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Fatal echovirus 7 infection during an outbreak in a special care baby unit
Journal of Infection (I989) I9, 229-236
F a t a l e c h o v i r u s 7 i n f e c t i o n d u r i n g an o u t b r e a k in a s p e c i a l care baby unit T. G. Wreghitt,* G. M. Sutehall,* A. K i n g t and G. M. Gandy~
* Clinical Microbiology and Public Health Laboratory, t Department of Histopathology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QW and ~ Neonatal Unit, Rosie Maternity Hospital, Hills Road, Cambridge CB2 2QW, U.K. Accepted for publication 24 May I989 Summary A case of fatal echovirus 7 infection in a neonate which was probably acquired from the symptomatic mother and an outbreak of infection in a neonatal unit are described. The baby who died had extensive haemorrhagic necrosis of the brain, liver, adrenal glands and kidneys as well as disseminated intravascular coagulation. Three other babies and one member of staff were found to be infected. No other babies died. Human normal immunoglobulin was administered to all babies on the unit.
Introduction Echoviruses cause various syndromes in children and adults. T h e y include inapparent infection, upper respiratory tract symptoms, severe diarrhoea, a rash, hepatitis, abdominal pain, myocarditis, meningitis, pleurodynia and mild paralytic disease. Despite echoviruses being endemic most years, reports of fatal infection are mainly confined to neonates in special-care baby units. T h e most severe situation arises when the m o t h e r is infected in late pregnancy and transmits the infection to her baby who m a y be born prematurely. A l t h o u g h several echoviruses have been associated with fatal neonatal infection, most reports have described echovirus i i infections. 1-7 Fatal neonatal infections involving echovirus 6,1' s echovirus I 2 , 7 echovirus I 9 9 and echovirus 2I 1° have been reported. F r o m m i d - I 9 8 4 to early I985, echovirus 7 was the most prevalent enterovirus in England. T h i s serotype, sometimes associated with aseptic meningitis n and diarrhoeal disease, TM 12 has been recovered from parenchymal tissue of infants who died unexpectedly. 13 C e r n y et al. 14 reported a nosocomial epidemic of echovirus 7 in a neonatal unit involving five babies and five m e m b e r s of staff. T h e r e have been only three brief reports of fatal neonatal echovirus 7 infections.15' 16,17 H e r e we fully describe one of those cases, and the associated outbreak which arose in I984 in the special-care baby unit (SCBU) in Cambridge.
The outbreak T h e index case (case I) was a I9-year-old m o t h e r who was booked at io weeks' gestation. H e r pregnancy was progressing normally at 28 weeks. At 31 weeks she was a d m i t t e d to hospital in premature labour. On admission she had oI63-4453/89/o6o229+o8 $02.00/0
© I989 The British Society for the Study of Infection
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respiratory tract symptoms and a temperature of 37"5 °C. Her uterus was contracting regularly; it was tender but not tense. Ritodrine was infused intravenously. After z h, she complained of chest pain and her pulse rate had risen from 88/min to I4o/min. T h e infusion was stopped but very severe abdominal pain with an extremely tender abdomen (even between contractions) continued although the uterus was not tense. T h e fetal heart rate rose to I7o/min and then the beat became difficult to find. About 5 h after admission, an emergency Caesarean section was performed for fetal distress and the possibility of concealed ante-partum haemorrhage. At operation there was no evidence of abruption of the placenta or inflammation in the abdomen. Postoperatively the patient remained febrile and had a dry cough. T h e baby, a girl (case 2), weighed ~'98 kg, and was in good condition with an Apgar score of 5 at 3 min following resuscitation by bag and mask. She developed respiratory distress syndrome and required ventilation at 4 h. Progress was satisfactory and she was extubated on day 5. On day 6 she developed a mixed respiratory and metabolic acidosis which responded to Trihydroxymethylaminomethane and positive pressure ventilation. On day 8 she became more unwell with a clinical picture of septicaemia. Swabs for bacteriological investigation were taken. Cerebro-spinal fluid was heavily blood stained. This was attributed to a traumatic lumbar puncture. An infusion of 5 ~o human albumin solution was given. Antibiotics were changed from ceftazidime to penicillin, gentamicin and chloramphenicol. On day 9 the baby's abdomen was distended. She was hypotensive, oliguric and jaundiced (serum bilirubin 232/~mol/I). She also had a metabolic acidosis and evidence of disseminated intravascular coagulation. She was treated with dopamine, T H A M and an exchange blood transfusion. On day Io the baby convulsed. She remained hypotensive, acidotic and oliguric. T h e r e was virtually no response to anticonvulsants, to massive infusions of bicarbonate, to frusemide or to peritoneal dialysis. T h e baby died on day ia. Bacterial cultures were negative but viral specimens taken on day 8 yielded echovirus 7 although the results of the viral cultures were not known until the day after death took place. At necropsy, extensive haemorrhagic necrosis was noted in the brain, liver, adrenal glands and renal medulla. Plates I and z show the appearance of the kidneys and liver. On histological examination, microthrombi were seen in capillaries in the periadrenal fat and renal cortex, suggesting disseminated intravascular coagulation. These changes are typical of echovirus infection. 5 As soon as it was realised that case 2 had an enterovirus-like infection, the existing policy of handwashing with spirit hand rub is already in use, was reinforced, and admissions to the unit were restricted to emergencies and those babies who could not be accommodated in alternative units. Routine virological surveillance of all babies on the special-care baby unit and staff with symptoms led to three other babies and one member of staff being found with echovirus 7 infection (Fig. i). All three babies had mild symptoms comprising fever and gastrointestinal disturbances. One baby (case 5), born on ia July and given Ia5 mg human normal immunoglobulin ( H N I G ) shortly after admission to the unit on I3 July, nevertheless acquired echovirus 7 infection and was found to be excreting the virus in faeces sampled between 20 July and 6 August. Two other members of staff had symptoms that
yournal of Infection
Plate I
Plate I. Post-mortem appearance of a kidney and adrenal gland. T h e r e is extensive haemorrhage in the renal medttlla and involving the entire adrenal gland.
