- Email: [email protected]
LISTERIOSIS ASSOCIATED WITH ANTITHYMOCYTE GLOBULIN TREATMENT
280 and abl. Lod scores separated by sex are shown in the table, where the previously published results are also shown for comparison. As far as we are aware there are no other published data on the linkage. The data do not distinguish between two possibilities-namely, that TSC is loosely linked to abl in all families or that in some families the mutation for TSC is not in the 9q linkage group at all. Until this is resolved it seems premature to use abl as a marker for prenatal diagnosis of TSC. the Tuberous Sclerosis Association of Great Britain. The
Supported by v-abl probe
was
kindly supplied by Dr Natalie Tyke (ICRF, London).
MRC Human Biochemical Genetics Unit, Galton Laboratory, London NW1 2HE
S. POVEY M. W. BURLEY
Welsh National School of Medicine, Cardiff
A. E. FRYER
Royal United Hospital, Bath
J. OSBORNE
Department of Genetic Counselling, General Infirmary, Leeds
L. I. AL-GAZALI R. MUELLER
University College London,
1 Fryer AE, Chalmers A, Connor JM, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9 Lancet 1987, i: 659-61. 2. Connor JM, Pirrit LA, Yates JRW, Fryer AE, Ferguson-Smith MA. Linkage of the tuberous sclerosis locus to a DNA polymorphism detected by v-abl J Med Genet 1987, 24: 544-46. 3 Connor JM, Loughlin SAR, Whittle MJ First trimester prenatal exclusion of tuberous sclerosis Lancet 1987, i: 1269 4. Dale B, Ozanne B Characterization of mouse cellular deoxyribonucleic acid homologous to Abelson murme leukaemia virus-specific sequences. Mol Cell Biol 1981; 1: 731-12
LISTERIOSIS ASSOCIATED WITH ANTITHYMOCYTE GLOBULIN TREATMENT
SIR,-Aplastic anaemia renders patients more susceptible to infections primarily due to agranulocytosis and subsequently to the immunosuppressive treatments. These infections in children are mainly caused by staphylococci and enteric gram-negative rods. Theoretically, such patients should be readily affected also by intracellular pathogens if, additionally, the T-cell mediated immunity is suppressed. This association, however, has to our knowledge not been previously reported. Therefore, we describe a patient with aplastic anaemia in whom, during treatment with antithymocyte globulin (ATG) and corticosteroids, listerial septicaemia and meningitis developed. A 9-year-old previously healthy boy was referred to the Children’s Hospital, University of Helsinki, because of 2 weeks of pallor and fever. His general condition was good; he had no sign of bleeding and liver and spleen were not palpable. His haemoglobin was 71 g/1, white blood cell count 1 x 109/1, platelets 5 x 109/1. Bone marrow biopsy confirmed severe aplastic anaemia. Serum alanine aminotransferase (267 U/1) was raised, but alkaline phosphatase (374 U/1) and total bilirubin (19 (Jmol/1) were normal. Hepatitis A and B and cytomegalovirus antigens and antibodies as well as other antiviral antibodies were not diagnostic. Fetal haemoglobulin
has been free of infectious complications. When the positive blood culture was taken the total blood lymphocyte count was only 0-39 x 109/1 (0-93 x 109/1 at admission). After the ATG treatment the lymphocyte count rose to 2-3 x 109/1. Immunocompromised patients, like recipients of renal transplants or patients with lymphoproliferative disorders, are at increased risk of listerial infections.1 Our case demonstrates an association between acquired lymphopenia and a listerial septicaemia and meningitis. Reports of food-bome listerial infections2-4 and isolation of listeria from food supplies5 suggest that the incidence of such infections is increasing. Listeria infection should be borne in - mind by clinicians dealing with immunocompromised patients especially those on ATG treatment, which impairs cell-mediated immunity. Although the origin of the pathogen in our case remained unexplored, the diet of such patients may require special attention to avoid contaminated food, as discussed by Dr Kerr and colleagues (July 2, p 37). Hospital, University of Helsinki
H. SAXÉN M. HEIKINHEIMO
Aurora Hospital, Nordenskioldinkatu 20, 00250 Helsinki, Finland
J. RAJANTIE
Children’s
1. Hooper DC, Pruitt AA, Rubin RH. Central nervous system infection chronically immunosuppressed Medicine 1982; 61: 166-88.
