- Email: [email protected]
International notes
85 Infectious Diseases N e w s l e t t e r
of Petersdorf et al. has been followed by large series which clearly identify infection, neoplasm, and collagen vascular disease as the major causes of FUO in older individuals. I-3 Children and infants most commonly have prolonged fever secondary to infection and to common infections, at that; viruses and bacteria that usually result in acute self-limited and clearly definable disorders. 4-6 On occasion, the infection is more indolent with little or no localizing signs and no symptoms suggesting a specific etiology. Our child is no exception; she manifested fever, weight loss, moderate but nonspecific abdominal pain, and a brief episode of diarrhea. These can be the symptoms of infection but can also occur with collagen vascular~;diseases, inflammatory but noninfectious bowel disease, and some forms of malignancy. Physical examination was also not helpful. Focal abdominal tenderness did not conform to any specific entity such as appendicitis and the absence of significant organomegaly made some possibilities less likely but did not rule out, or in, any of the myriad of possibilities. No specific therapy was instituted, and, as her cultures remained sterile, consideration of noninfectious causes, particularly inflammatory bowel disease, assumed greater prominence. Just as diagnostic efforts were about to be launched, a report of the isolation of Salmonella enteritidis was made simultaneously with the discovery of seven discrete erythematous macules, which blanched on pressure, on her torso. No rash was observed on face or extremities. These macules were thought to represent "rose spots". She was initially treated with chloramphenicol and had a dramatic response to treatment with reduction in fever, loss of abdominal findings, and a sense of well-being. Subsequent analysis of the isolate at the Centers for Disease Control (CDC) resulted in re-identification as Salmonella typhi. This identification fit her dlse~"----ase,---,-,~erose spots, the relative bradycardia, and leukopenia better than did an S. enteritidis etiology. 7 She had classic typhoid fever, and, despite some perturbations in therapy, ultimately received ampicillin, was discharged, and has remained well.
Vincent, A. Fulginiti, M.D. Professor and Head Department of Pediatrics Arizona Health Sciences Center
References i. 2. 3. 4. 5. 6. 7.
Petersdorf RG, Beeson PP, Medicine 40:1, 1961. Jacoby GA, Swartz MN, N Engl J Med 289:1407, 1973. Wolff SM et al., Ann Rev Med 26:277, 1975. Pizzo PA, et al., Pediatr 55:468, 1975. McClung HJ, Am J Dis Child 124:544, 1972. Lohr J, Hendley OJ, Clin Pediatr 16:768, 1977. Black PH, et al., N Engl J Med 262:811, 864, 921, 1960.
INTERNATIONAL NOTES Reinfection Rubella: Subclinical reinfection with rubella is a well known phenomenon. Verified re-infection which is symptomatic with rash, however, has been reported rarely. Morgan-Capner and colleagues from London report a 19-yearold woman with acute lymphoblastic leukemia since April, 1982 developed aching limbs, episodes of shivering, and loose stools in July. She had fever, conjunctival infection but no arthropathy or lymphadenopathy. A fine macular rash appeared over her arms and back. Her white count was 3400 with 66% lymphocytes and 14% monocytes. Clinically, she was suspected of having rubella and it was discovered that she had contact with a child with a rubelliform rash 3 weeks prior to admission. She had a history of rubella as a child and denied having been vaccinated against rubella. Her illness resolved within 3 days. Serologic studies were conducted on the day of admission and at several intervals thereafter. When initially seen, she had specific IgG antibody in low titer and subsequently developed specific IgM rubella antibody which was sustained for a period of months. The authors point out that although their patient has disturbed immunologic function, the results obtained do indicate that rubella-specific IgM may be detectable in re-infections when previous seroconversion is due to natural disease. The amount of rubella-specific IgM, however, was much less than is usually seen in primary disease. Br Med J 286:1616, 1983 Rabies Vaccine: Warrell and a host of colleagus from Bangkok, Oxford, Liver.~ooi, and Harrow suggest that an economical way to use human diploid cell strain antirabies virus vaccine for post-exposure prophylaxis is to administer 0.i ml
86 Infectious Diseases Newsletter
