to be responding well to therapy when suddenly, six hours after admission, a generalized convulsion occurred. The rectal temperature was 101 ~ F. The convulsion was terminated with the administration of phenobarbital sodium intramuscularly and ether by open drop. A spinal tap was done and revealed cloudy fluid u n d e r increased pressure. There were 6,000 white blood cells per cubic millimeter, p r e d o m i n a n t l y polynuclears. A g r a m stain of the sediment revealed gram-negative diplococci. A cut-down was p e r f o r m e d on the right saphenous vein and patent e r m fluids administered. Sodium sulfadiazine, 1.0 Gm. initially, and 0.33 Gm. every f o u r hours, was started, intravenously. Penicillin dosage was increased to 1 million units every three hours. Ten cubic centimeters of adrenal cortical extract was given intravenously. A rectal tube was inserted to help relieve the abdominal distention. Eighteen hours a f t e r admission, it was evident t h a t the response to thera p y was excellent. The rectal temperature was 100 ~ F. The i n f a n t was alert, taking fluids b y mouth avariciously, a n d u r i n a t i n g well. There were no meningeal signs. There was a m a r k e d generalized p u r p u r a which was very p r o m i n e n t over the buttocks and thighs and the possibility of a slough was suspected (Fig. 1). The tip of the spleen was palpable, and a systolic m u r m u r was h e a r d at the apex. An electrocardiogram at this time, however, was normal except f o r a sinus
STERNBERG
ET
AL. :
SHWARTZMAN
371
PHENOMENON
]Fig. 1.
Fig.
2.
]~'ig. 3.
Fig. 1.--The marked, confluent purpura that occurred early over the buttocks and upper is readily seen. Fig. 2.--The areas of purpura seen in Fig. 1 now exhibit necrotic changes and are shown having an escharlike appearance, with beginning undermining slough at the periphery. Fig. 3.--The whole area has sloughed, and granulations with epithelization are seen. tidghs
372
THE
J O U R N A L OF P E D I A T R I C S
taehycardia. Intravenous fluids were were superficially infected. Small discontinued. Penicillin dosage was re- doses of ultraviolet irradiation were duced to 100,000 units intramuscularly started and aureomycin therapy given. every three hours, aureomycin therapy On the twenty-first day, the infant bewas stopped, and sulfadiazine was came afebrile and remained so for the given by mouth. remainder of his hospital stay. By the twenty-fouI~h day, the necrotic skin On the third hospital day, the temperature began to spike between 100 ~ over the buttocks and thighs had comand 103 ~ F., but the infant was alert pletely sloughed and relatively clean and the only new physical findings granulations were forming. On the thirty-fourth hospital day, were erosion of skin and blister formation in certain of the ecehymotic areas, the infant's general condition was good especially over the buttocks. The tem- and the buttocks were epithelializing Therapy w a s perature rise was ascribeable to the from the periphery. start of necrosis and gangrene of the limited to aureomycin, ultraviolet irskin and abso~:ption of blood from the radiation, and supportive therapy with blood and irradiated plasma transfuextensive purpnra. sions. At this stage, surgery did not The next day the infant's clinical appear to be indicated, although the condition appeared good but the fever possibility that skin grafting might bepersisted. AureoInyein 100 rag. every come necessary was considered. On the four hours by mouth was instituted. forty-seventh hospital day, the patient A repeated spinal tap revealed fluid was discharged from the hospital. At that was faintly cloudy, with 220 white this time his buttocks were healing so blood cells, 75 per cent polynuclear. well that no further treatment was inThe spinal fluid culture was negative. dicated (F~g. 3). I t was apparent that the primary Specimens of blood taken from the therapeutic problem at this time was patient on Dee. 31, 1949, and Jan. 13, the care of the infant's skin. The pa- 1950, revealed that his serum was agtient was placed on his abdomen and glutinated with type specific monovacovered with a heat cradle that sap- lent meningocoecie antigen of Group ported sterile bed linens. For the sec- 1-3 in a titer of 1:1,600. ondary anemia and the skin condition, blood transfusions of 125 e.c. each were COMMENT given for the next three days. The De Fuceio and Dresner .5 recently retemperature continued to range between 100 ~ and 102.4 ~ F. until the ported a case of meningococcemia with eighth hospital day, when the infant meningococeal meningitis in a 7-yearbecame afebrile. Meanwhile the pur- old Negro male, that was complicated parle spots were fading except for an by gangrene of the lower extremities, area 1.5 era. in circumference on the necessitating amputation of the lower right cheek, and the buttocks and up- third of both legs. These authors do per posterior region of the thighs not mention the possible role of the phenomenon in the etiwhich had a black eschar that started Shwartzman sloughing along the periphery (Fig. 2). ology of the complication of gangrene By the thirteenth day, the Iesion on the in their case. cheek had sloughed, leavihg a clean, Hill and Kinney, 6 in a study of deep, granulating ulcer. Sulfadiazine twenty-five autopsied cases, presented and aureomycin therapy was stopped the clinical and pathological features but penicillin was continued. On the of the skin lesions in acute meningosixteenth hospital day, the infant had coccemia. Most of their cases presented a temperature of 100 ~ to 101.6 ~ F. The varied cutaneous lesions, including erychild was well except for the skin, thematous macules, papules, nodules, which showed sloughing of the but- vesicles, petechiae, and purpura. Mactocks with deep ulcers, some of which ales over the trunk and lower extremi-
