Journal of Infection (1988) i6, 273-277
CASE REPORT Listeriosis and recurrent abortion in a renal transplant recipient J. P . R. D i c k , * A. P a l f r a m a n n ~ f a n d D. V. H a m i l t o n ~
Royal Cornwall Hospital ( Treliske), Truro, Cornwall U.K. Accepted for publication 7 September I987 Summary A 29-year-old farmer's wife had received a kidney from her brother (of identical H L A type) at the age of 22 years. She was afterwards immunosuppressed with prednisolone and azathioprine. Her first pregnancy had been uneventful but the second and third had terminated spontaneously at 15 and 24 weeks gestation respectively. Following the third pregnancy, Listeria monocytogenes (serotype 4) was grown from the fetus, the placenta and maternal blood. Over the next I8 months, antibody titres which were assessed by an IgG indirect immunofluorescent antibody assay remained high. When the patient became pregnant for a fourth time, 9 months after her second abortion, 250 mg ampicillin were administered three times daily for the remaining duration of the pregnancy. A second child was successfully delivered by Caesarean section at 39 weeks' gestation.
Introduction Listeria monocytogenes is a Gram-positive bacillus notable for causing infection in wild and domestic animals, especially d u r i n g pregnancy. 1 Infection in h u m a n beings often involves the central nervous system 2-4 but early reports suggested that disease of m o t h e r and infant was commonfl' 3, 5 As well as those pregnant, others at special risk include the i m m u n o s u p p r e s s e d , those with neoplastic disease and the very y o u n g and very old. 1' ~ Listeria monoeytogenes is k n o w n to invoke a p r e d o m i n a n t l y cell-mediated i m m u n e response 6 and m a n y of the conditions associated with increased susceptibility are characterised by altered T-cell function. We report the case of a renal transplant recipient who had two consecutive, spontaneous abortions. T h e second was due to fetal and maternal infection with L. monocytogenes.
Case report A 29-year-old farmer's wife from East Anglia presented at 24 weeks' gestation with a severe headache and swinging pyrexia. She had u n d e r g o n e bilateral n e p h r o - u r e t e r e c t o m y 7 years previously for chronic pyelonephritis and had received a kidney from her H L A - i d e n t i c a l brother. She was i m m u n o s u p pressed with prednisolone 5 m g and azathioprine I25 mg daily. T h e doses of * Present address and to whom all correspondence should be addressed: Department of Neurology, North Manchester General Hospital, Crumpsall, Manchester M8 7QB, U.K. t Present address: Heathgate Surgery, Poringland, Norwich, Norfolk, U.K. Present address : Department of Renal Medicine, Norfolk and Norwich Hospitals, Norfolk, U.K.
oI63-4453/88/o3o273 +o 5 $o2.oo/o
© I988 The British Society for the Study of Infection
274
J. P. R. D I C K E T A L .
these were not altered during pregnancy. H e r creatinine clearance was 90 m l / min. She had not required any antihypertensive treatment since her transplant. At the time of admission to Treliske Hospital, T r u r o she had had three pregnancies. F r o m the first, a female infant weighing 3-7 kg had been delivered by Caesarean section at 4o weeks' gestation and was developing normally. T h e second pregnancy, 2o months later had terminated spontaneously at 15 weeks. A cause for this was not established at the time and pathological material had not been stored. She became pregnant again 5 months later. During the third pregnancy there had been a ' s h o w ' at I5 weeks. Ultrasonography had then revealed a normally developing fetus with a small degree of abruptio placentae. She had been well until 3 weeks before admission when she had a 3 days' illness characterised by headache, fever and listlessness. T h e headache was of subacute onset. It was associated with photophobia and some difficulty with neck movements but without nausea or visual disturbance. T h e fever reached 38"5 °C but was not associated with upper respiratory, gastro-intestinal or urinary tract symptoms. T h e headache settled with paracetamol although the patient remained listless for the next 2 weeks. On the day before admission, there had been some mucopurulent vaginal discharge. On the afternoon of the day of admission she developed a severe bifrontal headache of subacute onset. This was associated with neck stiffness, photophobia and a swinging temperature up to 38"9 °C. On examination, she was flushed, had a heart rate of 9o beats per minute, blood pressure of I 3 o / 8o m m H g supine, normal ocular fundi. There was no evidence of fluid retention. T h e abdomen was not tender but the fundus uteri corresponding with a pregnancy of 24 weeks duration was palpable. A transplanted kidney in the left iliac fossa was not tender. Vaginal and rectal examinations