of the vaccine intradermally. By measuring neutralizing antibody titer for 3 months after the iniation of therapy, they found that antibody was detected earliest in subjects given this dose in each of 8 sites. The highest antibody titers from day 14 on were found after intramuscular administration but the multiple site intradermal regimen, requiring only one-quarter of the volume of vaccine, gave similar results provided that a booster was given on day 91. The authors suggest that a treatment schedule based on this regimen would be suitable for post-exposure prophylaxis. They also found that a vaccine a d j u v a n t e ~ with aluminum hydroxide and given intradermally gave similar results. An incidental finding was it~at the human rabies immune globulin given at the high dose of 40 international units per kilogram suppressed the antibody response to some of the regimens. Lancet ii:301, 1983 Herpes Simplex Outbreak: Hammerberg and colleagues, in Canada, report an 1800 gram premature infant who developed respiratory distress and died at 12 days with the unexpected finding of herpes simplex virus isolated from cerebrospinal fluid. The infant had no mucocutaneous lesions. Within 10 days, 3 other infants aged 40, 69 and ii days developed vesicles which were positive for herpes simplex virus. These 3 infants were treated with vidarabine and did not develop systemic symptoms. Using monoclonal antibodies and an immunofluorescent technique, all fohr viruses turned out to be herpes simplex type i. Restriction endonuclease cleavage of viral DNA determined that the isolates were identical. Although the source of the outbreak has remained unknown, the authors discuss the possibility that manual transmission from the initial infant to the secondary cases was likely. They also point out that cohort i s o l a t i o n o f all the exposed patients in the nursery prevented further cases. Pediatr Infect Dis 2:290, 1983 Type A Hepatitis: Soldiers in the Israel defense forces have a high risk for type A infectious hepatitis. Clark reports that the use of pre-exposure prophylaxis, in an indigenous population, in whom approximately 70% have antibody to hepatitis A virus at age 18, was compared to a field trial with routine post-exposure use of ISG. Units were randomized into an intervention group in which all subjects received ISG and a second group in which 50% of the subjects were to be immunized. The actual immunized rates were 79% and 36%, respectively. A third nonimmunized control group was observed. The incidence rates were 0 in the group
of which 79% received ISG, 1.31/1000 in the group in which only 36% received ISG, and 1.72 among the nonimmunized. The author concludes that pre-exposure ISG afforded excellent protection, and, even at the low rate of incidence, was cost effective; and discusses the possibility of herd immunity. Scand J Infect Dis 15:3, 1983 Christchurch, New Zealand: Grimwood and colleagues studied the spread of rotavirus infection over 4 weeks in 28 families exposed to a single child with rotavirus infection. They showed a high incidence of intrafamilial infection with 46% of members of these families developing clinical infections compared to none in another series of 18 families. Children in the families in which an index case was infected were more frequently affected than adults; 75% of children developed rotavirus infection but only 33% of the adults. A more severe form of infection was seen in children when compared to adults. The authors re-emphasize that intrafamilial contact is important in transmitting rotavirus infection and preventive measures should aim at reducing cross-infection within families. Br Med J 287:575, 1983 Sheffield, England: Fenton and colleagues report the occurrence of pneumococcal bacteremia in a mother and son. A 69-year-old woman with chronic bronchitis was admitted with increasing dyspnea, left-sided pleuritic pain, and nonproductive cough. She also had cyanosis and central nervous system signs of confusion. Pulmonary consolidation was apparent at the left base. She was treated with ampicillin and dicloxacillin, and, when Streptococcus pneumoniae capsular subtype 1 was isolated from the blood culture, her treatment was changed to benzyl penicillin, 2 million units every 6 hours. Despite a stormy course, she finally recovered and was discharged on the 18th hospital day. Her 32-year-old son presented with a history of severe dyspnea and pleuritic chest pain on the right. He had a history of asthma but had never been given corticosteroids. He had fever and a radiograph showed a dense area of consolidation in the right upper lobe. Streptococcus pneumoniae type 1 was also isolated from his blood culture and his fever resolved within 24 hours of starting treatment. He recovered uneventfully. The authors emphasize that this is an unusual circumstance and emphasize the need to establish whether this type of transmission is common. Br Med J 287:529, 1983 Johannesburg, South Africa: In a study of diarrhea, in children under 2
9 1983 by Elsevier Science Pub~hing Co., Inc.
