990

ocular complaints. HCV infection was diagnosed by secondgeneration ELISA (Ortho, with radioimmunoblot confirmation) and by exclusion of other known causes of liver damage. Schirmer’s test, tear break-up time, and fluorescein or rose-bengal dye tests for corneal epithelial damage were done: PBC

Test

HCV-CLD

established that plasma Cl-inh was decreased in our patient, we decided to use Cl-inhibitor concentrate. Our findings suggest that the classical pathway of complement system is implicated in the pathogenesis of SLCS. Thus Cl-inhibitor concentrate should be considered for potentially fatal attacks of SCLS. Activation of the complement system is also thought to play an important part in acquired forms of SCLS during cytokine administration (eg, IL-2) in cancer patients. Coadministration of Cl-inhibitor concentrate might, therefore, ameliorate dose-limiting cytokine toxicity in these

patients. Our results confirm that lacrimal dysfunction affects patients with PBC and other CLDs, often in the absence of ocular symptoms. Schirmer’s test seems to be the most specific index for the diagnosis of PBC. The mechanism of lacrimal damage by chronic HCV infection seems to differ from that operating in PBC. PIERO ALMASIO GIUSEPPE PROVENZANO MASSIMO SCIMEMI GIOVANNI CASCIO ANTONIO CRAXÌ LUIGI PAGLIARO

Medical Clinic R and Ophthalmology Service,

Ospedale V Cervello, 90146 Palermo, Italy 1. Giovannini 2.

A, Ballardini G, Amatetti S, Bonazzoli P, Bianchi FB. Patterns of lacrimal dysfunction in primary biliary cirrhosis. BrJ Ophthalmol 1985; 69: 832-35. Golding PI, Bowh R, Mason AMS. Sicca complex in liver disease. Br Med J 1970; iv: 340-42.

C1-inhibitor concentrate for sepsis-related capillary leak syndrome -

-""’’’.-.7

.__n

-

7..-.

dopamine infusion could be reduced from

11-6flg/kg

the circulation stabilised. Within 6 days body starting values and parenteral nutrition could be reduced as oral feeding with formula milk (Beba HA) was increased from 20 ml/kg per day to 80 ml/kg daily. The patient died at age 23 days from liver failure. Post-mortem haemochromatosis was seen, and was probably attributable to intrauterine erythrocyte transfusions. Despite the fatal outcome that seemed to be unrelated per min to

zero as

weight fell

to

to

SCLS

we

propose treatment with Cl-inhibitor concentrate.

of blood samples of patients with acute SCLS has uncontrolled activation of the classical pathway of complement with reduced plasma concentrations of Clq, C4, CH50, and Cl-inh, and raised plasma concentrations ofClr-ClsCl-inh complexes and the anaphylatoxin C3a.1-4 The reduced Cl-inh plasma concentrations as well as the periodicity of the attacks are reminiscent of hereditary and acquired angioneurotic oedema. A further common feature of SCLS and acquired angioneurotic oedema is the presence of monoclonal immunoglobulins, which are thought to be the triggering factor for accelerated consumption of C l-inh. 2,4,5 The only known causal treatment of angioneurotic oedema is administration of Cl-inhibitor concentrate. Since we had

Analyses

shown

an

and Paediatric Intensive Care Unit, Heinrich Heine University, D-4000 Düsseldorf, Germany

WENZEL NÜRNBERGER ULRICH GOBEL HANS STANNIGEL

Behringwerke AG, D-3550 Marburg/Lahn

BERND EISELE ALFONS JANSSEN ULRICH DELVOS

CJ, van Es A, Valenthijn RM, van Es LA. Systemic capillary leak syndrome preventive treatment with terbutaline. Neth J Med 1988; 32: 178-84. Lofdahl CG, Solvell L, Laurell AB, Johansson BR Systemic capillary leak syndrome with monoclonal IgG gammopathy and complement alterations Acta Med Scand

1 Doorenbos

2.