T. G. WREGHITT ET AL.
(Facing p. 230 )
Journal of Infection
Plate 2
Plate 2. Post-mortem appearance of the liver. Low power view of a section of liver showing extensive haemorrhagic necrosis. Only a rim of periportal hepatic parenchyma appears to be viable.
T. G. WREGHITT E T
AL.
F a t a l echovirus 7 infection
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suggested enteroviral infection, but a virus was not cultured from faecal samples taken from them during the acute stage of presumed infection (Fig. I). All staff with symptoms that suggested enterovirus infection were excluded from the unit until symptoms subsided. On 13 July, shortly after echovirus 7 had been grown from case 2, all babies already on the special-care baby unit were given one prophylactic dose of H N I G (very small babies, 83 ms, small babies, 125 ms, larger babies, 25o ms), as were those subsequently admitted to the unit up to i5 August. Virological m e t h o d s
Specimens for virus isolation (faecal samples or throat swabs in virus transport medium) were inoculated into tube cultures of primary human amnion and human embryonic lung fibroblast (MRC-5) cells. Inoculated tubes were incubated at 37 °C for up to 7 days. An enterovirus cytopathic effect was always observed within 48 h. Isolates were identified by neutralisation tests with type-specific rabbit antisera. Serum samples from mothers and babies were examined for serum neutralising antibody by microneutralisation tests with primary human amnion cells and IOO T C I D 5 o of echovirus 7. Several batches of H N I G were also tested, in case they might be needed for prophylactic use. Serum samples which had been taken during visits to the ante-natal clinic from several of the mothers whose babies were on the unit were tested. Later samples were taken by general practitioners. Blood samples from women attending the ante-natal clinic during the same period of time (about 6 months before the outbreak) and a further group of similar samples from a period 6 months after the outbreak were examined also and served as controls. Serum samples from many of the babies in the unit were available (paired samples in several cases) and samples from unexposed babies were available for use as controls. Serum samples taken from three members of staff shortly after they developed symptoms suggestive of enterovirus infection were examined also. Results Virus culture Case 2
Echovirus 7 was identified in faeces and a throat swab taken when the baby was 9 days old and also from a sample of cerebro-spinal fluid taken a day earlier. Post-mortem specimens of kidney, liver, spleen, pleural fluid and gut contents all contained the virus. Screening
Throat swabs and faecal specimens were collected from 35 babies and eight members of staff. Samples from babies were taken twice a week initially. After 2 weeks, the frequency of sampling was reduced to once a week for babies not found to be excreting virus. A total of 211 specimens was examined, including 96 faecal samples and lO6 throat swabs. Echovirus 7 was identified in 13 faecal specimens from three babies but was not grown from any of the throat swabs.
Fatal echovirus 7 infection
233
200 Echovlrus 7
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140
120
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1985
1984
1986
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Fig. 2. Number of cases of Echovirus 7 infections in England and Wales reported to the Public Health Laboratory Service Communicable Disease Surveillance Centre, London between I983 and I986. (Reproduced with permission.)