were normal. There were no signs of meningism. Fetal movements, first noticed at 16 weeks of pregnancy, had not been felt for 24 h before admission. T h e fetal heart could not be heard clinically or with 'Sonicaid'. T h e patient's haemoglobin concentration was I2"6g/dl with a mean corpuscular volume of Io6 fl. A white blood cell count was I5"6 × Io 9 (85 % neutrophils, 8 % lymphocytes, 6 % monocytes). Urea, creatinine and electrolyte values were all normal. Examination of the cerebrospinal fluid (CSF) revealed a protein concentration of o'22 g/1 and microscopy showed 2 × Io9/1 red blood cells and < 1 x IO9/1 white blood cells. Organisms were not seen. T h e concentration of glucose in the C S F was 3"5 mmol/1 and in the blood 5"3 mmol/1. Culture of the C S F was sterile. Leucocytes were not seen in the urine which remained sterile on culture. Septicaemia due to an unidentified organism was diagnosed and treatment with intravenous ampicillin (5oo mg 6 hourly) began pending further microbiological information. During the course of the night, uterine contractions started and a dead fetus was delivered 36 h after admission. Listeria monocytogenes, subsequently identified as serotype 4, was grown from maternal blood, from the placenta and from the dead fetus. There was no such growth from the mother's C S F or from a high vaginal swab taken 24 h before delivery. T h e swinging fever settled after delivery of the dead fetus. Pathological examination showed a macerated fetus corresponding to a period of 24 weeks' gestation. Congenital abnormalities were not observed
Listeriosis and recurrent abortion
275
either externally or internally. T h e placenta weighed 290 g and had a small amount of yellowish material adherent to the maternal surface. Microscopical examination showed marked inflammatory changes affecting the chorion and villi. Microabscesses were present among the villi with areas of central necrosis. Such abscesses were also present in the fetal liver and lung although here the neutrophil reaction was less. T h e distribution of the microabscesses supported haematogenous or inhalational rather than ascending spread. T h e i r histological characteristics were consistent with listeriosis. Despite determined attempts over the following 9 months to grow L. monocytogenes from faecal and vaginal material by use of cold-enriched culture media, high vaginal swabs remained consistently sterile and L. monocytogenes could not be demonstrated in the faeces. Nevertheless, repeated serological testing for IgG against L. monocytogenes (serotype 4) by means of an IgG indirect immunofluorescent antibody assay, showed a persistent titre of 64. (A titre of 8 or above is regarded as indicating previous infection.) T h e titre was still 64 some I2 months later. Thus, when 9 months after her second spontaneous abortion, the patient became pregnant for a fourth time, a course of prophylactic ampicillin in a dosage of 250 mg three times daily was started and continued throughout pregnancy. A normal male infant weighing 4"4 kg was delivered by Caesarean section at 39 weeks of gestation. T h e placenta weighed 750 g, appeared normal macroscopically and was sterile on culture. Cultures of specimens taken at the time of delivery from maternal and fetal blood, liquor amnii and the vagina also remained sterile. Discussion
Pregnancy among female transplant recipients while previously rare, 7 is becoming accepted as a reality by both patients and physicians. 7-9 Such patients are, by virtue of immunosuppression and pregnancy, at increased risk of various opportunistic infections. Listeriosis has a predilection not only for the immunosuppressed but also for the pregnant. Its likelihood should therefore be strongly considered in transplant recipients with episodes of infection during pregnancy. More than a h u n d r e d cases of listeriosis have been reported from among transplant recipients. 10As in the normal population, 11 these appeared typically in epidemics and in most cases (70 %) the central nervous system was infected. With a frequency equal to that of the normal population, 3 however, there were seven cases of pneumonia and 23 of isolated septicaemia but none of spontaneous abortion. Of I86 cases of listeriosis reviewed from the American literature over a period of IO years, 45 were unrelated cases of isolated listerial septicaemia. Of these, eight occurred during pregnancy. Listerial septicaemia in the mother does not inevitably lead to spontaneous abortion 12 but it is the usual mode of fetal infection. 13 Since listerial septicaemia is perhaps more common in transplant recipients, it is surprising that cases of abortion associated with listeriosis have not so far been reported. Spontaneous abortion is commoner in the transplanted than in the normal population, 14 In one study 9 in which it was related to the degree of
