Repeated episodes of shock due to food sensitisation

THE LANCET

ALL

BMT

ASGPR

+

+

+

–

–

–

–

–

ANA

+

+

–

–

–

–

–

–

SMA

+

+

–

–

–

–

–

–

Helper

+

+

+

–

–

–

–

–

T-cell function

Suppressor –

–

–

–

–

+

+

+

Liver histology

13

4

1

AST

118

94

76

82

65

31

20

18

–4

–3

–2

–1

0

1

15

51

Autoantibodies

ASGPR-specific

Time (months) Figure: Course of autoimmune hepatitis ASGPR, asialoglycoprotein receptor; ANA, anti-nuclear antibodies; SMA, anti-actin smooth muscle antibodies; liver histology, in Knodell score; AST, aspartate aminotransferase; ALL, acute lymphoblastic leukaemia; BMT, bone-marrow transplantation; +, detectable; –, undetectable

actin smooth muscle (SMA, 1:80), and antiasialoglycoprotein receptor (ASGPR, 1/400) antibodies were positive in serum; T-cell immunity to ASGPR was detected by both T-lymphocyte migration inhibitory factor (TLIF)2 and lymphoproliferative assays; a TLIF test also showed a defect in the antigen-specific suppressor-inducer T cell control of immune responses to ASGPR (figure). In October, 1991, his white cell count was 35⫻109/L with 90% lymphoblasts, 56⫻109/L platelets, 10·3 g/dL haemoglobin. Bone-marrow biopsy specimen contained 90% blasts with CD2+,CD4+,CD8+,CD34+ immunophenotype. Cytochemical analysis showed positive staining for acid phosphatase and periodic acid-Schiff. He was treated with intramuscular methotrexate and L-asparaginase; and intravenous cyclophosphamide and vincristine; oral prednisone and intrathecal methotrexate, followed by irradiation of 1800 Gy to his skull. As soon as remission was confirmed, his 25-year-old healthy brother was selected as a potential HLA A,B,DR-matched, MLC-non-reactive bonemarrow donor. The brother had an A3, 11;B7,44;DR2, 3 HLA phenotype, no immune reactivity to ASGPR, normal antigen-specific suppressor-inducer T cell activity, negative serum ANA and SMA. He was ABO incompatible with the patient (types A and O, respectively). After conditioning with fractionated total body irradiation (12 Gy in six fractions over 3 days) then etoposide, cyclophosphamide, and fractionated total lymphoid irradiation (6 Gy in four fractions over 2 days), the patient received, in January, 1992, 6·8⫻108 per kg bone-marrow cells (total 4·7⫻1010 cells) from which erythrocytes had been removed. T-cells were depleted with an anti-CDW52 rat antihuman lymphocyte antibody. 1 day after bone-marrow transplantation (BMT) the patient received 105 donor’s peripheral blood T lymphocytes/kg body weight (total of 69⫻105 T lymphocytes) as part of a protocol designed to amplify the donor T lymphocyte attack against residual host leukaemia cells. No post-BMT anti-graftversus-host disease (GVHD) prophylaxis was given, but after he had the donor T lymphocytes he developed grade 1 acute skin GVHD and was treated with prednisolone (1mg/kg) and cyclosporin A, 6 mg/kg orally for 35 days, with gradual reduction over 3 weeks. ALT and AST values (measured at daily intervals for 1 month and then weekly for 3 months, and monthly thereafter) have been normal on all occasions; ANA, SMA, and ASGPR antibodies were not detected from 1 month before BMT and throughout follow-up. 1 month after BMT, full donor chimerism was confirmed