2. Bannister BA. Listeria monocytogenes meningitis associated with eating of soft cheese.
J Infect 1987; 15: 165-68. 3. James SM, Fannin SL, Agee BA, et al. Listeriosis outbreak associated with Mexican-style cheese—California. MMWR 1985; 34: 357-59. 4. Department of Health and Social Security. Swiss Vacherin Mont d’Or soft cheese Press release 87/419. London: DHSS, 1987. 5. Beckers HJ, Soentoro PSS, Delfgou-van Asch EHM. The occurrence of Listeria monocytogenes in soft cheese and raw milk and its resistance to heat Int J Food Microbiol 1987; 4: 249-56.
CIBENZOLINE AND HYPOGLYCAEMIA
bacterial
concentration was normal. No HLA compatible bone marrow donor was available and the patient was given equine antihuman thymocyte globulin (20 mg/kg daily for 10 days; ’ATGAM’, Upjohn), starting 3 weeks after the diagnosis. Oral prednisolone 40 mg/m2 daily was started with ATG administration to abrogate symptoms of serum sickness. Prednisolone was given for 3 weeks. The patient remained symptom-free until day 8 after starting the ATG therapy. At that time the patient had a severe headache, a clonal left Achilles reflex, and intensified left-sided patellar reflex. Computerised tomography of the head revealed no bleeding or other abnormalities. The headache persisted but the child’s general condition remained good. 2 days after onset of the headache the patient became highly febrile and a previously taken blood culture turned out to be positive for Listeria monocytogenes. The same bacterium could also be cultured from the cerebrospinal fluid. Ampicillin and netilmicin were started. Netilmicin was discontinued on the following day and the patient was treated with ampicillin for 10 days, during which the patient’s general condition rapidly improved. Since then the patient
in the
SiR,-Dr Jeandel and colleagues (May 28, p 1232) report a case of hypoglycaemia associated with cibenzoline overdose. They exclude hypersecretion of insulin as a mechanism, but previous data’ and the following case do not support that view. A 63-year-old woman was admitted to hospital with recurrent atrial fibrillation. 2 months earlier she had had an ischaemic cerebral infarction. She had normal liver and renal function and a fasting blood glucose of 5-2 mmol/1.Calcium heparinate was given subcutaneously. Cibenzoline 130 mg orally twice a day was started on day 5. On day 6 her fasting blood sugar was 1-4 mmol 1; the patient had no cerebral or adrenergic signs of hypoglycaemia. On day 7 her plasma insulin was 27 uUmI and her blood glucose was 1-9 mmol/l. Cibenzoline was withdrawn and the blood glucose returned to normal. The plasma concentration of cibenzoline could not be measured. The resolution of asymptomatic hypoglycaemia with cessation of cibenzoline strongly suggests causality. In the absence of renal insufficiency or potential effect of other drugs, such as captopril2 the pathogenesis of this incident remains unclear. The inappropriately high serum insulin during hypoglycaemia in this case suggests stimulation of insulin secretion by cibenzoline. Moreover, in a report of three other cases Lefort et al’ found high serum insulin levels in two patients. However, in their third patient and in another case,3 plasma insulin levels were normal. Other mechanisms, such as impaired glycogenolysis or increased peripheral glucose utilisation, cannot therefore be excluded. BERTRAND A. GACHOT* MARC BEZIER JEAN-FRANCOIS CHERRIER JEAN DAUBEZE
Cardiology Service, Saint-Esprit,
Centre Hospitalier Agen, France *Present address. 1 Lefort
Groupe Hospitalier, Bichat-Claude Bernard, 75018 Paris, France
G, Haissaguerre M, Floro J, Beauffigeau P, Warm JF, Latapie JL
Hypoglycémies
au
cours
de
surdosages
par
un
nouvel
anti-arythmique
la
cibenzoline; trois observations Presse Méd 1988; 17: 687-91. 2 Femere M, Lachkar H, Richard JL, Bringer J, Orsetti A, Mirouze J. Captopril and insulin sensitivity. Ann Intern Med 1985; 102: 134-35 3 Hilleman DE, Mohiuddin SM, Ahmed IS, Dahl JM Cibenzoline-induced hypoglycaemia Drug Intell Clin Pharm 1987; 21: 38-40
Supported by v-abl probe
was
kindly supplied by Dr Natalie Tyke (ICRF, London).
