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Disseminated intravascular coagulation in a newborn infant with Listeria sepsis
640
Brief clinical and laboratory observations
Disseminated intravascular coagulation in a newborn infant with Listeria sepsis Ron Miller, M.D., and C. T h o m a s Kisker, M.D., ~
Cincinnati, Ohio
D i s s E ~ i N A T E D intravascular coagulation ( D I C ) has been reported in the newborn i n f a n t associated with abruptio placenta, stillbirths, twin pregnancies with dead fetus, toxemia, shock states, central nervous system hemorrhage, idiopathic respiratory distress syndrome, herpes simplex virus infections, and the septicemia of m a n y gramnegative bacteria. However, D I C associated with Listeria monocytogenes infection has not been reported in the n e w b o r n infant, although babies with Listeria sepsis may develop a bleeding disorder? We have observed an i n f a n t with Listeria sepsis who developed petechiae a n d abnormalities of coagulation consistent with the diagnosis of disseminated intravascular coagulation. Although all previously reported cases of neonatal Listeria sepsis with petechiae died, our i n f a n t was treated with h e p a r i n a n d survived.
METHODS Coagulation studies were performed on venous blood d r a w n in plastic syringes as previously describedY Circulating fibrin was measured by the method of Kisker a n d Rushy
From the Department of Pediatrics, University o[ Cincinnati College o[ Medicine, The Children's Hospital, and The Children's Hospital Research Foundation. Supported by Research Grant HE 14619-01 [rom the National Institutes o] Health. ~Reprint address: The Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
The Journal o[ Pediatrics October 1973
CASE REPORT Patient M. N. was admitted to The Children's Hospital of Cincinnati at age 45 hours. He was a 3,870 Gin. full-term infant born after an uncomplicated pregnancy to a 32-year-old, gravida 7, para 3, Rh-positive woman whose second conception was a tubal pregnancy, and whose third and fourth pregnancies were miscarriages. At the time of delivery, the mother had a fever of 102 ~ F. and was treated with ampicillin. Meconium staining of the amniotic fluid was noted when the membranes ruptured one hour prior to delivery. The infant's Apgar score was 8 at one minute, and 9 at 5 minutes after birth, At age 24 hours the infant developed a temperature of 104 ~ F. and a high-pitched cry, and he was jaundiced and lethargic. Cerebrospinal fluid examination was normal. Therapy was started with gentamicin and when he did not respond to the antibiotic, he was transferred to The Children's Hospital. The infant appeared septic on arrival, had respiratory distress, rales in all lung fields, and hepatosplenomegaly. His blood pressure was 80/45, the pulse rate was 140, and the respiratory rate was 50. The initial white blood count was 9,500 per cubic millimeter, with 75 per cent neutrophils and 25 per cent lymphocytes. Platelets appeared to be present in normal numbers in a blood smear. Cultures of blood, nasopharynx, urine, and stool were obtained, and the infant was given intravenous aqueous penicillin, 100,000 units per kilogram per day, intramuscular gentamiein, 5.0 mg. per kilogram per day, intravenous fluids, and oxygen. He improved clinically after 15 hours of therapy, but 36 hours after admission a petechial rash appeared and increased bleeding with nasopharyngeal suctioning and heel sticks was noted. Although the coagulation studies listed in Table I, Column A, were normal, the platelets appeared decreased on a blood smear. The gentamicin was changed from the intramuscular to the intravenous route. Because of continued bleeding the coagulation studies were repeated 24 hours later (Table I, Column B). At that time the infant had an abnormal prothrombin time, a prolonged thrombin time, a positive serial protamine sulfate dilution (SPSD) test, increased soluble circulating fibrin, a decreased fibrinogen concentration, and fragmentation of red blood cells with almost complete absence of platelets on the blood smear. Although the organism in a blood culture was not completely identified,
Volume 83 Number 4
Brief clinical and laboratory observations
64 1
Table I Date and time B
Laboratory studies
A 9/17, 8 A.M.
Prothrombin time (normal 11.7 + 0.4 sec.)
12 sec.
Partial thromboplastin time (normal 34 + 5
42 see.
seC. )
Thrombin time (normal 18 + 2 sec.)