T h e virus was grown from the faeces of one member of staff (Fig. z) but not from the other two affected persons. Serology T h e only echovirus 7 infection diagnosed serologically by seroconversion was in the index case. Seven of z8 (39 %) mothers of babies in the special-care baby unit at the time of the outbreak showed evidence of past echovirus 7 infection but their antibody titres were low and not likely to have indicated recent infection. It should be noted that echovirus 7 was the most prevalent enterovirus in England and Wales in I984 (Fig. z). Of the 25 control ante-natal samples taken before the outbreak, I (4 %) had detectable antibody to echovirus 7; of the post-outbreak samples, two of 25 (8 %) had detectable antibody. There were three of 2o (I5 %) exposed babies in w h o m antibody to echovirus 7 was detected at the time of the outbreak. This antibody was presumed to be of maternal origin. Similarly, three of I6 (I9 %) of the babies in the control group had detectable antibody to echovirus 7. N o n e of the acute serum samples from the three symptomatic members of staff tested had such antibody. All of seven batches of H N I G had echovirus 7 neutralising antibody titres of between 4o and I6O. Discussion T h e clinical features and post-mortem findings of echovirus 7 infection in case 2 were remarkably similar to those in previous reports of echovirus 10-2
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(particularly echovirus I I ) infection in babies in special-care b a b y units. 3' ~' 16.19 Babies in these reports died b e t w e e n 5 and i I days of age after a short illness characterised b y collapse, acidosis and bleeding. P o s t m o r t e m there was evidence of disseminated intravascular coagulation with haemorrhage into m a n y organs, especially the renal medulla, adrenal glands and central nervous system. T h e origin of the outbreak described here was similar to those reported for other echovirus infections, 3' 19 i.e. w o m e n in the third trimester of pregnancy who experienced a febrile illness with abdominal pain and who were subsequently delivered b y Caesarian section. Often, w h e n echovirus infection arises in special-care b a b y units, there are signs that the virus has transmitted to other babies on the unit. 19 T h e most probable means of such transmission is likely to be via staff, either indirectly, through inadequate hand-washing, or directly as a result of enterovirus infection among staff. In years when enterovirus infection is endemic, the virus m a y be repeatedly introduced into a unit b y infected mothers. 2° It is generally accepted that frequent and t h o r o u g h hand-washing with a spirit rub 18 is a desirable precaution against cross-infection. T h i s policy has been in force in our unit since the first outbreak of echovirus I I infection in 1977 .~ This policy was reinforced as soon as it seemed likely that a person with enterovirus infection had entered the unit. Despite this precaution, three other babies became infected with echovirus 7. Since these babies were not nursed close to case 2 and there was no evidence of echovirus 7 infection in the mothers of babies on the unit, it must be p r e s u m e d that they were infected indirectly via staff. Direct transmission from infected m e m b e r s of staff seems unlikely. T h r e e m e m b e r s of staff had s y m p t o m s that suggested enterovirus infection during the period of the outbreak. T h e timing of their s y m p t o m s and the isolation of echovirus 7 from the only confirmed case, however, do not suggest staff-to-patient transmission. Administration of H N I G has been advocated as an effective prophylactic measure to prevent further echovirus infection. 16' 20.21 H N I G was therefore administered to babies on the unit on 13 July. Although there were three cases of infection a few days later, these babies were p r o b a b l y infected before the administration of H N I G . Case 5 was given H N I G on the day of admission to the unit. H e m a y have been infected before he was given H N I G and the dose administered (I25 mg) m a y have been sufficient to suppress s y m p t o m s b u t not enough to prevent colonisation of the gut. T h e efficacy of H N I G prophylaxis was reported b y N a g i n g t o n et al. 2° w h o showed that none of 2o5 babies given 250 mg H N I G during an outbreak of echovirus I I in C a m b r i d g e acquired infection, although 2I babies not given H N I G were infected earlier in the outbreak. W h e n administration of H N I G was stopped, a further case was noted 4 days after admission to the unit. T h e administration of less than 25o m g H N I G to the smaller babies in our unit m a y explain w h y case 5 was colonised with echovirus 7. In retrospect, it m a y have been m o r e appropriate to have given 25o m g H N I G to all babies irrespective of size. Nagington 21 also showed that s y m p t o m a t i c echovirus I I infection was found in 7 of 24 babies whose mothers did not have echovirus I I neutralising antibody at the time of delivery, whereas infections were not detected in I2 babies whose mothers did possess echovirus I I neutralising antibody, thereby suggesting that passive
Fatal echovirus 7 infection
235