MRC Human Biochemical Genetics Unit, Galton Laboratory, London NW1 2HE
S. POVEY M. W. BURLEY
Welsh National School of Medicine, Cardiff
A. E. FRYER
Royal United Hospital, Bath
J. OSBORNE
Department of Genetic Counselling, General Infirmary, Leeds
L. I. AL-GAZALI R. MUELLER
University College London,
1 Fryer AE, Chalmers A, Connor JM, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9 Lancet 1987, i: 659-61. 2. Connor JM, Pirrit LA, Yates JRW, Fryer AE, Ferguson-Smith MA. Linkage of the tuberous sclerosis locus to a DNA polymorphism detected by v-abl J Med Genet 1987, 24: 544-46. 3 Connor JM, Loughlin SAR, Whittle MJ First trimester prenatal exclusion of tuberous sclerosis Lancet 1987, i: 1269 4. Dale B, Ozanne B Characterization of mouse cellular deoxyribonucleic acid homologous to Abelson murme leukaemia virus-specific sequences. Mol Cell Biol 1981; 1: 731-12
LISTERIOSIS ASSOCIATED WITH ANTITHYMOCYTE GLOBULIN TREATMENT
SIR,-Aplastic anaemia renders patients more susceptible to infections primarily due to agranulocytosis and subsequently to the immunosuppressive treatments. These infections in children are mainly caused by staphylococci and enteric gram-negative rods. Theoretically, such patients should be readily affected also by intracellular pathogens if, additionally, the T-cell mediated immunity is suppressed. This association, however, has to our knowledge not been previously reported. Therefore, we describe a patient with aplastic anaemia in whom, during treatment with antithymocyte globulin (ATG) and corticosteroids, listerial septicaemia and meningitis developed. A 9-year-old previously healthy boy was referred to the Children’s Hospital, University of Helsinki, because of 2 weeks of pallor and fever. His general condition was good; he had no sign of bleeding and liver and spleen were not palpable. His haemoglobin was 71 g/1, white blood cell count 1 x 109/1, platelets 5 x 109/1. Bone marrow biopsy confirmed severe aplastic anaemia. Serum alanine aminotransferase (267 U/1) was raised, but alkaline phosphatase (374 U/1) and total bilirubin (19 (Jmol/1) were normal. Hepatitis A and B and cytomegalovirus antigens and antibodies as well as other antiviral antibodies were not diagnostic. Fetal haemoglobulin
has been free of infectious complications. When the positive blood culture was taken the total blood lymphocyte count was only 0-39 x 109/1 (0-93 x 109/1 at admission). After the ATG treatment the lymphocyte count rose to 2-3 x 109/1. Immunocompromised patients, like recipients of renal transplants or patients with lymphoproliferative disorders, are at increased risk of listerial infections.1 Our case demonstrates an association between acquired lymphopenia and a listerial septicaemia and meningitis. Reports of food-bome listerial infections2-4 and isolation of listeria from food supplies5 suggest that the incidence of such infections is increasing. Listeria infection should be borne in - mind by clinicians dealing with immunocompromised patients especially those on ATG treatment, which impairs cell-mediated immunity. Although the origin of the pathogen in our case remained unexplored, the diet of such patients may require special attention to avoid contaminated food, as discussed by Dr Kerr and colleagues (July 2, p 37). Hospital, University of Helsinki
H. SAXÉN M. HEIKINHEIMO
Aurora Hospital, Nordenskioldinkatu 20, 00250 Helsinki, Finland
J. RAJANTIE
Children’s
1. Hooper DC, Pruitt AA, Rubin RH. Central nervous system infection chronically immunosuppressed Medicine 1982; 61: 166-88.