87 Infectious Diseases Newsletter
years of age, in Soweto, South Africa, Camphylobacter ~ was isolated in 18 of 60 children under 9 months of age with diarrhea compared to a lesser incidence in age-matched controls. In older children, 16 of 51 with diarrhea and 17 of 51 control children excreted this organism in their feces. Richardson and his colleagues believe that a change in susceptibility to Campylobacter jejuni, in ~hildren over 9 months of age, is evident from this data. Campylobacter enteritis in young children was mild without macroscopic blood in the feces and with prolonged excretion of the o r g a n i s m a f t e r acute attacks. Breast feeding did not seem to p r o t e c t against colonization with C. jenuni. Arch D~s Child 58:616, 1983.
NATIONAL NOTES AIDS in Infants: Arye Rubinstein reports on the acquired immune deficiency syndrome (AIDS) in infants and children. In 1982, his group described the first five infants with an AIDS-like disease. Since then, they have identified 26 children in the Bronx and also cite 19 sporadic pediatric cases reported from Manhattan, Newark, California, and among Haitian immigrants. He indicates the difficulty in establishing this diagnosis because of the occurrence of genetically determined disorders in this age group and a variety of congenital infections which may be confounding. In his review of a total of 45 cases, none fell into any well-defined genetic immunodeficiency and opportunistic infections and immune imbalances were similar to those reported in t h e a d u l t counterparts of AIDS. The only genetic immunodeficiency that resembles AIDS in infants is the poorly defined Nezelof's syndrome. In the patients considered to have A I D S ~ d 0 ' ~ i s t o l o g i c evidence for ..... thymic dysplasia, a hallmark of Nezelof's syndrome, was present. Another difference is that the serum immunoglobulin levels in Nezelof's syndrome are low, or at best, normal, whereas in 42 of the 45 infants with AIDS, immunoglobulin levels were greatly elevated. Among the clinical, immunologic, and maternal features in infants with AIDS and with the AIDS prodrome are the following: (i) low birthweight; (2) failure to thrive; (3) generalized lymphadenopathy; (4) hepatosplenomegaly; (5) interstitial pneumonia due to unknown cause; (6) parotitis; (77 chronic diarrhea; (8) recurrent bacterial and viral infections; (9) persistent EBV infection; and (10) oro-
9
pharyngeal thrush. In the AIDS syndrome, opportunistic infections occurred whereas in the AIDS prodrome these had not yet occurred. Thrombocytopenia was seen in the AIDS prodrome and not in the AIDS patients. Common to both was lymphopenia, elevated IgG levels, circulating immune complexes, a reversed T-4/T-8 ratio, a decrease in the in vitro mitogenic lymphocyte responses, and depressed in vitro responses to specific antigens. In b o t h g r o u p s , maternal drug use and/or promiscuity was noted. The evidence that links AIDS-like disease in infants to a similar disease in adults is as follows: (I) the geographic concurrence; (2) mothers of these infants belong to high-risk groups in which AIDS develops; (3) the constellation of clinical findings and the evolution of disease in infants is similar to that in adults; (4) the immunologic aberrations in infants are identical to those in their mothers and to those in adult patients with AIDS; and, finally, (5) an identical disease developed in an infant receiving AIDS-contaminated blood products, as previously reported. Rubinstein concludes that a new, potentially fatal disease in infants closely resembles the AIDS syndrome in adults and his group believes that the two are identical. Am J Dis Child 137:825, 1983 GBS in Neonates: Lannering and colleagues from Vanderbilt University describe a 7-year-experience of early onset Group B streptococcal (GBS) disease. One hundred and twenty cases of GBS infection are reported with disease manifestations varying from asymptomatic bacteremia to fatal cardiopulmonary collapse. The authors indicate that prematurity, a low Apgar score at 5 minutes, the presence of shock, leukopenia, rupture of the membranes for more than 12 hours, and a delay in treatment after the onset of symptoms were all associated with poor outcome. They developed a scoring system for the probability of mortality based on these six factors. Over the 7-year period mortality decreased from 50% to 10%. The only factor identified was a significant decrease in the number of hours between the onset of symptoms and the beginning of treatment. The authors~s make a strong plea for early recognition and prompt treatment as a means of decreasing mortality from this devastating infection. Acta Paediatr Scand 72:597, 1983 The Polle Syndrome: Liston and colleagues report a case of polymicrobial 'bacteremia in an infant for whom no underlying cause could be substantiated. Subsequent investigation determined that
by Elsevier Science Publish'i'n~Co.. Inc.
