1529
CLINICAL FEATURES OF 5 PATIENTS WITH HAEMOLYTIC-URAEMIC SYNDROME
who were chronic HBeAg and HBsAg positive HBV carriers with murine monoclonal antibody directed against the viral coat protein to attempt clearance of the chronic infection. The mouse IgGmonoclonal antibody (RF-HBs-1) had proved able to prevent HBV infection in chimpanzees.3 Oligopeptide binding studies have shown it to bind to the peptide region 124-137 on the HBsAg molecule.4 The antibody was grown in mycoplasmafree cell lines and purified on an HBsAg/cyanogen bromide ’Sepharose’ affinity column. The final solution was sterile and
pyrogen-free. Patient
was a man aged 24 with common variable hypogammaglobulinaemia (IgG on presentation less than 20 g/1, IgA and IgM undetectable) who had been a chronic HBV carrier for
1
least 10 years. He was persistently unwell with recurrent chest infections. He had ascites and splenomegaly, and during severe infective episodes became encephalopathic. He refused liver biopsy. For the previous 6 years he had had persistently raised transaminases and a low serum albumin. He was on regular intravenous gammaglobulin therapy (’Sandoglobulin’). 2 a Patient was boy aged 16 with X-linked agammaglobulinaemia. He was known to be HBeAg-positive for the six years before referral to us. His transaminases had been persistently raised during this time. He was clinically well although liver biopsy had shown widespread fibrosis with possible cirrhosis. He was also on regular intravenous gammaglobulin replacement at
hours). These caused a temporary increase in the platelet Aspirin and dipyridamole were given to reduce platelet aggregation. E coli 0157:H7 was isolated only from patient 4, but culture-negative patients had symptoms typical of this infection. Isolation is most effective during the first few days of diarrhoea,2 and the excretion period may have passed by time of presentation. Free verotoxin and antitoxin antibodies were not sought. No other pathogens likely to have triggered HUS were isolated. The staphylococcal septicaemia in patient 1 was judged a secondary
over
24
count.
infection. The use of plasma, prostacylin, and anti-platelet agents in the management of HUS is contentious.’ Some features of the disease did improve during treatment in patient 5, but no firm conclusions about the usefulness of these agents may be drawn from these data. We wish to alert doctors to the diagnosis of HUS in adults: it is not exclusively a disease of childhood. These patients demonstrate the potentially serious nature of the condition. Clinicians should be aware of the possible development of HUS in association with haemorrhagic colitis, and especially with E coli 0157:H7 infection. We thank Dr H. Pullen for permission to report these
cases.
Department of Infectious Diseases, Seacroft Hospital, Leeds LS14 6UH, UK
BARBARA A. CROSSE
Department of Medicine (Elderly), St James’ University Hospital, Leeds
JOHN R. NAYLOR
1. Neill
MA, Agosti J, Rosen H. Hemorrhagic colitis preceding adult haemolytic-uraemic syndrome.
with Escherichia coli O157:H7 Arch Intern Med 1985; 145:
2215-17. 2. Carter AO, Borczyk AA, Carlson AK, et al. A severe outbreak of Escherichia coli O157:H7-associated hemorrhagic colitis in a nursing home. N Engl J Med 1987; 317: 1496-500. 3. O’Brien AD, Lively TA, Chay TW, Gorbach SC. Purification of Shigella dysenteria 1 (shiga)-like toxin from Escherichia coli O157:H7 strain associated with haemorrhagic colitis. Lancet 1983; i: 573. 4. Defrey G, Proesmans W, Madin SJ, Lemnens F, Vermyler J. Abnormal prostacyclin metabolism in the haemolytic-uraemic syndrome; equivocal effects of a prostacylin infusion. Clin Nephrol 1982; 18: 43-49. 5. Cleary TG. Cytotoxin-producing Escherichia coli and the hemolytic-uremic syndrome. Paed Clin N Am 1988; 35: 485-501. 6. Smith HR, Rowe B, Gross RJ, Fry NK. Haemorrhagic colitis and vero-cytotoxinproducing Escherichia coli in England and Wales. Lancet 1987; i: 1062-65. 7. Pong JSC, de Chaderevian J-P, Kaplan BS. Hemolytic-uremic syndrome. Current concepts and management. Ped Clin N Am 1982; 29: 835-56.
therapy. 06 mg of RF-HBs-1 (0-6 mg/ml) was thawed and added to 100 ml of salt-poor albumin as a carrier protein. This was given to each patient by intravenous infusion over 30 min. Doses were repeated at one-month intervals. Patient 2 remained well and HBeAg negative and remained so for twelve months with no further treatment, but was then noted to have become HBeAg-positive without symptoms. Two months later murine antibody was restarted monthly for three doses. Liver biopsy was done and on this occasion showed normal architecture and only small foci of lobular inflammation. The biopsy specimen did not have evidence of HBsAg or HBeAg by immunological staining. Patient 1 showed a rapid improvement in liver function tests after loss of HBeAg. He remained HBeAg-negative until his death from an unrelated cause 2 years later. We have demonstrated that murine monoclonal antibody to HBsAg can be used safely in patients with chronic HBV infection who are agammaglobulinaemic. Replacement of the normal neutralising humoral immune response which these patients lack led to improvement in clinical and laboratory indices for disease and to loss of markers of viral replication. In addition, sequential liver biopsies in patient 2 showed an improvement in liver histology after treatment.
