- Email: [email protected]
Possible role of virus infection in sudden unexpected death
COMMENTS CURRENT
ON LITERATURE
Possible role of virus infection in sudden unexpected death pulmonary edema and congestion, with the presence of minimal-to-moderate cellular infiltration in some or all parts of the mucosa lining the upper respiratory tract. In most instances this inflammatory process did not appear to be sufficient cause to account for the death of the child. Huntington and Jarzynka 2 have pointed out that in the past "such deaths have been ascribed to status thymicolymphaticus and to mechanical asphyxia. A large thymus is, of course, normal for persons of this age who have not suffered wasting disease. The notion of mechanical asphyxia is based on the assumption that the infant has s o m e h o w . . , covered its airway with bedcovers or mattress and has been unable to free itself. ''2 It has been considered difficult to explain how such a thing could happen to a healthy active infant, and pathologists have been consistent in pointing out the differences between the necropsy findings in these instances and in those of true mechanical suffocation. Definite microscopic evidence of a pneumonie process has been found in about one half the infants on whom autopsies were performed with findings less clear in about one half. Viral etiology and the individual host response to virus infection have long been suspected as a possible explanation, 1, s a suggestion which has led to a search for etiologic agents, bacterial or viral. Fatal
F o R many years sudden and unexpected death in infancy and early childhood, the so-called crib death, has constituted a major pediatric problem. The characteristic features have been described by a number of investigators 1, 2: unexpected death in an infant or young child who seemed well or whose illness appeared to be so mild that any possibility of fatal outcome could not be anticipated. Such children were either moribund by the time the true character of the illness was recognized or were found dead. The history usually follows a definite pattern, well-known to pediatricians. "A well nourished and apparently well cared for infant is put to bed. Frequently it has manifested evidence of a 'little cold'. Rather frequently, there is the story of a 'cold going around in the family'. Occasionally, very timorous parents have called a doctor. Usually there has been no request for medical attention. The next member of the family to visit the infant finds that it has died. ''2 In only a few instances had any signs of illness been present for more than 48 hours. Although such sudden deaths have been designated as crib deaths, signifying more frequent occurrence in infancy, instances have been recorded in children as old as 5 years. At necropsy, the only definite pathologic findings in the majority of these infants were 631
63 2
Comments
on c u r r e n t l i t e r a t u r e
complications suggested have included laryngospasm secondary to a viral laryngitis or possibly an overwhelming viremia2, ~ Attempts at virus isolation, however, have not met with any degree of success. One of the most thorough investigations of this type was that reported by Gold and his associates 4 in 1961. Viral isolation was attempted from tissues obtained at autopsy from 48 infants whose deaths were sudden and unexplained on the basis of any clinical findings. Infectious agents were recovered from specimens obtained from 12 of these 48 infants. In 5 of the twelve the agent was isolated from the pharynx or stool, and in 7 from central nervous system tissues. All the agents were identified as members of the enterovirus group, chiefly Coxsackie viruses, Group A. Coxsackie A virus, type 4, was recovered from 8 infants, and was present in the central nervous system of 6 of them. Poliovirus type 3 was isolated from the central nervous system tissues of one infant, and Coxsackie virus Group A, type 4, from the stool of this same infant. Coxsackie A virus, type 8, was demonstrated in the feces of 2 infants. Coxsackie viruses of the A group were known to be prevalent in the community as indicated by epidemiologic studies of aseptic meningitis which were being conducted at this time. In 1963 Valdes-Dapena and Hummeler 5 reported the results of extensive necropsy studies in 109 deaths occurring in apparently well infants. Eight different specimens of tissue were obtained at each of the 109 autopsies performed on infants who had died suddenly or unexpectedly. The methods employed in attempted virus isolation included the use of adult mice, suckling mice, embryonated eggs, and tissue culture preparations of He La cells and monkey kidney cells. A viral agent was recovered in one instance only; a strain of Coxsackie Ba virus was isolated from the lungs of a female infant, 3 months of age "in whom there was no histologic evidence of pneumonia. ''s This child had no clinical evidence of illness at the time of death. At autopsy there was evidence of epiglottitis and tracheitis, but
October 1964