1979, 206: 405-12. JR, Bourgoignie JJ, Ahn YS, Schulz DR. Systemic capillary leak syndrome (SCLS): a rare cause of systemic edema. Kidney Int 1986; 29: 181. 4. Atkinson JP, Waldmann TA, Stem SF, et al. Systemic capillary leak syndrome and monoclonal IgG gammopathy. studies in a sixth patient and a review of the literature. Medicine 1977; 56: 225-39. 5. Frigas E Angioedema with acquired deficiency of the Cl-inhibitor: a constellation of syndromes. Mayo Clin Proc 1989; 64: 1269-75. 3. Cain

.....

SIR,-Dr Hack and colleagues (Feb 8, p 378) report their experience with Cl-esterase inhibitor (Cl-inh) substitution in sepsis. We report a patient with sepsis-related systemic capillary leak syndrome (SCLS) who has been managed by a novel therapeutic principle. Our patient was a newborn baby. Caesarean section was done at 33 weeks of gestation for imminent cardiac decompensation of the fetus. The fetus had received a total of seven erythrocyte transfusions for anaemia due to rhesus incompatibility. Postpartum the baby had sepsis syndrome needing mechanical ventilation; antibiotics; antithrombin III, heparin, platelets, and plasma transfusions for disseminated intravascular coagulation; and catecholamines and volume substitution for hypotension. In the first days of life, characteristic signs of capillary leak syndrome developed-presence of pericardial fluids, generalised oedema, hypotension, and weight gain from 2600 g to 3100 g. Laboratory tests revealed reduced Cl-inh in plasma. On day 8, Cl-inhibitor concentrate (Berinert P, Behringwerke, Germany) was given at an initial dose of 300 U/kg, and 100 U/kg and 50 U/kg on the following days. This resulted in an increase of Cl-inh plasma concentrations from 51 % to 130% of pooled normal human serum. Subsequently, within 36 h

Department of Paediatric Haematology and Oncology,

Sex of children born to women with fibrosis

cystic

SiR,—Dr Metz (March 21, p 739) reports the outcome of 31 pregnancies in 27 women with cystic fibrosis in Germany. He describes a predominance of male children (21 of 26) and discusses possible underlying genetic mechanisms. We are reviewing 48 pregnancies in 44 women with cystic fibrosis treated at the adult cystic fibrosis clinic at the Royal Brompton Hospital. 3 women are currently pregnant and 4 have had two pregnancies, all of which have been successful. 3 pregnancies ended in spontaneous abortions and 9 medical reasons. 1 mother died at

terminated for social or months’ gestation and II women have subsequently died, 7 of whom had children. 33 children have been born and 19 of these were female.I female child was homozygous for cystic fibrosis and died aged 18 years. The average ratio of male to female children born in the past five years in the general population is 1-05.1 So the expected number of female children is 16. This number does not differ from that in our patients (X2 test). We conclude that the sex-related selection that Metz notes is artifactual. were

seven

Department of Cystic Fibrosis, Royal Brompton National Heart and Lung Hospital, London SW3 6NP, UK 1. Office of Population Censuses and

Surveys.

D. M. G. HALPIN M. E. HODSON D. M. GEDDES

1989 birth statistics. Senes

FM1, no 18

London: HM Stationery Office, 1991.

Respiratory disease in very-low-birthweight infants SIR,-Professor Ballard and colleagues (Feb 29, p 510) demonstrate the additional benefit of prenatal thyrotropin-releasing hormone (TRH) in reducing the frequency of chronic lung disease in very-low-birthweight (VLBW) infants (< 1500 g). We were surprised, however, at the large proportion of survivors who needed prolonged ventilation-7 or more days in 50% and 28 or more days in 35% of babies in the steroid control (S-alone) group. We reviewed our data for ventilated VLBW infants over the two years 1990-91 in our neonatal unit, which serves a fairly deprived area, with 3500 deliveries per year. Our patients seem to have needed substantially less respiratory support than those of Ballard et al. We had 31 VLBW infants who needed mechanical ventilation. There were 22 (71%) survivors (birthweight 680-1430 g, mean