2. Bannister BA. Listeria monocytogenes meningitis associated with eating of soft cheese.
J Infect 1987; 15: 165-68. 3. James SM, Fannin SL, Agee BA, et al. Listeriosis outbreak associated with Mexican-style cheese—California. MMWR 1985; 34: 357-59. 4. Department of Health and Social Security. Swiss Vacherin Mont d’Or soft cheese Press release 87/419. London: DHSS, 1987. 5. Beckers HJ, Soentoro PSS, Delfgou-van Asch EHM. The occurrence of Listeria monocytogenes in soft cheese and raw milk and its resistance to heat Int J Food Microbiol 1987; 4: 249-56.
CIBENZOLINE AND HYPOGLYCAEMIA
bacterial
concentration was normal. No HLA compatible bone marrow donor was available and the patient was given equine antihuman thymocyte globulin (20 mg/kg daily for 10 days; ’ATGAM’, Upjohn), starting 3 weeks after the diagnosis. Oral prednisolone 40 mg/m2 daily was started with ATG administration to abrogate symptoms of serum sickness. Prednisolone was given for 3 weeks. The patient remained symptom-free until day 8 after starting the ATG therapy. At that time the patient had a severe headache, a clonal left Achilles reflex, and intensified left-sided patellar reflex. Computerised tomography of the head revealed no bleeding or other abnormalities. The headache persisted but the child’s general condition remained good. 2 days after onset of the headache the patient became highly febrile and a previously taken blood culture turned out to be positive for Listeria monocytogenes. The same bacterium could also be cultured from the cerebrospinal fluid. Ampicillin and netilmicin were started. Netilmicin was discontinued on the following day and the patient was treated with ampicillin for 10 days, during which the patient’s general condition rapidly improved. Since then the patient
in the
SiR,-Dr Jeandel and colleagues (May 28, p 1232) report a case of hypoglycaemia associated with cibenzoline overdose. They exclude hypersecretion of insulin as a mechanism, but previous data’ and the following case do not support that view. A 63-year-old woman was admitted to hospital with recurrent atrial fibrillation. 2 months earlier she had had an ischaemic cerebral infarction. She had normal liver and renal function and a fasting blood glucose of 5-2 mmol/1.Calcium heparinate was given subcutaneously. Cibenzoline 130 mg orally twice a day was started on day 5. On day 6 her fasting blood sugar was 1-4 mmol 1; the patient had no cerebral or adrenergic signs of hypoglycaemia. On day 7 her plasma insulin was 27 uUmI and her blood glucose was 1-9 mmol/l. Cibenzoline was withdrawn and the blood glucose returned to normal. The plasma concentration of cibenzoline could not be measured. The resolution of asymptomatic hypoglycaemia with cessation of cibenzoline strongly suggests causality. In the absence of renal insufficiency or potential effect of other drugs, such as captopril2 the pathogenesis of this incident remains unclear. The inappropriately high serum insulin during hypoglycaemia in this case suggests stimulation of insulin secretion by cibenzoline. Moreover, in a report of three other cases Lefort et al’ found high serum insulin levels in two patients. However, in their third patient and in another case,3 plasma insulin levels were normal. Other mechanisms, such as impaired glycogenolysis or increased peripheral glucose utilisation, cannot therefore be excluded. BERTRAND A. GACHOT* MARC BEZIER JEAN-FRANCOIS CHERRIER JEAN DAUBEZE
Cardiology Service, Saint-Esprit,
Centre Hospitalier Agen, France *Present address. 1 Lefort
Groupe Hospitalier, Bichat-Claude Bernard, 75018 Paris, France
G, Haissaguerre M, Floro J, Beauffigeau P, Warm JF, Latapie JL
Hypoglycémies
au
cours
de
surdosages
par
un
nouvel
anti-arythmique
la
cibenzoline; trois observations Presse Méd 1988; 17: 687-91. 2 Femere M, Lachkar H, Richard JL, Bringer J, Orsetti A, Mirouze J. Captopril and insulin sensitivity. Ann Intern Med 1985; 102: 134-35 3 Hilleman DE, Mohiuddin SM, Ahmed IS, Dahl JM Cibenzoline-induced hypoglycaemia Drug Intell Clin Pharm 1987; 21: 38-40