none of pneumonitis, tn two other instances, the autopsy findings strongly suggested viral infection of the respiratory tract, but no agents were recovered. Of special interest is a recent publication from the Communicable Disease Center, United States Public Health Service, Phoenix, Arizona. This report by Moore and colleagues ~ described the isolation of viral agents from autopsy material obtained from a group of 10 infants whose deaths were sudden and unexpected. These ten infant deaths occurred within a 12 month period in the metropolitan area of Phoenix. To the best available information, none of the families or the infants included in the study was acquainted with or had contact with another. However, epidemiologic studies being carried out in the area at this time indicated the presence of these same strains of virus in the community. In none of these sudden infant deaths were the pathologist's findings considered adequate to explain the death of the infant. The necropsy findings, however, were somewhat variable, and included "pulmonary congestion and edema with microscopic evidence of peribronchiolar thickening of the alveolar septae and infiltration with mononuclear cells. ''6 In some instances subepicardial and subpleural hemorrhages were observed. In attempted virus isolation, inoculation of adult and suckling mice and of tissue culture preparations was employed, with tissue culture preparations proving the more effective method of virus isolation. On the basis of previous experience, human embryonic epithelial lung cultures ( H E L ) and primary renal cultures obtained from the grivet, or Abyssinian green monkey, were selected. Viral agents were isolated from the stool or the tissues of 7 of 10 infants studied. Forty-five specimens including brain, lung, liver, whole blood, and stool were available for investigation. E C H O virus type 7 was recovered from stool specimens of 3 of the seven infants and from the liver, the lung, and the brain of each of 2 infants. In the case of one of these isolations from the brain there was corresponding recovery of
Volume 65
Number 4
virus from the stool; in the other no virus was detected in the stool. E C H O virus type 22 was recovered from a single stool specimen in the case of one infant. Poliovirus type 1 was isolated from the stool and also from the liver in the case of another infant. Poliovirus type 2 was recovered from the stool of one of the seven infants. Thus 9 of 12 isolations of virus from the stool or tissues of the seven infants yielded strains identified as E C H O virus type 7 : 2 isolations from the brain, 2 from the lung, 2 from the liver, and 3 from the stool. Three of the twelve isolations yielded other strains of virus: E C H O virus type 22 from a stool specimen; poliovirus type 1 from stool and from liver, and polio virus type 2 from stool. Identification of the newly isolated strains of virus was accomplished by neutralization and hemagglutination tests, and hemagglutination inhibition studies, wherever feasible. Comparison of the cultural characteristics of the newly isolated strains with those of a prototype E C H O 7 virus was possible. This prototype strain of E C H O virus type 7 was obtained from the Communicable Disease Center Laboratories in Atlanta, Georgia. In summary these authors emphasized the possible significance of infectious processes in the etiology of sudden unexpected death in infancy and early childhood. They suggested that "many agents could be involved and that the significance of any one might depend on the susceptibility of the individual infant, the microbe(s) present in the area at
C o m m e n t s on current literature
63 3
the time, and physiological factors as yet little understood. ''6 Although these current studies support viral etiology, it is well to point out that other extensive investigations carefully executed and employing similar techniques have not implicated viruses as a primary cause of "unexplained deaths." Whether such viral agents as those recovered play a significant role in the etiology of this perplexing syndrome must be determined by additional investigations. RUSSELL J. BLATTNER, M.D.
REFERENCES
1. Adams, J. M.: Sudden death in infants due to pneumonia, J. P~DIAT. 23; 189, 1943; Adams, J. M.: Newer virus diseases: Clinical differentiation of acute respiratory infections, New York, 1960, The Macmillan Company, p. 192. 2. Huntington, R. W., Jr., and Jarzynka, J. J.: Sudden and unexpected death in infancy, with special reference to the so-called crib deaths~ Am. J. Clin. Path. 38: 637, 1962. 3. Adelson, L., and[ Kinney, E. R.: Sudden and unexpected death in infancy and childhood, Pediatrics 17" 663, 1956. 4. Gold, E., Carver, D. H., Heineberg, H., Adelson, L., and Robbins, F. C.: Viral infection: A possible cause of sudden unexpected death in infants, New England J. Med. 264" 53, 1961. 5. Valdes-Dapena, M. A., and Hummeler, K.: Sudden and unexpected death in infants: II. Viral infections as causative factors, J. PEDIAT. 63' 398, 1963. 6. Moore, M. L., Hooser, L. E., Davis, E. V., and Siena, R. A.: Sudden unexpected death in infancy. Isolations of ECHO type 7 virus, Proc. Soc. Exper. Biol. & Med. 116- 23t, I964.