STERNBERG ET AL. :
SHWARTZMAN
ties appeared first. Many petechiae coalesced to form larger p u r p u r i e lesions, some of which even enveloped an entire segment of the b o d y . The extremities were the commonest site for the skin lesions but other areas subjeet to pressure and friction were frequently involved. Peteehiae were commonest over the joints while p u r p u r a showed a predilection for the extremities and back. The skin lesions generally appeared twelve to thirty-six hours after the institution of chemotherapy, the maculopapular lesions usually faded, but hemorrhagic lesions were not affected. Two surviving patients presented necrosis and sloughing of the p u r p u r i c lesions, with complicating gangrene of the extremities. One of these patients required amputation of the toes, and both underwent a long period of hospitalization. In discussing the pathology of the cutaneous lesions in acute meningocoecemia, Hill and Kinrmy ~ emphasize that the fundamental lesion is one of diffuse vascular damage featured by a d i l a t a t i o n and engorgement of the blood vessels. Smaller blood vessels and capillaries have a swelling of the endothelial cells. Platelet thrombi are present in many blood vessels. The authors feel that the presence of the meningoeocei causes the vascular damage. The organisms localize in the endothelium, resulting in endothelial changes and inflammation of the vessel wails, with subsequent necrosis and thrombosis. The hemorrhagic tesions are caused by the extravasation of red blood cells from the damaged vessels. Vascular thrombi account for the late complication of gangrene. A p p a r e n t l y the control of the bacteriemia did not prevent the occurrence of gangrene in the authors' two cited cases. Dehydration, loss of vascular tone, and stasis promote the continued propagation of the thrombi, and account for the eventual gangrene. The authors feel that as modern chemotherapy helps more patients survive the initial baeteriemia, the skin complications will become more apparent.
PHENOMENON
373
The Waterhouse-Friderichsen syndrome, which is at times a dramatic complication of meningococcemia, is a p p a r e n t l y not part of the Shwartzman phenomenon. Black~Sehaffer, Hiebert, and K e r b y 3 point out that since only a small number of patients with p u r p u r i c meningocoeeemia develop adrenal necrosis that p u r p u r i c meningococcemia is not synonymous with the Waterhouse-Frideriehsen syndrome. Experimentally, a single intravenous inoculation of potent bacterial filtrate can produce adrenal necrosis. However, t h e Sehwartzman phenomenon m a y be elicited only by first preparing the site and then provoking the response by an intravenous inoculation. Therefore, they feel that the adrenal necrosis may not be considered part of the Shwartzman phenomenon. The adrenal lesions are a byproduct of a general toxemia and not a result of the Shwartzman phenomenon. The excellent pathological descriptions of Hill and Kinney s bear a striking resemblanee to the gross and mieroseopie descriptions of the Shwartzman phenomenon, tIowever, Hill and Kinney s do not consider, nor mention this simi]arity. We feel that the work of Shwartzman and Black-Schaffer and his co-workers represents strong experimental evidence for the incrimination of the Shwartzman phenomenon as an underlying cause for the complicating cutaneous lesions in acute meningococcemia. Therefore, .we consider our patient as a ease os acute meningococcemia with meningitis, complicated by the appearance of the Shwartzman phenomenon. " I n terms of the phenomenon the obvious mechanism is as follows: the toxic products of meningocoeei lodged in the capillaries of the skin may serve as the p r e p a r a t o r y factor, while the meningoeocci or their toxic products circulating in the btood stream may serve as the provocative factor. ' ,7 SUMMARY
1. A ease of acute meningoeoeeemia with meningitis complicated by the
374
THE
JOURNAL
Shwartzman phenomenon in a 7-monthold white male infant is reported. 2. The Shwartzman phenomenon is briefly described and the etiological and pathological aspects of the cutaneous complications of acute meningocoecemia are reviewed. 3. The role of the Shwartzman phenomenon in causing cutaneous lesions in acute meningococeemia is emphasized. We wish to express our deep g r a t i t u d e to Dr. Bela Schiek, of the Department of Pediatrics of the Beth-E1 Hospital, for his encouragement and assistance in the preparation of this paper. We wish also to thank :Dr. Gregory Shwartzman for reviewing this paper and for pointing out to us the mechanism
of the Shwarizman phenomenon in the case we have reported.
OF
PEDIATRICS
REFERENCES 1. Shwartzman, G.: Studies on Bacillus Typhosus Toxic Substances: I. Phenomenon of Local Skin Reactivity to B. Typhosus Culture Filtrate, J. Exper. Med. 48: 247, 1928. 2. Shwartzman, G.: Phenomenon of Local Tissue Reactivity. New York, 1937, Paul B. tIoeber, Inc. 3. Black-Schaffer, B., Hiebert, T. G., and Kerby, G. P . : Experimental Study of Purpuric Meningococcemia in Relation to the Shwartzman Phenomenon, Arch. Path. 43: 28, 1947. 4. Black-Sehaffer, B. : The Clinical Implications of the Shwartzman Phenomenon, J. Mt. s i n a i Hosp. 16: 207~ 1949. 5. De Fuecio, C. P., a n d Dresner, E v e l y n : Meningococcemia With Meningitis Accompanied by Bilateral Gangrene of the Lower Extremities, Pediatrics 3: 837, :I949. 6. Hil% W. 1%., and Kinney, T. D.: Tile Cutaneous Lesions in Acute M eningococcemia, J. A. M. A. 134: 513, 1947. 7. Shwartzman, G.: Personal eommunlcation, New York. June, 1950.