991

1102 g) and of these, 9 (41 %) babies had mechanical ventilation for days and only 3 (14%) were ventilated for more than 28 days, despite no prenatal TRH or betamethasone. We wonder whether the good results Ballard et al achieve-a 30% reduction in babies ventilated at 7 days and almost 50% at 28 days-can be applied to the UK, where it is our impression that fewer babies neeed such prolonged respiratory support.

more than 7

We thank Dr D. Thistlethwaite, Dr I. L. Swann, and Dr I. H. Brown for

permission to report results for their patients. Paediatric Department,

A. SHRIVASTAVA P. EHRHARDT

Burnley General Hospital, Burnley BB10 2PQ, UK

Pertussis in infants SIR,-Your Feb 29 editorial, "Pertussis: adults, infants, and herds", neglects the most important component of its title-the infants. Pertussis is an unusual childhood infection in that it can affect babies only days old, often with devastating results. Indeed the highest mortality rates for pertussis are among infants too young to receive the vaccine. You suggest that babies will not get pertussis if their siblings are immune, but Nelson, in an 18-year review of pertussis in infancy in the USA,’ concluded that the principal source of infection shifted during that time from older siblings to adults; this was especially true for neonatal infections. Other workers have emphasised the importance of mothers as the source of such infections Z3 As the adult population comes to rely increasingly on vaccination during infancy for its immunity to pertussis, so will the pool of susceptible young adults increase. It is this pool that provides the source for infections in very young infants. Few vaccines afford protection that is as lasting as that given by exposure to the disease in question. In countries that enjoy high vaccination rates many future adults will not be immune to diseases such as measles and pertussis. International travel to countries where the diseases are still common could provide index cases for outbreaks among non-immune adults. The ultimate goal of vaccination programmes should be global disease eradication. Where this is not possible programmes should aim to provide lifelong immunity for vaccinees. With current vaccines this will not be achieved if vaccination is confined to early childhood. MRC Laboratories, PO Box 273, Banjul, Gambia

KIM MULHOLLAND

1 Nelson JD. The changing epidemiology of pertussis in young infants.

Am J Dis Child

1978, 132: 371-73. 2 Trollfors B, Rabo E. Whooping cough in adults. Br Med J 1981; 283: 696-97. 3. Williams WO. Whooping cough m adults. Br Med J 1981; 283: 1122.

Possible association of erythema multiforme with acamprosate SiR,-Acamprosate is on the market in France for the prevention of alcoholic relapsed Severe skin reactions have not hitherto been reported. We describe a case of erythema multiforme developing shortly after the introduction of acamprosate in a patient with cirrhosis of the liver. A 40-year-old woman with alcoholic cirrhosis was admitted for ascites in August, 1991. Vulvar herpes was diagnosed on Sept 4, lasting a few days, with no sign of skin extension. She was discharged on Sept 12 on spironolactone and acamprosate 1-3 g daily. She was readmitted on Sept 24 for an eruption that had appeared 2 days earlier, consisting of many pruriginous erythematous target plaques with a purpuric centre, on the trunk and limbs, but not affecting the face or mucosae (mouth, eyes, or vulva). Laboratory tests confirmed liver disease and revealed mild eosinophilia. Antibodies against viral and bacterial agents implicated in erythema multiforme were sought before and after the episode but there was no evidence of viral infection (hepatitis A, B, and C, influenza A and B, paramyxovirus A, B, and C, adenovirus,