276
J. P. R. DICK E T A L .
i m m u n o s u p p r e s s i o n , the f r e q u e n c y r e a c h e d 2 4 % . T h i s h i g h e r rate o f s p o n t a n e o u s a b o r t i o n m a y possibly be related to an increased incidence o f infection b y L . monocytogenes b u t m e n t i o n o f listeriosis was not m a d e in these earlier reports. 9' 14 I n o r d e r to define m o r e clearly the incidence o f listeriosis in t r a n s p l a n t recipients w h o s p o n t a n e o u s l y abort, it w o u l d be useful to cul t ure p r o d u c t s o f c o n c e p t i o n r o u t i n e l y for L. monocytogenes. R e c e n t evidence suggests that listeriosis occurs in e p i d e m i c s ) 1 E v e n so, sporadic cases do arise. 13 T h e r e were several p r e d i s p o s i n g factors in o u r patient. First, she was p r e g n a n t and i m m u n o s u p p r e s s e d ; second, she was a f a r m e r ' s wife. T h i s last f e a t ur e m a y be significant since those in contact with animals m a y have a h i g h e r rate o f faecal carriage o f L. monocytogenes. 1"15 W h e t h e r b o t h h e r s p o n t a n e o u s abortions w ere due to c h r o n i c or r e c u r r e n t listeriosis is controversial. R a p a p o r t and colleagues 16 r e p o r t e d several cases o f r e c u r r e n t s p o n t a n e o u s a b o r t i o n due to listeriosis. T h e i r conclusions were based o n the presence, in cervical secretions, o f listeria-like organisms f o r m i n g typical colonies on specific c ul t ur e media. T h e s e results have n e v e r b e e n repeated. 17 I n a review o f t he microbiological findings, B o t t o n e and Sierra s c o n c l u d e d that ' d ef i ni t e data r e g a r d i n g t he causal role o f Listeria monocytogenes in r e p e a t e d abortions is w ant i ng '. M o r e m o d e r n phage t y p i n g t e c h n i q u e s have c o n f i r m e d r e c u r r e n t infection in only t h r e e o f 456 cases seen in Britain by the P u b l i c H e a l t h L a b o r a t o r y Service b e t w e e n I967 and 1984 .11 A l t h o u g h the serological findings in o u r pat i ent m a y be i n t e r p r e t e d as suggesting chroni c listerial infection w hi c h c oul d have a n t e d a t e d the second abort i on, t h e r e is no i n c o n t r o v e r t i b l e evidence that the first s p o n t a n e o u s a b o r t i o n was due to listeriosis. T h e n o t i o n that she had r e c u r r e n t listeriosis remains conjectural.
(We wish to thank staff of the Department of Morbid Anatomy, T ruro and of the Department of Microbiology, Addenbrooke's Hospital, Cambridge for help and advice. We are grateful to staff of the Central Public Health Laboratory, Colindale, London, who serotyped the organism and to Dr D. B. Evans and Mr R. E. Robinson for permission to report this case.) References I. Smith G, Wilson G. Erysipelothrix and Listerial infections. In: Wilson GS, Miles AA, Parker MT, Eds, Topley & Wilson's principles of bacteriology, virology and immunity, (7th edn). New York: Edward Arnold, 1984; 3: 26-3I. 2. Bottone EJ, Sierra MF. Listeria monocytogenes: another look at the 'cinderella among pathogenic bacteria'. M t Sinai ff Med 1977; 44: 42-59. 3. Nieman RE, Lorber B. Listeriosis in adults : a changing pattern. Report of 8 cases and a review of the literature, I968-I978. Rev Infect Dis 198o; 2: 207-227. 4. Pollock SS, Pollock TM, Harrison MJG. Infection of the central nervous system by Listeria monocytogenes; a review of 54 adult and juvenile cases. Q ff Med I984; 2II: 331-34o. 5. Potel J. Listeriosen. Zentralbl Veterinarmed, Beiheft I ; 1958:7o-7 I. 6. Glynn AA. Immunity to bacterial infection. In: Lachmann PJ, Peters DK, Eds, Clinical immunology, Vol. 2 (2nd edn). Oxford: Blackwell I982; 14o6-14o7. 7- Report of the Association of Dialysis and Transplantation in Europe (I979--I98O). Successful pregnancies in women treated by dialysis and transplantation. Br J Obst I98O; 87 : 839--845.
Listeriosis and recurrent abortion
277
8. Brynger H, Brunner FP, Chantler C et al. Combined report on regular dialysis and transplantation in Europe (I979-I98O). Proc Eur Dial Transplant Assoc I98O; I7: 4-59. O'Donnell D, Sevitz H, Seggie JL, Meyers AM, Botha JR, Myburgh JA. Pregnancy after renal transplantation. Aust N Z J Med I985 ; x5 : 320-325. Io. Stamm A, Dismukes WE, Simmons BP et al. Listeriosis in renal transplant recipients: report on an outbreak and review of Io2 cases. Rev Infect Dis I982; 4: 665-674. I I. McLaughlin J, Audurier A, Taylor AG. Aspects of the epidemiology of human Listeria monocytogenes infections in Britain I967-I984; the use of serotyping and phage typing. J Med Microbiol I986; zz: 367-377. ~ I2. Zerouvdakis IA~ Cederquist L L . Effects of Listeria monocytogenes septicaemia during pregnancy on the offspring. A m J Obstet Gynecol I977; I29: 465-477. 13. Anon. Perinatal Listeriosis. Lancet I98o; i: 9 i t . I4. Rudolph JE, Scwizer R T , Bartus S. Pregnancy in renal transplant patients. Transplantation ~979; 2I (i): 26-29. 15. Bojsen-Muller J. Human Listeriosis. Diagnostic~ epidemiological and clinical studies. Acta Pathol Microbiol Scand (B) Suppl. I972; 229: I - I 5 7 . 16. Rapaport F, Rabinowitz M, Taoff R, Krochnik N. Genital Listeriosis as a cause of repeated abortion. Lancet I96O; i: I273-I275. I7. Rabau E, David A. Genital Listeriosis. Lancet I963; i: 228--229.
11
J I N 16