We
are
unaware
of other reports of
a
murine monoclonal
antibody for treatment of a specific chronic viral infection. In patients with specific or generalised defects in immunity this approach may have wider applications as human monoclonal antibodies become available. We thank Dr A. D. B. Webster for helpful advice in the management of these patients. This work was supported by the Wellcome Trust.
Department of Cellular and Molecular Sciences, St George’s Hospital Medical School, London SW17 0RE, UK
ANDREW M. L. LEVER
JENNY WATERS
Monoclonal antibody to HBsAg for chronic hepatitis B virus infection with
hypogammaglobulinaemia SIR,—Patients with hypogammaglobulinaemia have normal cellmediated immunity.1 In these patients, hepatitis B virus (HBV) infection may be severe2 because their cellular immune system
rapidly destroys virus-infected cells. Such patients do not produce antibodies to heterologous protein and can therefore be treated with animal-derived monoclonal antibody or polyclonal antisera. We have treated two patients with primary hypogammaglobulinaemia
St Mary’s Hospital Medical School, London
1 Asherson
M. GARY BROOK PETER KARAYIANNIS H. C. THOMAS
GL, Webster ADB. Diagnosis and treatment of immunodeficiency disease. London: Blackwell, 1980. 2 Good R, Page AR. Fatal complications of viral hepatitis in two patients with agammaglobulinaemia. Am J Med 1980; 29: 804-10. 3. Iwarson S, Tabor E, Thomas HC, et al. Neutralisation of HBV infectivity by a murine monoclonal antibody: an experimental study in the chimpanzee. JMed Virol 1985; 16: 89-96. 4. Waters J, Pignatelli M, Galpin S, Ishihara K, Thomas HC Virus neutralising antibodies to the hepatitis B virus the nature of an immunogenic epitope on the S peptide J Gen Virol 1986; 67: 2467-73.
CLINICAL FEATURES OF 5 PATIENTS WITH HAEMOLYTIC-URAEMIC SYNDROME
who were chronic HBeAg and HBsAg positive HBV carriers with murine monoclonal antibody directed against the viral coat protein to attempt clearance of the chronic infection. The mouse IgGmonoclonal antibody (RF-HBs-1) had proved able to prevent HBV infection in chimpanzees.3 Oligopeptide binding studies have shown it to bind to the peptide region 124-137 on the HBsAg molecule.4 The antibody was grown in mycoplasmafree cell lines and purified on an HBsAg/cyanogen bromide ’Sepharose’ affinity column. The final solution was sterile and
pyrogen-free. Patient
was a man aged 24 with common variable hypogammaglobulinaemia (IgG on presentation less than 20 g/1, IgA and IgM undetectable) who had been a chronic HBV carrier for
1
least 10 years. He was persistently unwell with recurrent chest infections. He had ascites and splenomegaly, and during severe infective episodes became encephalopathic. He refused liver biopsy. For the previous 6 years he had had persistently raised transaminases and a low serum albumin. He was on regular intravenous gammaglobulin therapy (’Sandoglobulin’). 2 a Patient was boy aged 16 with X-linked agammaglobulinaemia. He was known to be HBeAg-positive for the six years before referral to us. His transaminases had been persistently raised during this time. He was clinically well although liver biopsy had shown widespread fibrosis with possible cirrhosis. He was also on regular intravenous gammaglobulin replacement at
hours). These caused a temporary increase in the platelet Aspirin and dipyridamole were given to reduce platelet aggregation. E coli 0157:H7 was isolated only from patient 4, but culture-negative patients had symptoms typical of this infection. Isolation is most effective during the first few days of diarrhoea,2 and the excretion period may have passed by time of presentation. Free verotoxin and antitoxin antibodies were not sought. No other pathogens likely to have triggered HUS were isolated. The staphylococcal septicaemia in patient 1 was judged a secondary
over
24
count.
infection. The use of plasma, prostacylin, and anti-platelet agents in the management of HUS is contentious.’ Some features of the disease did improve during treatment in patient 5, but no firm conclusions about the usefulness of these agents may be drawn from these data. We wish to alert doctors to the diagnosis of HUS in adults: it is not exclusively a disease of childhood. These patients demonstrate the potentially serious nature of the condition. Clinicians should be aware of the possible development of HUS in association with haemorrhagic colitis, and especially with E coli 0157:H7 infection. We thank Dr H. Pullen for permission to report these
cases.