Vol 348 • August 24, 1996

by restriction-fragment length polymorphism analysis of lymphocyte DNA.3 From 1 month after BMT, ASGPRspecific suppressor-inducer T-cell activity (which was defective until the day before the procedure) has been normal on 27 occasions, and T-cell immunity to the same antigen has not been detected. Liver histology showed improvement (Knodell score 4) in April, 1993, and resolution (score 1) of liver disease in April, 1996, leukaemia has not relapsed. Allogeneic BMT and injection of donor’s T cells led, in this case, a return to normal of T-cell reactions to ASGPR, disappearance of antibodies to the same autoantigen, and apparent cure of autoimmune hepatitis. Complete resolution does not occur spontaneously in severe cases of AH and is rare even after effective and protracted conventional treatment.4 Although it may be that immunosuppressive treatment of ALL and the immunosuppressive preparation for BMT induced remission of AH in this patient, the fact that the remission is sustained, and that after BMT, ASGPRspecific suppressor-inducer T-cell activity has become normal (a finding so far reported in only one other patient during immunosuppressive treatment2) suggests that donor T cells provided the suppressor function which was defective in this patient. In addition, clonal elimination of helper T cells responsible for perpetuating liver damage may have been achieved. Remission of severe rheumatoid arthritis after BMT has been reported in two patients.5 Our report suggests that adoptive cellular immunotherapy may be an option in patients with AH if conventional immunosuppressive treatment fails. *Sandro Vento, Francesca Cainelli, Carlo Renzini, Giancarlo Ghironzi, Ercole Concia *Department of Infectious Diseases, University of Verona, 37124 Verona, Italy; and Department of Internal Medicine, San Marino State Hospital, Republic of San Marino

1

2

3

4

5

Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431–35. Vento S, Eddleston A. Autoimmunity and liver diseases. In: Popper H, Schaffner F, eds. Progress in liver diseases, vol IX. Philadelphia: WB Saunders, 1990: 335–43. Knowlton RG, Brown VA, Braman JC, et al. Use of highly polymorphic DNA probes for genotypic analysis following bone marrow transplantation. Blood 1986; 68: 378–85. Schvarcz R, Glaumann H, Weiland O. Survival and histological resolution of fibrosis in patients with autoimmune chronic active hepatitis. J Hepatol 1993; 18: 15–23. Lowenthal RM, Cohen ML, Atkinson K, Biggs JC. Apparent cure of rheumatoid arthritis by bone marrow transplantation. J Rheumatol 1993; 20: 137–40.

Repeated episodes of shock due to food sensitisation SIR—We report an infant with repeated episodes of shock who responded to a food-elimination diet. A 4-week-old boy was admitted because of pallor and hypotonia lasting 25 min after breast-feeding. Upper endoscopy showed mild oesophagitis and pH was below 4 for 15% of the time during 24 h pH monitoring. Electroencephalographic and electrocardiographic recordings were normal. The baby was discharged with cisapride, positional therapy, and ranitidine. At 2 months, a relapse with hypotonia and lack of reactivity occurred after breast-feeding, prompting admission. Since discharge, the baby had exhibited frequent episodes of pallor after feeding without hypotonia, and for 2 weeks, mild eczema and constipation. Endoscopic results were similar to before and

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THE LANCET

ranitidine was changed to omeprazole. Weaning began at 4 months. The child was readmitted at 7 months because of loss of consciousness and hypotonia lasting 15 min after feeding. Daily relapses while in hospital prompted neurological and cardiological investigations that were normal. Endoscopy showed mild oesophagitis and pH monitoring showed pH below 4 7·5% of the time. Total IgE and radioallergosorbent tests to foods were negative. Skinprick tests were positive for cow’s milk protein, wheat, egg, peanut, and banana. These foods were excluded from the diet and the child had no more episodes of shock. Oral food challenges induced eczema with cow’s milk protein and urticaria with wheat. They were negative with banana and peanut. Each challenge with egg, at ages 8 and 14 months, was interrupted, because the contact of egg with lips triggered local urticaria, pallor, and loss of consciousness for 10 min. The child did not relapse during a 10 month followup on a diet excluding cow’s milk protein, wheat, and egg. Food allergy can cause gastroesophageal reflux (GOR),1 which in turn may induce apnoea and reflux bradycardia.2 In our case protracted oesophagitis indicates GOR, but hypotonia and loss of consciousness are not classical GOR manifestations. The likely mechanism of shock here is anaphylaxis. This anaphylactic hypothesis is strongly supported by subsequent episodes of pallor and loss of consciousness with urticaria, triggered by contact of the child’s lips with egg. Sensitisation to egg via breastmilk was probably responsible for the episodes when the child was only breastfed.3 High tryptase levels have been reported in post-mortem sera from infants with sudden infant death syndrome (SIDS) compared with none in controls,4,5 suggesting that anaphylaxis could be the pathogenetic mechanism involved in some cases of SIDS. Whatever the mechanism, food allergy must be suspected in the presence of repeated episodes of shock after feeding in infants, even in the presence of GOR. The elimination diet is not burdensome at this age and could be life saving. *Delphine de Boissieu, Christophe Dupont Service de Pédiatrie, Hôpital Saint Vincent de Paul, 75014 Paris, France