19 see:
Serial protamine sulfate dilution (SPSD) test ( normal--negative)
Negative
Soluble circulating fibrin (normal 164 -+ 35 DPM/mg. fibrinogen) Fibrinogen associated antigen in serum (tanned red cell hemagglutination inhibition immunoassay) (normal--less than 2 #g) Factor V (normal 97 + 36%) Factor VIII (normal 104 + 56%) Fibrinogen (normal 200 + 50 rag.%) PlateIets
162 DPM/ mg.
225 Adequate on blood smear
it was sensitive in vitro to penicillin and gentamicin. Because of the laboratory evidence for DIC and continued bleeding, the infant was treated with heparin, 100 units per kilogram every 4 hours, and given one unit of cryoprecipitate. The studies in Table I, Column C, obtained 8 hours after heparin therapy was begun, show a slight increase in fibrinogen-assoeiated antigen in the serum, but soluble circulating fibrin as measured by 14C glycine ethyl ester incorporation was absent. Coagulation studies (Table I, Column D) obtained 24. hours after initiation of heparin therapy showed a normal fibrinogen concentration, a negative SPSD test, and no soluble circulating fibrin. Heparin therapy was then discontinued. Listeria monocytogenes was identified in the blood culture 2 days later. The infant improved steadily and appears normal at age 7 months. DISCUSSION Listeria sepsis in the n e w b o r n i n f a n t , "granulomatosis infantiseptica," is a wellk n o w n b u t u n c o m m o n infection. Although reviews 1 have described petechiae a n d / o r
9/18, 8 A.M. (before heparin) 14.2 sec.
C 9/18, 4 P.M. (heparin) Heparin effect ) 60 see. 43 sec. Heparin effect ~ 120 see. 49 sec. Heparin effect > 60 sec. Positive 30 Positive 30 rain. and 24 rain. and hr. 24 hr. 335 DPM/mg. 142 DPM/ rag. 2 #g 4 ~g 100% 86% 50 Decreased on blood smear
110
D 9/19, 8 A.M. (heparin) Heparin effect 60 see. Heparin effect 120 see. Heparin effect 60 see. Negative 146 DPM/ rag. 4 #g
225 241,000/mm. a
p u r p u r a in infants with Listeria sepsis, studies to d o c u m e n t D I C have not been reported. All infants reported previously with petechiae or p u r p u r a associated with Listeria sepsis died. l, a T h e present i n f a n t developed clear evidence of D I C with decreased platelets on the blood smear, a b n o r m a l red blood cell morphology, decreased fibrinogen concentration, increased soluble circulating fibrin, a positive SPSD test, a n d increased fibrinogenrelated a n t i g e n in the serum. Previous studies in patients with meningococcal sepsis have suggested that antibiotics and supportive measures m a y be of more critical importance i n limiting the episode of D I C t h a n is h e p a r i n therapy, s, 4 However, in this report of Listeria sepsis the D I C occurred at a time when the i n f a n t had been receiving the appropriate antibiotics and supportive measures for more t h a n 36 hours. I t is possible, since Listeria is a n intracellular organism, that the death of Listeria as a result of antibiotic therapy caused release of thromboplastic substances initiating the D I C .
64 2
Brief clinical and laboratory observations
T h e episode of D I C could have resolved spontaneously; however, the r a p i d clearance of soluble circulating fibrin coincident with the institution of h e p a r i n t h e r a p y suggests that h e p a r i n m a y have been instrumental in limiting the process. F u r t h e r m o r e , all previously reported newborn infants with Listeria sepsis a n d petechiae not treated with h e p a r i n have died. T h e findings, therefore, suggest that a short course of h e p a r i n should be given to infants with Listeria sepsis in w h o m intravascular coagulation is documented.
Mixed connective tissue disease in a child Doris Y. Sanders, M.D.,* C a r o l y n C. Huntley, M.D., Winston-Salem, N. C., a n d G o r d o n C. Sharp, M.D., Columbia,
mo. M I x E D connective tissue disease associated with a specific serum antibody for extractable nuclear antigen ( E N A ) appears to be a distinct clinical entity? In the initial r e p o r t the youngest patient was 13 years of age. This brief report describes an 11-year-old girl with this syndrome associated with E N A antibody. This child also h a d recurrent bilateral parotitis and was found to have absent serum and salivary IgA. CASE
REPORT
A 9-year-old white girl was first seen in the diagnostic clinic of the Bowman Gray School of Medicine with a history of recurrent bilateral parotid swelling, recurrent fever, chronic fatigue,
From the Department of Pediatrics, The Pediatric Service of The North Carolina Baptist Hospital, Bowman Gray School o[ Medicine, and the Department o[ Medicine, University of Mbsouri School o[ Medicine. ~Address: Department o] Pediatrics, Bowman Gray School o] Medicine, Winston-Salem, N. C. 27103.