of Petersdorf et al. has been followed by large series which clearly identify infection, neoplasm, and collagen vascular disease as the major causes of FUO in older individuals. I-3 Children and infants most commonly have prolonged fever secondary to infection and to common infections, at that; viruses and bacteria that usually result in acute self-limited and clearly definable disorders. 4-6 On occasion, the infection is more indolent with little or no localizing signs and no symptoms suggesting a specific etiology. Our child is no exception; she manifested fever, weight loss, moderate but nonspecific abdominal pain, and a brief episode of diarrhea. These can be the symptoms of infection but can also occur with collagen vascular~;diseases, inflammatory but noninfectious bowel disease, and some forms of malignancy. Physical examination was also not helpful. Focal abdominal tenderness did not conform to any specific entity such as appendicitis and the absence of significant organomegaly made some possibilities less likely but did not rule out, or in, any of the myriad of possibilities. No specific therapy was instituted, and, as her cultures remained sterile, consideration of noninfectious causes, particularly inflammatory bowel disease, assumed greater prominence. Just as diagnostic efforts were about to be launched, a report of the isolation of Salmonella enteritidis was made simultaneously with the discovery of seven discrete erythematous macules, which blanched on pressure, on her torso. No rash was observed on face or extremities. These macules were thought to represent "rose spots". She was initially treated with chloramphenicol and had a dramatic response to treatment with reduction in fever, loss of abdominal findings, and a sense of well-being. Subsequent analysis of the isolate at the Centers for Disease Control (CDC) resulted in re-identification as Salmonella typhi. This identification fit her dlse~"----ase,---,-,~erose spots, the relative bradycardia, and leukopenia better than did an S. enteritidis etiology. 7 She had classic typhoid fever, and, despite some perturbations in therapy, ultimately received ampicillin, was discharged, and has remained well.
Vincent, A. Fulginiti, M.D. Professor and Head Department of Pediatrics Arizona Health Sciences Center
References i. 2. 3. 4. 5. 6. 7.
Petersdorf RG, Beeson PP, Medicine 40:1, 1961. Jacoby GA, Swartz MN, N Engl J Med 289:1407, 1973. Wolff SM et al., Ann Rev Med 26:277, 1975. Pizzo PA, et al., Pediatr 55:468, 1975. McClung HJ, Am J Dis Child 124:544, 1972. Lohr J, Hendley OJ, Clin Pediatr 16:768, 1977. Black PH, et al., N Engl J Med 262:811, 864, 921, 1960.
INTERNATIONAL NOTES Reinfection Rubella: Subclinical reinfection with rubella is a well known phenomenon. Verified re-infection which is symptomatic with rash, however, has been reported rarely. Morgan-Capner and colleagues from London report a 19-yearold woman with acute lymphoblastic leukemia since April, 1982 developed aching limbs, episodes of shivering, and loose stools in July. She had fever, conjunctival infection but no arthropathy or lymphadenopathy. A fine macular rash appeared over her arms and back. Her white count was 3400 with 66% lymphocytes and 14% monocytes. Clinically, she was suspected of having rubella and it was discovered that she had contact with a child with a rubelliform rash 3 weeks prior to admission. She had a history of rubella as a child and denied having been vaccinated against rubella. Her illness resolved within 3 days. Serologic studies were conducted on the day of admission and at several intervals thereafter. When initially seen, she had specific IgG antibody in low titer and subsequently developed specific IgM rubella antibody which was sustained for a period of months. The authors point out that although their patient has disturbed immunologic function, the results obtained do indicate that rubella-specific IgM may be detectable in re-infections when previous seroconversion is due to natural disease. The amount of rubella-specific IgM, however, was much less than is usually seen in primary disease. Br Med J 286:1616, 1983 Rabies Vaccine: Warrell and a host of colleagus from Bangkok, Oxford, Liver.~ooi, and Harrow suggest that an economical way to use human diploid cell strain antirabies virus vaccine for post-exposure prophylaxis is to administer 0.i ml
86 Infectious Diseases Newsletter