a n t i b o d y does p r o t e c t against infection. M o d l i n et al. 22 also show ed that babies b o r n to w o m e n excreting echovirus at t erm , and who had echovirus a n t i b o d y in co r d s er u m , were a s y m p t o m a t i c b u t shed virus f r o m their r e s p i r a t o r y or gastro-intestinal tracts by 3 days o f age. An interesting feature o f the babies in this o u t b r e a k was that, with the ex cep tio n o f case 2, echovirus 7 was isolated f r o m faeces b u t not f r o m t h r o a t swabs taken in the acute stage of infection. T h i s has also been n o t e d by M o d l i n et al. 2~ and indicates the i m p o r t a n c e o f surveillance by examining faecal samples d u r i n g an ent er ovi r us outbreak. T h e fact that m e m b e r s o f staff m ay be infected d u r i n g ent erovi rus out breaks in special-care b a b y units emphasises the i m p o r t a n c e of excluding s y m p tomatic staff f r o m the unit until e n t e r o v i r u s infection has been e x c l u d e d or their s y m p t o m s have subsided. A l t h o u g h the m o s t significant r o u t e o f echovirus infection is f r o m m o t h e r to neonate, o t h e r means o f spread m a y lead to serious or fatal infection, z' 19.23 Fatal infections are t h o u g h t to be a c q u i r e d either directly f r o m infected and s y m p t o m a t i c m e m b e r s of staff or as a result of inadequate hand-washing. It is difficult to k n o w w h e t h e r or n o t to restrict admissions to a S C B U with en ter o v ir u s infection. Som e feel that closing a regional neonatal intensive care unit each time an e n t e r o v i r u s infection is diagnosed is not justified. 17 A l t h o u g h it w o u l d be u n r e a s o n a b l e to d e n y intensive care facilities to those babies in u r g e n t need, it m a y be p r u d e n t , w h e n cases o f ent erovi rus infection are f o u n d on a unit, to restrict admissions to emergencies and to those babies who cannot be a d m i t t e d to o t h e r local S C B U s . I n these circumstances, all new admissions should be given H N I G which m a y p r e v e n t or ameliorate e n t e r o v i r u s infections in neonates. It is questionable w h e t h e r r o u t i n e surveillance o f babies in S C B U s for evidence o f e n t e r o v i r u s infection is necessary. 24 W h e n enteroviruses are e n d e m i c in the c o m m u n i t y , the possibility o f infection being i n t r o d u c e d into a S C B U m u s t be b o r n e in m i n d and precaut i ons such as the f r e q u e n t use o f alcohol h a n d r ub vigorously observed. (We thank the Director of the Public Health Laboratory Service Communicable Disease Surveillance Centre, London for permission to reproduce Figure 2.) References
i. Krous HF, Dietzman D, Ray CG. Fatal infections with Echovirus types 6 and I I in early infancy. A m J Dis Child I973 ; I26 : 842--846. 2. Drew JH. Echo I I virus infection : a cause of acquired neonatal hepatitis. Aust Paediatr J I974; IO: I77-I79. 3. Nagington J, Wreghitt TG, Gandy G, Roberton NRC, Berry PJ. Fatal Echovirus I I infections in outbreak in special-care baby unit. Lancet I978 ; ii: 725-728. 4. Davies DP, Hughes CA, MacVicar J, Hawkes P, Mair HJ. Echovirus I I infection in a special-care baby unit. Lancet r979; i: 96. 5- Berry PJ, Nagington J. Fatal infection with Echovirus i i. Arch Dis Child I982; 57: 22-29. 6. Nawab RA. Fatal Echo virus I I infection in one of newborn twins. Indian J Pathol Microbiol I984; z7: I9-26. 7. Speer ME, Yawn DH. Fatal hepatoadrenal necrosis in the neonate associated with Echovirus types II and I2 presenting as a surgical emergency. J Pediatr Surg I984; I9: 591-593 •
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8. Boyd M T , Jordan SW, Davis LE. Fatal pneumonitis from congenital Echovirus type 6 infection. Pediatr Infect Dis J I987; 6: x i 3 8 - I I 3 9 . 9- Philip A G S , Larson EJ. Overwhelming neonatal infection with echo 19 virus. J Pediatr I973; 82: 391-397. IO. Georgieff M K , Johnson DE, Thompson TR, Belani K, Ferrieri P. Fulminant hepatic necrosis in an infant with perinatally acquired Echovirus 2i infection. Pediatr Infect Dis J I987; 6: 71-73. I I. Conolly JH, Russell JD, Robinson F L J , Canavan DA. Echovirus type 7 outbreak in Northern Ireland during x984. Ulster M e d J I985; 54: I 9 I - I 9 5 . I2. Welke G, Herman J. Diarrhoea diseases caused by the Echovirus type 7. Dtsch Gesundh Wes I975; 3o: I 6 9 - I 7 I . I3. Melnick JL, Wenner HA, Phillips CA. In: Lennette EH, Schmidt NJ, Eds. Diagnostic procedures for viral, rickettsial and chlamydial infections, 5th ed. Washington: American Public Health Association, I979; 476. I4. Cerny E, K i n d C, Bachi T. Nosocomial epidemic of echovirus type 7 in a neonatology department. Helv Paediatr Acta I983 ; 38: 457-465. I5. Wreghitt T G , Gandy G M , King A, Sutehall G. Fatal neonatal Echo 7 virus infection. Lancet I984; ii: 465. I6. Carolane D J, Long AM, McKeever PA, Hobbs SJ, Roome AP. Prevention of spread of Echovirus 6 in a special-care baby unit. Arch Dis Child I985; 6o: 674-676. I7. Isaacs D, Wilkinson A, Moxon ER. Prevention of spread of Echovirus 6 in a special-care baby unit. Arch Dis Child I985 ; 6o: I2o5-I2O6. I8. Kurtz JB, Lee T W , Parsons AJ. T h e action of alcohols on rotaviruses, astroviruses and enteroviruses. J Hosp Infect I98O; I : 3 2 I - 5. I9. Modlin JF. Perinatal echovirus infection. Insights from a literature review of 6I cases of serious infection and I6 outbreaks in nurseries. Rev Infect Dis I986; 8: 9I 8-26. 20. Nagington J, Gandy G, Walker JR, Gray JJ. Use of normal immunoglobulin in an Echovirus x I outbreak in a special-care baby unit. Lancet I983; ii: 443-446. 2I. Nagington J. Echovirus 11 infection and prophylactic antiserum. Lancet I98Z; i: 446. zz. Modlin JF, Polk BF, Horton P, Etkind P, Crane E, Spiliotes A. Perinatal Echovirus infection. Risk of transmission during a community outbreak. New Engl J Med x981 ; 3o5: 368-37I. 23. Chow CB, Tse H H , Chan KY et al. Outbreak of Echo Virus type I I infection in newborn infants in a maternity ward. Clinical presentation. J Trop Pediatr I987; 3 3 : 3 0 5 - 3 °8. 24. Appleton H, Buckley M, Robertson MH, Thorn BT. A search for faecal viruses in newborn and other infants. J Hyg (Camb) I978; 8x: 279-283.