The Journal o[ Pediatrics October 1973
REFERENCES
1. Ray, C. G., and Wedgwood, R. J.: Neonatal listeriosis, Pediatrics 34: 378, 1964. 2. Kisker, C. T., and Rush, R.: Circulating fibrin in meningocoecemia, J. PEDIATR. 82: 787, 1973. 3. Johnston, W. H., Morton, S. A., Wong, IV[. H., and Roy, T. E.: Septieaemia of the newborn due to Listeria monocytogenes, Can. Med. Assoc. J. 73: 402, 1955. 4. Corrigan, J. J., and Jordan, C. M.: Heparin therapy in septicemia with disseminated intravascular coagulation, N. Engl. J. Med. 283: 778, 1970.
proximal muscle weakness, generalized arthralgia, and Raynaud's phenomenon of approximately one year's duration. The first episode of parotid swelling occurred when the child's two sisters had mumps. Physical examination revealed an afebrile, normotensive girl. Height was 5 0 ~ inches and weight was 52 pounds. A violaceous discoloration of the skin was present over the knees and elbows. The skin over the hands was ery.thematous, tight, and shiny. The toes were also markedly erythematous. The child was weak and required assistance getting on and off the examining table. Except for the presence of several carious teeth, no other abnormalities were detected. Laboratory studies included a hemoglobin concentration of 11.5 Gm. per 100 ml., hematocrit of 33 volumes per cent, white blood cell count of 4,500 per cubic millimeter with a differential count of 63 neutrophils, 32 lymphocytes, and 5 monocytes, Urinalysis was negative. Wintrobe sedimentation rate was 44 mm. per hour. Roentgenogram of the chest was normal. Total serum protein value * was 8.1 Gm. (albumin 3.4 Gm./globulin 4.7 Gm.). Serum immunoglobulinst2 were determined by a simple gel diffusion "XNormal serum pJotein values in our laboratory range . from 6.0 to 8.0 Gin. p e r 100 ml, "}'Normal serum immunoglobulin levels (geometric means in r a g . / 1 0 0 m l . ) for age. 2
Age (yr.) I 9 10 11 Adult
IgG 1.006 991 989 1.061
I
lgA 230 188 257 266
I
lgM 56 60 56 76
Brief clinical and laboratory observations
Disseminated intravascular coagulation in a newborn infant with Listeria sepsis Ron Miller, M.D., and C. T h o m a s Kisker, M.D., ~
Cincinnati, Ohio
D i s s E ~ i N A T E D intravascular coagulation ( D I C ) has been reported in the newborn i n f a n t associated with abruptio placenta, stillbirths, twin pregnancies with dead fetus, toxemia, shock states, central nervous system hemorrhage, idiopathic respiratory distress syndrome, herpes simplex virus infections, and the septicemia of m a n y gramnegative bacteria. However, D I C associated with Listeria monocytogenes infection has not been reported in the n e w b o r n infant, although babies with Listeria sepsis may develop a bleeding disorder? We have observed an i n f a n t with Listeria sepsis who developed petechiae a n d abnormalities of coagulation consistent with the diagnosis of disseminated intravascular coagulation. Although all previously reported cases of neonatal Listeria sepsis with petechiae died, our i n f a n t was treated with h e p a r i n a n d survived.