ON LITERATURE
Possible role of virus infection in sudden unexpected death pulmonary edema and congestion, with the presence of minimal-to-moderate cellular infiltration in some or all parts of the mucosa lining the upper respiratory tract. In most instances this inflammatory process did not appear to be sufficient cause to account for the death of the child. Huntington and Jarzynka 2 have pointed out that in the past "such deaths have been ascribed to status thymicolymphaticus and to mechanical asphyxia. A large thymus is, of course, normal for persons of this age who have not suffered wasting disease. The notion of mechanical asphyxia is based on the assumption that the infant has s o m e h o w . . , covered its airway with bedcovers or mattress and has been unable to free itself. ''2 It has been considered difficult to explain how such a thing could happen to a healthy active infant, and pathologists have been consistent in pointing out the differences between the necropsy findings in these instances and in those of true mechanical suffocation. Definite microscopic evidence of a pneumonie process has been found in about one half the infants on whom autopsies were performed with findings less clear in about one half. Viral etiology and the individual host response to virus infection have long been suspected as a possible explanation, 1, s a suggestion which has led to a search for etiologic agents, bacterial or viral. Fatal
F o R many years sudden and unexpected death in infancy and early childhood, the so-called crib death, has constituted a major pediatric problem. The characteristic features have been described by a number of investigators 1, 2: unexpected death in an infant or young child who seemed well or whose illness appeared to be so mild that any possibility of fatal outcome could not be anticipated. Such children were either moribund by the time the true character of the illness was recognized or were found dead. The history usually follows a definite pattern, well-known to pediatricians. "A well nourished and apparently well cared for infant is put to bed. Frequently it has manifested evidence of a 'little cold'. Rather frequently, there is the story of a 'cold going around in the family'. Occasionally, very timorous parents have called a doctor. Usually there has been no request for medical attention. The next member of the family to visit the infant finds that it has died. ''2 In only a few instances had any signs of illness been present for more than 48 hours. Although such sudden deaths have been designated as crib deaths, signifying more frequent occurrence in infancy, instances have been recorded in children as old as 5 years. At necropsy, the only definite pathologic findings in the majority of these infants were 631
63 2
Comments
on c u r r e n t l i t e r a t u r e
complications suggested have included laryngospasm secondary to a viral laryngitis or possibly an overwhelming viremia2, ~ Attempts at virus isolation, however, have not met with any degree of success. One of the most thorough investigations of this type was that reported by Gold and his associates 4 in 1961. Viral isolation was attempted from tissues obtained at autopsy from 48 infants whose deaths were sudden and unexplained on the basis of any clinical findings. Infectious agents were recovered from specimens obtained from 12 of these 48 infants. In 5 of the twelve the agent was isolated from the pharynx or stool, and in 7 from central nervous system tissues. All the agents were identified as members of the enterovirus group, chiefly Coxsackie viruses, Group A. Coxsackie A virus, type 4, was recovered from 8 infants, and was present in the central nervous system of 6 of them. Poliovirus type 3 was isolated from the central nervous system tissues of one infant, and Coxsackie virus Group A, type 4, from the stool of this same infant. Coxsackie A virus, type 8, was demonstrated in the feces of 2 infants. Coxsackie viruses of the A group were known to be prevalent in the community as indicated by epidemiologic studies of aseptic meningitis which were being conducted at this time. In 1963 Valdes-Dapena and Hummeler 5 reported the results of extensive necropsy studies in 109 deaths occurring in apparently well infants. Eight different specimens of tissue were obtained at each of the 109 autopsies performed on infants who had died suddenly or unexpectedly. The methods employed in attempted virus isolation included the use of adult mice, suckling mice, embryonated eggs, and tissue culture preparations of He La cells and monkey kidney cells. A viral agent was recovered in one instance only; a strain of Coxsackie Ba virus was isolated from the lungs of a female infant, 3 months of age "in whom there was no histologic evidence of pneumonia. ''s This child had no clinical evidence of illness at the time of death. At autopsy there was evidence of epiglottitis and tracheitis, but
October 1964