1

2 3

4

5

Iacono G, Carroccio A, Cavataio F, et al. Gastroesophageal reflux and cow’s milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996; 97: 822–27. Davies AEM, Sandhu BK. Diagnosis and treatment of gastrooesophageal reflux. Arch Dis Child 1995; 73: 82–86. De Boissieu D, Dupont C, Badoual J. Allergy to nondairy proteins in mother’s milk as assessed by intestinal permeability tests. Allergy 1994; 49: 882–84. Platt MS, Yunginger JW, Sekula-Perlman A, et al. Involvement of mast cells in sudden infant death syndrome. J Allergy Clin Immunol 1994; 94: 250–56. Holgate ST, Walters C, Walls AF, et al. The anaphylaxis hypothesis of sudden death syndrome (SIDS): mast cell degranulation in cot death revealed by elevated concentrations of tryptase in serum. Clin Exp Allergy 1994; 25: 1115–22.

A new route from heart to lungs SIR—A 45-year-old white man with end-stage renal failure secondary to IgA nephropathy, treated with hospital haemodialysis for 2
 years was transferred to Glasgow Royal Infirmary with an ischaemic right foot. On examination he had splinter haemorrhages and cutaneous infarcts on his right hand, which was pale and cold. There were no cutaneous infarcts or splinter haemorrhages on his left hand. He had a left radiocephalic fistula. His right foot was critically ischaemic with cutaneous infarcts in both feet.

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Figure: Patient’s forearms and palms There is an arteriovenous fistula on the left and multiple cutaneous infarcts on the fingertips of the right hand.

Infarcts were present on both buttocks and on his penis. He was pyrexial. A pansystolic murmur was audible at the cardiac apex. He had an enlarged spleen. A right pleural effusion was present along with a pleural rub on the same side. A diagnosis of bacterial endocarditis with multiple emboli was made. He had a leucocytosis (WCC 24·9⫻109/L) with a Creactive protein of 288 mg/L. Chest radiograph revealed a right basal effusion, electrocardiogram showed sinus rhythm, left-axis deviation, and left ventricular hypertrophy. Blood cultures showed no growth. Transthoracic and transoesophageal echocardiogram confirmed vegetations on both leaflets of the mitral valve. Doppler showed evidence of mitral regurgitation. Pleural tap showed the effusion to be an exudate, and was culture negative. He was started on gentamicin and benzylpenicillin, the latter being changed to vancomycin with the negative cultures. He required below knee amputation of his right leg. Endocarditis1 complicates the course of 2–6% of patients on chronic haemodialysis.2 Our patient had widespread systemic emboli which spared one hand due to his arteriovenous fistula. It is likely that emboli were passing through his fistula and back up his left cephalic vein, they would deposit in his pulmonary circulation, causing the chest signs. *C Deighan, M Boulton-Jones Renal Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

1 2

Nsouli KA, Lazarus JM, Schoenbaum SC, et al. Bacteraemic infection in haemodialysis. Arch Intern Med 1979; 139: 1255. Cross AS, Steigbigel RT. Infective endocarditis and access site infections in patients on haemodialysis. Medicine 1976; 55: 453–66.

Vol 348 • August 24, 1996