F a t a l e c h o v i r u s 7 i n f e c t i o n d u r i n g an o u t b r e a k in a s p e c i a l care baby unit T. G. Wreghitt,* G. M. Sutehall,* A. K i n g t and G. M. Gandy~
* Clinical Microbiology and Public Health Laboratory, t Department of Histopathology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QW and ~ Neonatal Unit, Rosie Maternity Hospital, Hills Road, Cambridge CB2 2QW, U.K. Accepted for publication 24 May I989 Summary A case of fatal echovirus 7 infection in a neonate which was probably acquired from the symptomatic mother and an outbreak of infection in a neonatal unit are described. The baby who died had extensive haemorrhagic necrosis of the brain, liver, adrenal glands and kidneys as well as disseminated intravascular coagulation. Three other babies and one member of staff were found to be infected. No other babies died. Human normal immunoglobulin was administered to all babies on the unit.
Introduction Echoviruses cause various syndromes in children and adults. T h e y include inapparent infection, upper respiratory tract symptoms, severe diarrhoea, a rash, hepatitis, abdominal pain, myocarditis, meningitis, pleurodynia and mild paralytic disease. Despite echoviruses being endemic most years, reports of fatal infection are mainly confined to neonates in special-care baby units. T h e most severe situation arises when the m o t h e r is infected in late pregnancy and transmits the infection to her baby who m a y be born prematurely. A l t h o u g h several echoviruses have been associated with fatal neonatal infection, most reports have described echovirus i i infections. 1-7 Fatal neonatal infections involving echovirus 6,1' s echovirus I 2 , 7 echovirus I 9 9 and echovirus 2I 1° have been reported. F r o m m i d - I 9 8 4 to early I985, echovirus 7 was the most prevalent enterovirus in England. T h i s serotype, sometimes associated with aseptic meningitis n and diarrhoeal disease, TM 12 has been recovered from parenchymal tissue of infants who died unexpectedly. 13 C e r n y et al. 14 reported a nosocomial epidemic of echovirus 7 in a neonatal unit involving five babies and five m e m b e r s of staff. T h e r e have been only three brief reports of fatal neonatal echovirus 7 infections.15' 16,17 H e r e we fully describe one of those cases, and the associated outbreak which arose in I984 in the special-care baby unit (SCBU) in Cambridge.
The outbreak T h e index case (case I) was a I9-year-old m o t h e r who was booked at io weeks' gestation. H e r pregnancy was progressing normally at 28 weeks. At 31 weeks she was a d m i t t e d to hospital in premature labour. On admission she had oI63-4453/89/o6o229+o8 $02.00/0
© I989 The British Society for the Study of Infection
230
T. G. W R E G H I T T E T A L .
respiratory tract symptoms and a temperature of 37"5 °C. Her uterus was contracting regularly; it was tender but not tense. Ritodrine was infused intravenously. After z h, she complained of chest pain and her pulse rate had risen from 88/min to I4o/min. T h e infusion was stopped but very severe abdominal pain with an extremely tender abdomen (even between contractions) continued although the uterus was not tense. T h e fetal heart rate rose to I7o/min and then the beat became difficult to find. About 5 h after admission, an emergency Caesarean section was performed for fetal distress and the possibility of concealed ante-partum haemorrhage. At operation there was no evidence of abruption of the placenta or inflammation in the abdomen. Postoperatively the patient remained febrile and had a dry cough. T h e baby, a girl (case 2), weighed ~'98 kg, and was in good condition with an Apgar score of 5 at 3 min following resuscitation by bag and mask. She developed respiratory distress syndrome and required ventilation at 4 h. Progress was satisfactory and she was extubated on day 5. On day 6 she developed a mixed respiratory and metabolic acidosis which responded to Trihydroxymethylaminomethane and positive pressure ventilation. On day 8 she became more unwell with a clinical picture of septicaemia. Swabs for bacteriological investigation were taken. Cerebro-spinal fluid was heavily blood stained. This was attributed to a traumatic lumbar puncture. An infusion of 5 ~o human albumin solution was given. Antibiotics were changed from ceftazidime to penicillin, gentamicin and chloramphenicol. On day 9 the baby's abdomen was distended. She was hypotensive, oliguric and jaundiced (serum bilirubin 232/~mol/I). She also had a metabolic acidosis and evidence of disseminated intravascular coagulation. She was treated with dopamine, T H A M and an exchange blood transfusion. On day Io the baby convulsed. She remained hypotensive, acidotic and oliguric. T h e r e was virtually no response to anticonvulsants, to massive infusions of bicarbonate, to frusemide or to peritoneal dialysis. T h e baby died on day ia. Bacterial cultures were negative but viral specimens taken on day 8 yielded echovirus 7 although the results of the viral cultures were not known until the day after death took place. At necropsy, extensive haemorrhagic necrosis was noted in the brain, liver, adrenal glands and renal medulla. Plates I and z show the appearance of the kidneys and liver. On histological examination, microthrombi were seen in capillaries in the periadrenal fat and renal cortex, suggesting disseminated intravascular coagulation. These changes are typical of echovirus infection. 5 As soon as it was realised that case 2 had an enterovirus-like infection, the existing policy of handwashing with spirit hand rub is already in use, was reinforced, and admissions to the unit were restricted to emergencies and those babies who could not be accommodated in alternative units. Routine virological surveillance of all babies on the special-care baby unit and staff with symptoms led to three other babies and one member of staff being found with echovirus 7 infection (Fig. i). All three babies had mild symptoms comprising fever and gastrointestinal disturbances. One baby (case 5), born on ia July and given Ia5 mg human normal immunoglobulin ( H N I G ) shortly after admission to the unit on I3 July, nevertheless acquired echovirus 7 infection and was found to be excreting the virus in faeces sampled between 20 July and 6 August. Two other members of staff had symptoms that
yournal of Infection
Plate I
Plate I. Post-mortem appearance of a kidney and adrenal gland. T h e r e is extensive haemorrhage in the renal medttlla and involving the entire adrenal gland.