none of pneumonitis, tn two other instances, the autopsy findings strongly suggested viral infection of the respiratory tract, but no agents were recovered. Of special interest is a recent publication from the Communicable Disease Center, United States Public Health Service, Phoenix, Arizona. This report by Moore and colleagues ~ described the isolation of viral agents from autopsy material obtained from a group of 10 infants whose deaths were sudden and unexpected. These ten infant deaths occurred within a 12 month period in the metropolitan area of Phoenix. To the best available information, none of the families or the infants included in the study was acquainted with or had contact with another. However, epidemiologic studies being carried out in the area at this time indicated the presence of these same strains of virus in the community. In none of these sudden infant deaths were the pathologist's findings considered adequate to explain the death of the infant. The necropsy findings, however, were somewhat variable, and included "pulmonary congestion and edema with microscopic evidence of peribronchiolar thickening of the alveolar septae and infiltration with mononuclear cells. ''6 In some instances subepicardial and subpleural hemorrhages were observed. In attempted virus isolation, inoculation of adult and suckling mice and of tissue culture preparations was employed, with tissue culture preparations proving the more effective method of virus isolation. On the basis of previous experience, human embryonic epithelial lung cultures ( H E L ) and primary renal cultures obtained from the grivet, or Abyssinian green monkey, were selected. Viral agents were isolated from the stool or the tissues of 7 of 10 infants studied. Forty-five specimens including brain, lung, liver, whole blood, and stool were available for investigation. E C H O virus type 7 was recovered from stool specimens of 3 of the seven infants and from the liver, the lung, and the brain of each of 2 infants. In the case of one of these isolations from the brain there was corresponding recovery of
Volume 65
Number 4
virus from the stool; in the other no virus was detected in the stool. E C H O virus type 22 was recovered from a single stool specimen in the case of one infant. Poliovirus type 1 was isolated from the stool and also from the liver in the case of another infant. Poliovirus type 2 was recovered from the stool of one of the seven infants. Thus 9 of 12 isolations of virus from the stool or tissues of the seven infants yielded strains identified as E C H O virus type 7 : 2 isolations from the brain, 2 from the lung, 2 from the liver, and 3 from the stool. Three of the twelve isolations yielded other strains of virus: E C H O virus type 22 from a stool specimen; poliovirus type 1 from stool and from liver, and polio virus type 2 from stool. Identification of the newly isolated strains of virus was accomplished by neutralization and hemagglutination tests, and hemagglutination inhibition studies, wherever feasible. Comparison of the cultural characteristics of the newly isolated strains with those of a prototype E C H O 7 virus was possible. This prototype strain of E C H O virus type 7 was obtained from the Communicable Disease Center Laboratories in Atlanta, Georgia. In summary these authors emphasized the possible significance of infectious processes in the etiology of sudden unexpected death in infancy and early childhood. They suggested that "many agents could be involved and that the significance of any one might depend on the susceptibility of the individual infant, the microbe(s) present in the area at
C o m m e n t s on current literature
63 3
the time, and physiological factors as yet little understood. ''6 Although these current studies support viral etiology, it is well to point out that other extensive investigations carefully executed and employing similar techniques have not implicated viruses as a primary cause of "unexplained deaths." Whether such viral agents as those recovered play a significant role in the etiology of this perplexing syndrome must be determined by additional investigations. RUSSELL J. BLATTNER, M.D.
REFERENCES
1. Adams, J. M.: Sudden death in infants due to pneumonia, J. P~DIAT. 23; 189, 1943; Adams, J. M.: Newer virus diseases: Clinical differentiation of acute respiratory infections, New York, 1960, The Macmillan Company, p. 192. 2. Huntington, R. W., Jr., and Jarzynka, J. J.: Sudden and unexpected death in infancy, with special reference to the so-called crib deaths~ Am. J. Clin. Path. 38: 637, 1962. 3. Adelson, L., and[ Kinney, E. R.: Sudden and unexpected death in infancy and childhood, Pediatrics 17" 663, 1956. 4. Gold, E., Carver, D. H., Heineberg, H., Adelson, L., and Robbins, F. C.: Viral infection: A possible cause of sudden unexpected death in infants, New England J. Med. 264" 53, 1961. 5. Valdes-Dapena, M. A., and Hummeler, K.: Sudden and unexpected death in infants: II. Viral infections as causative factors, J. PEDIAT. 63' 398, 1963. 6. Moore, M. L., Hooser, L. E., Davis, E. V., and Siena, R. A.: Sudden unexpected death in infancy. Isolations of ECHO type 7 virus, Proc. Soc. Exper. Biol. & Med. 116- 23t, I964.