of the vaccine intradermally. By measuring neutralizing antibody titer for 3 months after the iniation of therapy, they found that antibody was detected earliest in subjects given this dose in each of 8 sites. The highest antibody titers from day 14 on were found after intramuscular administration but the multiple site intradermal regimen, requiring only one-quarter of the volume of vaccine, gave similar results provided that a booster was given on day 91. The authors suggest that a treatment schedule based on this regimen would be suitable for post-exposure prophylaxis. They also found that a vaccine a d j u v a n t e ~ with aluminum hydroxide and given intradermally gave similar results. An incidental finding was it~at the human rabies immune globulin given at the high dose of 40 international units per kilogram suppressed the antibody response to some of the regimens. Lancet ii:301, 1983 Herpes Simplex Outbreak: Hammerberg and colleagues, in Canada, report an 1800 gram premature infant who developed respiratory distress and died at 12 days with the unexpected finding of herpes simplex virus isolated from cerebrospinal fluid. The infant had no mucocutaneous lesions. Within 10 days, 3 other infants aged 40, 69 and ii days developed vesicles which were positive for herpes simplex virus. These 3 infants were treated with vidarabine and did not develop systemic symptoms. Using monoclonal antibodies and an immunofluorescent technique, all fohr viruses turned out to be herpes simplex type i. Restriction endonuclease cleavage of viral DNA determined that the isolates were identical. Although the source of the outbreak has remained unknown, the authors discuss the possibility that manual transmission from the initial infant to the secondary cases was likely. They also point out that cohort i s o l a t i o n o f all the exposed patients in the nursery prevented further cases. Pediatr Infect Dis 2:290, 1983 Type A Hepatitis: Soldiers in the Israel defense forces have a high risk for type A infectious hepatitis. Clark reports that the use of pre-exposure prophylaxis, in an indigenous population, in whom approximately 70% have antibody to hepatitis A virus at age 18, was compared to a field trial with routine post-exposure use of ISG. Units were randomized into an intervention group in which all subjects received ISG and a second group in which 50% of the subjects were to be immunized. The actual immunized rates were 79% and 36%, respectively. A third nonimmunized control group was observed. The incidence rates were 0 in the group
of which 79% received ISG, 1.31/1000 in the group in which only 36% received ISG, and 1.72 among the nonimmunized. The author concludes that pre-exposure ISG afforded excellent protection, and, even at the low rate of incidence, was cost effective; and discusses the possibility of herd immunity. Scand J Infect Dis 15:3, 1983 Christchurch, New Zealand: Grimwood and colleagues studied the spread of rotavirus infection over 4 weeks in 28 families exposed to a single child with rotavirus infection. They showed a high incidence of intrafamilial infection with 46% of members of these families developing clinical infections compared to none in another series of 18 families. Children in the families in which an index case was infected were more frequently affected than adults; 75% of children developed rotavirus infection but only 33% of the adults. A more severe form of infection was seen in children when compared to adults. The authors re-emphasize that intrafamilial contact is important in transmitting rotavirus infection and preventive measures should aim at reducing cross-infection within families. Br Med J 287:575, 1983 Sheffield, England: Fenton and colleagues report the occurrence of pneumococcal bacteremia in a mother and son. A 69-year-old woman with chronic bronchitis was admitted with increasing dyspnea, left-sided pleuritic pain, and nonproductive cough. She also had cyanosis and central nervous system signs of confusion. Pulmonary consolidation was apparent at the left base. She was treated with ampicillin and dicloxacillin, and, when Streptococcus pneumoniae capsular subtype 1 was isolated from the blood culture, her treatment was changed to benzyl penicillin, 2 million units every 6 hours. Despite a stormy course, she finally recovered and was discharged on the 18th hospital day. Her 32-year-old son presented with a history of severe dyspnea and pleuritic chest pain on the right. He had a history of asthma but had never been given corticosteroids. He had fever and a radiograph showed a dense area of consolidation in the right upper lobe. Streptococcus pneumoniae type 1 was also isolated from his blood culture and his fever resolved within 24 hours of starting treatment. He recovered uneventfully. The authors emphasize that this is an unusual circumstance and emphasize the need to establish whether this type of transmission is common. Br Med J 287:529, 1983 Johannesburg, South Africa: In a study of diarrhea, in children under 2
9 1983 by Elsevier Science Pub~hing Co., Inc.