T. G. WREGHITT ET AL.
(Facing p. 230 )
Journal of Infection
Plate 2
Plate 2. Post-mortem appearance of the liver. Low power view of a section of liver showing extensive haemorrhagic necrosis. Only a rim of periportal hepatic parenchyma appears to be viable.
T. G. WREGHITT E T
AL.
F a t a l echovirus 7 infection
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suggested enteroviral infection, but a virus was not cultured from faecal samples taken from them during the acute stage of presumed infection (Fig. I). All staff with symptoms that suggested enterovirus infection were excluded from the unit until symptoms subsided. On 13 July, shortly after echovirus 7 had been grown from case 2, all babies already on the special-care baby unit were given one prophylactic dose of H N I G (very small babies, 83 ms, small babies, 125 ms, larger babies, 25o ms), as were those subsequently admitted to the unit up to i5 August. Virological m e t h o d s
Specimens for virus isolation (faecal samples or throat swabs in virus transport medium) were inoculated into tube cultures of primary human amnion and human embryonic lung fibroblast (MRC-5) cells. Inoculated tubes were incubated at 37 °C for up to 7 days. An enterovirus cytopathic effect was always observed within 48 h. Isolates were identified by neutralisation tests with type-specific rabbit antisera. Serum samples from mothers and babies were examined for serum neutralising antibody by microneutralisation tests with primary human amnion cells and IOO T C I D 5 o of echovirus 7. Several batches of H N I G were also tested, in case they might be needed for prophylactic use. Serum samples which had been taken during visits to the ante-natal clinic from several of the mothers whose babies were on the unit were tested. Later samples were taken by general practitioners. Blood samples from women attending the ante-natal clinic during the same period of time (about 6 months before the outbreak) and a further group of similar samples from a period 6 months after the outbreak were examined also and served as controls. Serum samples from many of the babies in the unit were available (paired samples in several cases) and samples from unexposed babies were available for use as controls. Serum samples taken from three members of staff shortly after they developed symptoms suggestive of enterovirus infection were examined also. Results Virus culture Case 2
Echovirus 7 was identified in faeces and a throat swab taken when the baby was 9 days old and also from a sample of cerebro-spinal fluid taken a day earlier. Post-mortem specimens of kidney, liver, spleen, pleural fluid and gut contents all contained the virus. Screening
Throat swabs and faecal specimens were collected from 35 babies and eight members of staff. Samples from babies were taken twice a week initially. After 2 weeks, the frequency of sampling was reduced to once a week for babies not found to be excreting virus. A total of 211 specimens was examined, including 96 faecal samples and lO6 throat swabs. Echovirus 7 was identified in 13 faecal specimens from three babies but was not grown from any of the throat swabs.
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200 Echovlrus 7
180 160
140
120
g
I00
"6
80 z
60
40
L
20 1983
1985
1984
1986
Year
Fig. 2. Number of cases of Echovirus 7 infections in England and Wales reported to the Public Health Laboratory Service Communicable Disease Surveillance Centre, London between I983 and I986. (Reproduced with permission.)