Epstein-Barr virus, cytomegalovirus, picomavirus, mumps, herpes zoster) or infection with Mycoplasma pneumoniae or chlamydiae. Her IgG titre against herpes was consistently high (2560 before and

after both the genital ulceration and the erythema multiforme). Skin biopsy revealed endothelial swelling, mixed lymphohistiocytic infiltrates, lymphohistiocytic exocytosis, and prenecrosis of keratinocytes, characteristic of erythema multiforme. The drugs were stopped and the rash resolved in 2 weeks. Erythema multiforme is usually either infective or drug-related.2 There are arguments against herpes being the culprit in this case: the woman had chronic herpes (as shown by stable high titres of IgG antibodies) but had not had erythema multiforme before; the interval between the onset of herpes and that of erythema (at least 21 days) is long, and the timing more favours acamprosate (10 days); and during the episode she had no sign of herpes recurrence or mucous lesions. Other arguments pointing to acamprosate as the culprit are severe itching, eosinophilia, and absence of subsequent recurrence. A rechallenge might have been hazardous and was not attempted. There was no evidence for any other infective cause; spironolactone was reintroduced uneventfully. We suggest that acamprosate caused this adverse skin reaction, even though herpes cannot be completely excluded. This drug is new, and physicians and patients should be on guard for such a reaction, at least until the frequency has been proven to be low. Department of Internal Medicine, Hôpital de Boisguillaume, 76233 Boisguillaume, France, Department of Pharmacology, Hôpital de Boisguillaume, and Department of Pathology, Hôpital Charles-Nicolle, Rouen

MARC FORTIER-BEAULIEU CATHERINE NOBLET FLORENCE CARDOT ELIZABETH THOMINE NICHOLAS MOORE JACQUES HEMET JACQUES BOURREILLE

1. Lhuintre JP, Moore N, Tran

G, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcoholism 1990; 25: 613-22. 2. Chan H, Stem R, Amdt K, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Arch Dermatol 1990; 126: 43-47.

Angiogenesis and regressing cutaneous malignant melanoma SIR,-Cutaneous malignant melanomas (CMM) less than 1 mm in thickness are associated with 5-year survival rates of about 95 to 100%.1 However, a small subset of these thin CMM metastasise and show regression on histological examinationAlthough some workers believe that regression has no effect on prognosis of CMM,3 two studies have shown an independent adverse effect of regression on survival.4,s Despite these findings, little is known about the mechanisms of CMM regression and metastasis. We report a patient with metastatic melanoma associated with a

completely regressed primary tumour. A 74-year-old man underwent biopsy for a mass on the spinal cord near the sixth cervical vertebra. Histological examination disclosed metastatic malignant melanoma. The patient had a lifelong pigmented lesion on the right second toe which had begun 1 year earlier. He also had right inguinal to change lymphadenopathy suspect for metastatic melanoma. The toe lesion was clinically suspect for primary CMM, and histological examination revealed

a

dense nodular accumulation of melanin-

containing macrophages in the papillary dermis. There was no evidence of residual CMM or a melanocytic naevus. The pathological features were typical of complete spontaneous regression of primary CMM. Striking vascular proliferation was also noted in and near the zones of regression. Microvessels (capillaries and venules) were identified microscopically by indirect immunoperoxidase studies with an antibody directed against Ulex Europaeus agglutinin-I (a marker for endothelium) (Barnhill RL, Fandrey K, Levy MA, Mihm MC, Hyman B, unpublished). The number of microvessels was quantified by counting all vessels within an ocular grid (area 7’84xl0"2mm2 at x 400 magnification). The mean vessel count for five microscopic fields was 63-0. We have quantified tumour vascularity in 38 primary CMM and recorded a mean vessel count of 24-9 (unpublished). Thus the density of vascularity at the site of regression in this man was about three times the vascularity found in the 38 tumours. Weidner and associates have reported that tumour vascularity is a risk factor for metastasis in breast carcinoma.6 These investigators

Respiratory disease in very-low-birthweight infants.

990 ocular complaints. HCV infection was diagnosed by secondgeneration ELISA (Ortho, with radioimmunoblot confirmation) and by exclusion of other kno...
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