Department of Infectious Diseases, Seacroft Hospital, Leeds LS14 6UH, UK
BARBARA A. CROSSE
Department of Medicine (Elderly), St James’ University Hospital, Leeds
JOHN R. NAYLOR
1. Neill
MA, Agosti J, Rosen H. Hemorrhagic colitis preceding adult haemolytic-uraemic syndrome.
with Escherichia coli O157:H7 Arch Intern Med 1985; 145:
2215-17. 2. Carter AO, Borczyk AA, Carlson AK, et al. A severe outbreak of Escherichia coli O157:H7-associated hemorrhagic colitis in a nursing home. N Engl J Med 1987; 317: 1496-500. 3. O’Brien AD, Lively TA, Chay TW, Gorbach SC. Purification of Shigella dysenteria 1 (shiga)-like toxin from Escherichia coli O157:H7 strain associated with haemorrhagic colitis. Lancet 1983; i: 573. 4. Defrey G, Proesmans W, Madin SJ, Lemnens F, Vermyler J. Abnormal prostacyclin metabolism in the haemolytic-uraemic syndrome; equivocal effects of a prostacylin infusion. Clin Nephrol 1982; 18: 43-49. 5. Cleary TG. Cytotoxin-producing Escherichia coli and the hemolytic-uremic syndrome. Paed Clin N Am 1988; 35: 485-501. 6. Smith HR, Rowe B, Gross RJ, Fry NK. Haemorrhagic colitis and vero-cytotoxinproducing Escherichia coli in England and Wales. Lancet 1987; i: 1062-65. 7. Pong JSC, de Chaderevian J-P, Kaplan BS. Hemolytic-uremic syndrome. Current concepts and management. Ped Clin N Am 1982; 29: 835-56.
therapy. 06 mg of RF-HBs-1 (0-6 mg/ml) was thawed and added to 100 ml of salt-poor albumin as a carrier protein. This was given to each patient by intravenous infusion over 30 min. Doses were repeated at one-month intervals. Patient 2 remained well and HBeAg negative and remained so for twelve months with no further treatment, but was then noted to have become HBeAg-positive without symptoms. Two months later murine antibody was restarted monthly for three doses. Liver biopsy was done and on this occasion showed normal architecture and only small foci of lobular inflammation. The biopsy specimen did not have evidence of HBsAg or HBeAg by immunological staining. Patient 1 showed a rapid improvement in liver function tests after loss of HBeAg. He remained HBeAg-negative until his death from an unrelated cause 2 years later. We have demonstrated that murine monoclonal antibody to HBsAg can be used safely in patients with chronic HBV infection who are agammaglobulinaemic. Replacement of the normal neutralising humoral immune response which these patients lack led to improvement in clinical and laboratory indices for disease and to loss of markers of viral replication. In addition, sequential liver biopsies in patient 2 showed an improvement in liver histology after treatment.
We
are
unaware
of other reports of
a
murine monoclonal
antibody for treatment of a specific chronic viral infection. In patients with specific or generalised defects in immunity this approach may have wider applications as human monoclonal antibodies become available. We thank Dr A. D. B. Webster for helpful advice in the management of these patients. This work was supported by the Wellcome Trust.
Department of Cellular and Molecular Sciences, St George’s Hospital Medical School, London SW17 0RE, UK
ANDREW M. L. LEVER
JENNY WATERS
Monoclonal antibody to HBsAg for chronic hepatitis B virus infection with
hypogammaglobulinaemia SIR,—Patients with hypogammaglobulinaemia have normal cellmediated immunity.1 In these patients, hepatitis B virus (HBV) infection may be severe2 because their cellular immune system
rapidly destroys virus-infected cells. Such patients do not produce antibodies to heterologous protein and can therefore be treated with animal-derived monoclonal antibody or polyclonal antisera. We have treated two patients with primary hypogammaglobulinaemia
St Mary’s Hospital Medical School, London
1 Asherson
M. GARY BROOK PETER KARAYIANNIS H. C. THOMAS
GL, Webster ADB. Diagnosis and treatment of immunodeficiency disease. London: Blackwell, 1980. 2 Good R, Page AR. Fatal complications of viral hepatitis in two patients with agammaglobulinaemia. Am J Med 1980; 29: 804-10. 3. Iwarson S, Tabor E, Thomas HC, et al. Neutralisation of HBV infectivity by a murine monoclonal antibody: an experimental study in the chimpanzee. JMed Virol 1985; 16: 89-96. 4. Waters J, Pignatelli M, Galpin S, Ishihara K, Thomas HC Virus neutralising antibodies to the hepatitis B virus the nature of an immunogenic epitope on the S peptide J Gen Virol 1986; 67: 2467-73.