T h e virus was grown from the faeces of one member of staff (Fig. z) but not from the other two affected persons. Serology T h e only echovirus 7 infection diagnosed serologically by seroconversion was in the index case. Seven of z8 (39 %) mothers of babies in the special-care baby unit at the time of the outbreak showed evidence of past echovirus 7 infection but their antibody titres were low and not likely to have indicated recent infection. It should be noted that echovirus 7 was the most prevalent enterovirus in England and Wales in I984 (Fig. z). Of the 25 control ante-natal samples taken before the outbreak, I (4 %) had detectable antibody to echovirus 7; of the post-outbreak samples, two of 25 (8 %) had detectable antibody. There were three of 2o (I5 %) exposed babies in w h o m antibody to echovirus 7 was detected at the time of the outbreak. This antibody was presumed to be of maternal origin. Similarly, three of I6 (I9 %) of the babies in the control group had detectable antibody to echovirus 7. N o n e of the acute serum samples from the three symptomatic members of staff tested had such antibody. All of seven batches of H N I G had echovirus 7 neutralising antibody titres of between 4o and I6O. Discussion T h e clinical features and post-mortem findings of echovirus 7 infection in case 2 were remarkably similar to those in previous reports of echovirus 10-2
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(particularly echovirus I I ) infection in babies in special-care b a b y units. 3' ~' 16.19 Babies in these reports died b e t w e e n 5 and i I days of age after a short illness characterised b y collapse, acidosis and bleeding. P o s t m o r t e m there was evidence of disseminated intravascular coagulation with haemorrhage into m a n y organs, especially the renal medulla, adrenal glands and central nervous system. T h e origin of the outbreak described here was similar to those reported for other echovirus infections, 3' 19 i.e. w o m e n in the third trimester of pregnancy who experienced a febrile illness with abdominal pain and who were subsequently delivered b y Caesarian section. Often, w h e n echovirus infection arises in special-care b a b y units, there are signs that the virus has transmitted to other babies on the unit. 19 T h e most probable means of such transmission is likely to be via staff, either indirectly, through inadequate hand-washing, or directly as a result of enterovirus infection among staff. In years when enterovirus infection is endemic, the virus m a y be repeatedly introduced into a unit b y infected mothers. 2° It is generally accepted that frequent and t h o r o u g h hand-washing with a spirit rub 18 is a desirable precaution against cross-infection. T h i s policy has been in force in our unit since the first outbreak of echovirus I I infection in 1977 .~ This policy was reinforced as soon as it seemed likely that a person with enterovirus infection had entered the unit. Despite this precaution, three other babies became infected with echovirus 7. Since these babies were not nursed close to case 2 and there was no evidence of echovirus 7 infection in the mothers of babies on the unit, it must be p r e s u m e d that they were infected indirectly via staff. Direct transmission from infected m e m b e r s of staff seems unlikely. T h r e e m e m b e r s of staff had s y m p t o m s that suggested enterovirus infection during the period of the outbreak. T h e timing of their s y m p t o m s and the isolation of echovirus 7 from the only confirmed case, however, do not suggest staff-to-patient transmission. Administration of H N I G has been advocated as an effective prophylactic measure to prevent further echovirus infection. 16' 20.21 H N I G was therefore administered to babies on the unit on 13 July. Although there were three cases of infection a few days later, these babies were p r o b a b l y infected before the administration of H N I G . Case 5 was given H N I G on the day of admission to the unit. H e m a y have been infected before he was given H N I G and the dose administered (I25 mg) m a y have been sufficient to suppress s y m p t o m s b u t not enough to prevent colonisation of the gut. T h e efficacy of H N I G prophylaxis was reported b y N a g i n g t o n et al. 2° w h o showed that none of 2o5 babies given 250 mg H N I G during an outbreak of echovirus I I in C a m b r i d g e acquired infection, although 2I babies not given H N I G were infected earlier in the outbreak. W h e n administration of H N I G was stopped, a further case was noted 4 days after admission to the unit. T h e administration of less than 25o m g H N I G to the smaller babies in our unit m a y explain w h y case 5 was colonised with echovirus 7. In retrospect, it m a y have been m o r e appropriate to have given 25o m g H N I G to all babies irrespective of size. Nagington 21 also showed that s y m p t o m a t i c echovirus I I infection was found in 7 of 24 babies whose mothers did not have echovirus I I neutralising antibody at the time of delivery, whereas infections were not detected in I2 babies whose mothers did possess echovirus I I neutralising antibody, thereby suggesting that passive
Fatal echovirus 7 infection
235