87 Infectious Diseases Newsletter
years of age, in Soweto, South Africa, Camphylobacter ~ was isolated in 18 of 60 children under 9 months of age with diarrhea compared to a lesser incidence in age-matched controls. In older children, 16 of 51 with diarrhea and 17 of 51 control children excreted this organism in their feces. Richardson and his colleagues believe that a change in susceptibility to Campylobacter jejuni, in ~hildren over 9 months of age, is evident from this data. Campylobacter enteritis in young children was mild without macroscopic blood in the feces and with prolonged excretion of the o r g a n i s m a f t e r acute attacks. Breast feeding did not seem to p r o t e c t against colonization with C. jenuni. Arch D~s Child 58:616, 1983.
NATIONAL NOTES AIDS in Infants: Arye Rubinstein reports on the acquired immune deficiency syndrome (AIDS) in infants and children. In 1982, his group described the first five infants with an AIDS-like disease. Since then, they have identified 26 children in the Bronx and also cite 19 sporadic pediatric cases reported from Manhattan, Newark, California, and among Haitian immigrants. He indicates the difficulty in establishing this diagnosis because of the occurrence of genetically determined disorders in this age group and a variety of congenital infections which may be confounding. In his review of a total of 45 cases, none fell into any well-defined genetic immunodeficiency and opportunistic infections and immune imbalances were similar to those reported in t h e a d u l t counterparts of AIDS. The only genetic immunodeficiency that resembles AIDS in infants is the poorly defined Nezelof's syndrome. In the patients considered to have A I D S ~ d 0 ' ~ i s t o l o g i c evidence for ..... thymic dysplasia, a hallmark of Nezelof's syndrome, was present. Another difference is that the serum immunoglobulin levels in Nezelof's syndrome are low, or at best, normal, whereas in 42 of the 45 infants with AIDS, immunoglobulin levels were greatly elevated. Among the clinical, immunologic, and maternal features in infants with AIDS and with the AIDS prodrome are the following: (i) low birthweight; (2) failure to thrive; (3) generalized lymphadenopathy; (4) hepatosplenomegaly; (5) interstitial pneumonia due to unknown cause; (6) parotitis; (77 chronic diarrhea; (8) recurrent bacterial and viral infections; (9) persistent EBV infection; and (10) oro-
9
pharyngeal thrush. In the AIDS syndrome, opportunistic infections occurred whereas in the AIDS prodrome these had not yet occurred. Thrombocytopenia was seen in the AIDS prodrome and not in the AIDS patients. Common to both was lymphopenia, elevated IgG levels, circulating immune complexes, a reversed T-4/T-8 ratio, a decrease in the in vitro mitogenic lymphocyte responses, and depressed in vitro responses to specific antigens. In b o t h g r o u p s , maternal drug use and/or promiscuity was noted. The evidence that links AIDS-like disease in infants to a similar disease in adults is as follows: (I) the geographic concurrence; (2) mothers of these infants belong to high-risk groups in which AIDS develops; (3) the constellation of clinical findings and the evolution of disease in infants is similar to that in adults; (4) the immunologic aberrations in infants are identical to those in their mothers and to those in adult patients with AIDS; and, finally, (5) an identical disease developed in an infant receiving AIDS-contaminated blood products, as previously reported. Rubinstein concludes that a new, potentially fatal disease in infants closely resembles the AIDS syndrome in adults and his group believes that the two are identical. Am J Dis Child 137:825, 1983 GBS in Neonates: Lannering and colleagues from Vanderbilt University describe a 7-year-experience of early onset Group B streptococcal (GBS) disease. One hundred and twenty cases of GBS infection are reported with disease manifestations varying from asymptomatic bacteremia to fatal cardiopulmonary collapse. The authors indicate that prematurity, a low Apgar score at 5 minutes, the presence of shock, leukopenia, rupture of the membranes for more than 12 hours, and a delay in treatment after the onset of symptoms were all associated with poor outcome. They developed a scoring system for the probability of mortality based on these six factors. Over the 7-year period mortality decreased from 50% to 10%. The only factor identified was a significant decrease in the number of hours between the onset of symptoms and the beginning of treatment. The authors~s make a strong plea for early recognition and prompt treatment as a means of decreasing mortality from this devastating infection. Acta Paediatr Scand 72:597, 1983 The Polle Syndrome: Liston and colleagues report a case of polymicrobial 'bacteremia in an infant for whom no underlying cause could be substantiated. Subsequent investigation determined that
by Elsevier Science Publish'i'n~Co.. Inc.