METHODS Coagulation studies were performed on venous blood d r a w n in plastic syringes as previously describedY Circulating fibrin was measured by the method of Kisker a n d Rushy
From the Department of Pediatrics, University o[ Cincinnati College o[ Medicine, The Children's Hospital, and The Children's Hospital Research Foundation. Supported by Research Grant HE 14619-01 [rom the National Institutes o] Health. ~Reprint address: The Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
The Journal o[ Pediatrics October 1973
CASE REPORT Patient M. N. was admitted to The Children's Hospital of Cincinnati at age 45 hours. He was a 3,870 Gin. full-term infant born after an uncomplicated pregnancy to a 32-year-old, gravida 7, para 3, Rh-positive woman whose second conception was a tubal pregnancy, and whose third and fourth pregnancies were miscarriages. At the time of delivery, the mother had a fever of 102 ~ F. and was treated with ampicillin. Meconium staining of the amniotic fluid was noted when the membranes ruptured one hour prior to delivery. The infant's Apgar score was 8 at one minute, and 9 at 5 minutes after birth, At age 24 hours the infant developed a temperature of 104 ~ F. and a high-pitched cry, and he was jaundiced and lethargic. Cerebrospinal fluid examination was normal. Therapy was started with gentamicin and when he did not respond to the antibiotic, he was transferred to The Children's Hospital. The infant appeared septic on arrival, had respiratory distress, rales in all lung fields, and hepatosplenomegaly. His blood pressure was 80/45, the pulse rate was 140, and the respiratory rate was 50. The initial white blood count was 9,500 per cubic millimeter, with 75 per cent neutrophils and 25 per cent lymphocytes. Platelets appeared to be present in normal numbers in a blood smear. Cultures of blood, nasopharynx, urine, and stool were obtained, and the infant was given intravenous aqueous penicillin, 100,000 units per kilogram per day, intramuscular gentamiein, 5.0 mg. per kilogram per day, intravenous fluids, and oxygen. He improved clinically after 15 hours of therapy, but 36 hours after admission a petechial rash appeared and increased bleeding with nasopharyngeal suctioning and heel sticks was noted. Although the coagulation studies listed in Table I, Column A, were normal, the platelets appeared decreased on a blood smear. The gentamicin was changed from the intramuscular to the intravenous route. Because of continued bleeding the coagulation studies were repeated 24 hours later (Table I, Column B). At that time the infant had an abnormal prothrombin time, a prolonged thrombin time, a positive serial protamine sulfate dilution (SPSD) test, increased soluble circulating fibrin, a decreased fibrinogen concentration, and fragmentation of red blood cells with almost complete absence of platelets on the blood smear. Although the organism in a blood culture was not completely identified,
Volume 83 Number 4
Brief clinical and laboratory observations
64 1
Table I Date and time B
Laboratory studies
A 9/17, 8 A.M.
Prothrombin time (normal 11.7 + 0.4 sec.)
12 sec.
Partial thromboplastin time (normal 34 + 5
42 see.
seC. )
Thrombin time (normal 18 + 2 sec.)
19 see:
Serial protamine sulfate dilution (SPSD) test ( normal--negative)
Negative
Soluble circulating fibrin (normal 164 -+ 35 DPM/mg. fibrinogen) Fibrinogen associated antigen in serum (tanned red cell hemagglutination inhibition immunoassay) (normal--less than 2 #g) Factor V (normal 97 + 36%) Factor VIII (normal 104 + 56%) Fibrinogen (normal 200 + 50 rag.%) PlateIets
162 DPM/ mg.
225 Adequate on blood smear
it was sensitive in vitro to penicillin and gentamicin. Because of the laboratory evidence for DIC and continued bleeding, the infant was treated with heparin, 100 units per kilogram every 4 hours, and given one unit of cryoprecipitate. The studies in Table I, Column C, obtained 8 hours after heparin therapy was begun, show a slight increase in fibrinogen-assoeiated antigen in the serum, but soluble circulating fibrin as measured by 14C glycine ethyl ester incorporation was absent. Coagulation studies (Table I, Column D) obtained 24. hours after initiation of heparin therapy showed a normal fibrinogen concentration, a negative SPSD test, and no soluble circulating fibrin. Heparin therapy was then discontinued. Listeria monocytogenes was identified in the blood culture 2 days later. The infant improved steadily and appears normal at age 7 months. DISCUSSION Listeria sepsis in the n e w b o r n i n f a n t , "granulomatosis infantiseptica," is a wellk n o w n b u t u n c o m m o n infection. Although reviews 1 have described petechiae a n d / o r
9/18, 8 A.M. (before heparin) 14.2 sec.
C 9/18, 4 P.M. (heparin) Heparin effect ) 60 see. 43 sec. Heparin effect ~ 120 see. 49 sec. Heparin effect > 60 sec. Positive 30 Positive 30 rain. and 24 rain. and hr. 24 hr. 335 DPM/mg. 142 DPM/ rag. 2 #g 4 ~g 100% 86% 50 Decreased on blood smear
110
D 9/19, 8 A.M. (heparin) Heparin effect 60 see. Heparin effect 120 see. Heparin effect 60 see. Negative 146 DPM/ rag. 4 #g
225 241,000/mm. a
p u r p u r a in infants with Listeria sepsis, studies to d o c u m e n t D I C have not been reported. All infants reported previously with petechiae or p u r p u r a associated with Listeria sepsis died. l, a T h e present i n f a n t developed clear evidence of D I C with decreased platelets on the blood smear, a b n o r m a l red blood cell morphology, decreased fibrinogen concentration, increased soluble circulating fibrin, a positive SPSD test, a n d increased fibrinogenrelated a n t i g e n in the serum. Previous studies in patients with meningococcal sepsis have suggested that antibiotics and supportive measures m a y be of more critical importance i n limiting the episode of D I C t h a n is h e p a r i n therapy, s, 4 However, in this report of Listeria sepsis the D I C occurred at a time when the i n f a n t had been receiving the appropriate antibiotics and supportive measures for more t h a n 36 hours. I t is possible, since Listeria is a n intracellular organism, that the death of Listeria as a result of antibiotic therapy caused release of thromboplastic substances initiating the D I C .