a n t i b o d y does p r o t e c t against infection. M o d l i n et al. 22 also show ed that babies b o r n to w o m e n excreting echovirus at t erm , and who had echovirus a n t i b o d y in co r d s er u m , were a s y m p t o m a t i c b u t shed virus f r o m their r e s p i r a t o r y or gastro-intestinal tracts by 3 days o f age. An interesting feature o f the babies in this o u t b r e a k was that, with the ex cep tio n o f case 2, echovirus 7 was isolated f r o m faeces b u t not f r o m t h r o a t swabs taken in the acute stage of infection. T h i s has also been n o t e d by M o d l i n et al. 2~ and indicates the i m p o r t a n c e o f surveillance by examining faecal samples d u r i n g an ent er ovi r us outbreak. T h e fact that m e m b e r s o f staff m ay be infected d u r i n g ent erovi rus out breaks in special-care b a b y units emphasises the i m p o r t a n c e of excluding s y m p tomatic staff f r o m the unit until e n t e r o v i r u s infection has been e x c l u d e d or their s y m p t o m s have subsided. A l t h o u g h the m o s t significant r o u t e o f echovirus infection is f r o m m o t h e r to neonate, o t h e r means o f spread m a y lead to serious or fatal infection, z' 19.23 Fatal infections are t h o u g h t to be a c q u i r e d either directly f r o m infected and s y m p t o m a t i c m e m b e r s of staff or as a result of inadequate hand-washing. It is difficult to k n o w w h e t h e r or n o t to restrict admissions to a S C B U with en ter o v ir u s infection. Som e feel that closing a regional neonatal intensive care unit each time an e n t e r o v i r u s infection is diagnosed is not justified. 17 A l t h o u g h it w o u l d be u n r e a s o n a b l e to d e n y intensive care facilities to those babies in u r g e n t need, it m a y be p r u d e n t , w h e n cases o f ent erovi rus infection are f o u n d on a unit, to restrict admissions to emergencies and to those babies who cannot be a d m i t t e d to o t h e r local S C B U s . I n these circumstances, all new admissions should be given H N I G which m a y p r e v e n t or ameliorate e n t e r o v i r u s infections in neonates. It is questionable w h e t h e r r o u t i n e surveillance o f babies in S C B U s for evidence o f e n t e r o v i r u s infection is necessary. 24 W h e n enteroviruses are e n d e m i c in the c o m m u n i t y , the possibility o f infection being i n t r o d u c e d into a S C B U m u s t be b o r n e in m i n d and precaut i ons such as the f r e q u e n t use o f alcohol h a n d r ub vigorously observed. (We thank the Director of the Public Health Laboratory Service Communicable Disease Surveillance Centre, London for permission to reproduce Figure 2.) References
i. Krous HF, Dietzman D, Ray CG. Fatal infections with Echovirus types 6 and I I in early infancy. A m J Dis Child I973 ; I26 : 842--846. 2. Drew JH. Echo I I virus infection : a cause of acquired neonatal hepatitis. Aust Paediatr J I974; IO: I77-I79. 3. Nagington J, Wreghitt TG, Gandy G, Roberton NRC, Berry PJ. Fatal Echovirus I I infections in outbreak in special-care baby unit. Lancet I978 ; ii: 725-728. 4. Davies DP, Hughes CA, MacVicar J, Hawkes P, Mair HJ. Echovirus I I infection in a special-care baby unit. Lancet r979; i: 96. 5- Berry PJ, Nagington J. Fatal infection with Echovirus i i. Arch Dis Child I982; 57: 22-29. 6. Nawab RA. Fatal Echo virus I I infection in one of newborn twins. Indian J Pathol Microbiol I984; z7: I9-26. 7. Speer ME, Yawn DH. Fatal hepatoadrenal necrosis in the neonate associated with Echovirus types II and I2 presenting as a surgical emergency. J Pediatr Surg I984; I9: 591-593 •
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8. Boyd M T , Jordan SW, Davis LE. Fatal pneumonitis from congenital Echovirus type 6 infection. Pediatr Infect Dis J I987; 6: x i 3 8 - I I 3 9 . 9- Philip A G S , Larson EJ. Overwhelming neonatal infection with echo 19 virus. J Pediatr I973; 82: 391-397. IO. Georgieff M K , Johnson DE, Thompson TR, Belani K, Ferrieri P. Fulminant hepatic necrosis in an infant with perinatally acquired Echovirus 2i infection. Pediatr Infect Dis J I987; 6: 71-73. I I. Conolly JH, Russell JD, Robinson F L J , Canavan DA. Echovirus type 7 outbreak in Northern Ireland during x984. Ulster M e d J I985; 54: I 9 I - I 9 5 . I2. Welke G, Herman J. Diarrhoea diseases caused by the Echovirus type 7. Dtsch Gesundh Wes I975; 3o: I 6 9 - I 7 I . I3. Melnick JL, Wenner HA, Phillips CA. In: Lennette EH, Schmidt NJ, Eds. Diagnostic procedures for viral, rickettsial and chlamydial infections, 5th ed. Washington: American Public Health Association, I979; 476. I4. Cerny E, K i n d C, Bachi T. Nosocomial epidemic of echovirus type 7 in a neonatology department. Helv Paediatr Acta I983 ; 38: 457-465. I5. Wreghitt T G , Gandy G M , King A, Sutehall G. Fatal neonatal Echo 7 virus infection. Lancet I984; ii: 465. I6. Carolane D J, Long AM, McKeever PA, Hobbs SJ, Roome AP. Prevention of spread of Echovirus 6 in a special-care baby unit. Arch Dis Child I985; 6o: 674-676. I7. Isaacs D, Wilkinson A, Moxon ER. Prevention of spread of Echovirus 6 in a special-care baby unit. Arch Dis Child I985 ; 6o: I2o5-I2O6. I8. Kurtz JB, Lee T W , Parsons AJ. T h e action of alcohols on rotaviruses, astroviruses and enteroviruses. J Hosp Infect I98O; I : 3 2 I - 5. I9. Modlin JF. Perinatal echovirus infection. Insights from a literature review of 6I cases of serious infection and I6 outbreaks in nurseries. Rev Infect Dis I986; 8: 9I 8-26. 20. Nagington J, Gandy G, Walker JR, Gray JJ. Use of normal immunoglobulin in an Echovirus x I outbreak in a special-care baby unit. Lancet I983; ii: 443-446. 2I. Nagington J. Echovirus 11 infection and prophylactic antiserum. Lancet I98Z; i: 446. zz. Modlin JF, Polk BF, Horton P, Etkind P, Crane E, Spiliotes A. Perinatal Echovirus infection. Risk of transmission during a community outbreak. New Engl J Med x981 ; 3o5: 368-37I. 23. Chow CB, Tse H H , Chan KY et al. Outbreak of Echo Virus type I I infection in newborn infants in a maternity ward. Clinical presentation. J Trop Pediatr I987; 3 3 : 3 0 5 - 3 °8. 24. Appleton H, Buckley M, Robertson MH, Thorn BT. A search for faecal viruses in newborn and other infants. J Hyg (Camb) I978; 8x: 279-283.