64 2
Brief clinical and laboratory observations
T h e episode of D I C could have resolved spontaneously; however, the r a p i d clearance of soluble circulating fibrin coincident with the institution of h e p a r i n t h e r a p y suggests that h e p a r i n m a y have been instrumental in limiting the process. F u r t h e r m o r e , all previously reported newborn infants with Listeria sepsis a n d petechiae not treated with h e p a r i n have died. T h e findings, therefore, suggest that a short course of h e p a r i n should be given to infants with Listeria sepsis in w h o m intravascular coagulation is documented.
Mixed connective tissue disease in a child Doris Y. Sanders, M.D.,* C a r o l y n C. Huntley, M.D., Winston-Salem, N. C., a n d G o r d o n C. Sharp, M.D., Columbia,
mo. M I x E D connective tissue disease associated with a specific serum antibody for extractable nuclear antigen ( E N A ) appears to be a distinct clinical entity? In the initial r e p o r t the youngest patient was 13 years of age. This brief report describes an 11-year-old girl with this syndrome associated with E N A antibody. This child also h a d recurrent bilateral parotitis and was found to have absent serum and salivary IgA. CASE
REPORT
A 9-year-old white girl was first seen in the diagnostic clinic of the Bowman Gray School of Medicine with a history of recurrent bilateral parotid swelling, recurrent fever, chronic fatigue,
From the Department of Pediatrics, The Pediatric Service of The North Carolina Baptist Hospital, Bowman Gray School o[ Medicine, and the Department o[ Medicine, University of Mbsouri School o[ Medicine. ~Address: Department o] Pediatrics, Bowman Gray School o] Medicine, Winston-Salem, N. C. 27103.
The Journal o[ Pediatrics October 1973
REFERENCES
1. Ray, C. G., and Wedgwood, R. J.: Neonatal listeriosis, Pediatrics 34: 378, 1964. 2. Kisker, C. T., and Rush, R.: Circulating fibrin in meningocoecemia, J. PEDIATR. 82: 787, 1973. 3. Johnston, W. H., Morton, S. A., Wong, IV[. H., and Roy, T. E.: Septieaemia of the newborn due to Listeria monocytogenes, Can. Med. Assoc. J. 73: 402, 1955. 4. Corrigan, J. J., and Jordan, C. M.: Heparin therapy in septicemia with disseminated intravascular coagulation, N. Engl. J. Med. 283: 778, 1970.
proximal muscle weakness, generalized arthralgia, and Raynaud's phenomenon of approximately one year's duration. The first episode of parotid swelling occurred when the child's two sisters had mumps. Physical examination revealed an afebrile, normotensive girl. Height was 5 0 ~ inches and weight was 52 pounds. A violaceous discoloration of the skin was present over the knees and elbows. The skin over the hands was ery.thematous, tight, and shiny. The toes were also markedly erythematous. The child was weak and required assistance getting on and off the examining table. Except for the presence of several carious teeth, no other abnormalities were detected. Laboratory studies included a hemoglobin concentration of 11.5 Gm. per 100 ml., hematocrit of 33 volumes per cent, white blood cell count of 4,500 per cubic millimeter with a differential count of 63 neutrophils, 32 lymphocytes, and 5 monocytes, Urinalysis was negative. Wintrobe sedimentation rate was 44 mm. per hour. Roentgenogram of the chest was normal. Total serum protein value * was 8.1 Gm. (albumin 3.4 Gm./globulin 4.7 Gm.). Serum immunoglobulinst2 were determined by a simple gel diffusion "XNormal serum pJotein values in our laboratory range . from 6.0 to 8.0 Gin. p e r 100 ml, "}'Normal serum immunoglobulin levels (geometric means in r a g . / 1 0 0 m l . ) for age. 2
Age (yr.) I 9 10 11 Adult
IgG 1.006 991 989 1.061
I
lgA 230 188 257 266
I
lgM 56 60 56 76