- Email: [email protected]
UVEITIS AFTER HEPATITIS B VACCINATION
631
attention from the "socioeconomic and political inequalities that sustain poverty". He challenges our statement that the intervention was relatively modest and inexpensive. Between 1 and 21 % of young children in developing countries2 suffer from severe malnutrition, and most are destined to develop poorly owing to a combination of malnutrition and sociocultural deprivation. Very little attention has been paid to treatment after the acute stage. Is your correspondent suggesting that we abandon attempts to rehabilitate these children? Money must be spent on the prevention of malnutrition, but it is precisely because the roots of malnutrition are based in social and economic inequalities that prevention is so difficult. Malnutrition is not going to be eradicated in the near future and for years to come millions of children will survive malnutrition and face a dismal future. We showed that malnourished children responded to modest treatment-the use of home visitors with readily available skills and home-made toys. The approach was inexpensive compared with most interventions reported on in child development. I agree that many poor communities could not afford the programme we described, and we are now exploring the effects of less frequent and shorter visits. The important point was to establish that children would respond to treatment and families would cooperate. However, some developing countries have primary health care networks which include paraprofessionals visiting homes, and the intervention was designed to be attached to this type of service. Programmes are already underway in other countries based on similar designs. I cannot accept the principle that when a means for preventing a disease is known, research on treatment or rehabilitation should cease, even though millions of cases are still occurring. Such a suggestion could be applied to many other diseases, such as cholera, malaria, and AIDS. It is sensible, humane, and good medicine to continue research into improving methods of treatment and
rehabilitation, as well as prevention, until numbers of malnourished children.
we no
Tropical Metabolism Research Unit, University of the West Indies, Mona, Kingston 7, Jamaica, WI 1
longer
see
large
The recognition of Munchausen syndrome by proxy is a milestone in child protection, and the increasing number of these tragic case-reports is a testimony to the astute observations of Dr S. R. Meadow. I suggest that "Meadow’s syndrome" be used in future reports not only as a tribute to Dr Meadow’s work but also in recognition of the fact that Baron von Munchausen never harmed a child. 13629 Hartsbourne Drive, Germantown, Maryland 20874, USA
STEPHEN LAZORITZ
1. Meadow R. Munchausen syndrome by proxy-the hinterland of child abuse. Lancet 1977; i: 343-45. 2. Strassburg H, Peuckert W. Not "Polle syndrome", please. Lancet 1984; i: 166. 3. Meadow R, Lennert T. Munchausen by proxy or Polle syndrome: which term is correct? Pediatrics 1984; 74: 554-56. 4. Editorial. Meadow’s and Munchausen. Lancet 1983; i: 456. 5. Warner J, Hathaway M. Allergic form of Meadow’s syndrome. Arch Dis’ Child 1984;
59: 151-56. 6.
Raspe RE Singular campaigns and adventures of Baron Munchausen (Carswell J, ed). London: Cresset Press, 1948: ix-xlv.
IATROGENIC SUBGLOTTIC STENOSIS LEADING TO TRACHEOSTOMY IN CHILDHOOD
SIR,--Children with tracheostomies generate a considerable workload, both in hospital and in the community. Over the past twenty years an increasing proportion of such tracheostomies have been done on infants with subglottic stenosis acquired as a result of neonatal intensive care. However, there are no data on the prevalence and aetiology of tracheostomy among children in the UK. I therefore undertook a survey in September, 1986. The 455 members of the British Association of Otolaryngologists were circulated with a questionnaire and 262 (58%) responded. This apparently low response can be explained in part by the fact that some surgeons replied on behalf of several centres and by the fact that the questionnaire indicated that those who had retired from clinical practice and senior registrars need not reply. A follow-up survey of a random 20 of the non-responders showed only 1 (5 %) to be caring for a child with a tracheostomy. On this basis I estimate that this survey missed about 10 children or 4% of the total, which 225. Indications for
was
SALLY MCGREGOR
tracheostomy were:
Grantham-McGregor SM, Schofield W, Powell C. Development of severely malnourished children who received psychosocial stimulation six year follow-up. Pediatrics 1987; 79: 247-54.
2. Grant JP. The state of the world’s children. New York: 3. Blaxter K. Future hunger? Lancet 1987; i: 309-13.
UNICEF,
1987.
MUNCHAUSEN BY PROXY OR MEADOW’S SYNDROME?
SiR,—In 1951, Richard Asher dedicated to Baron von Munchausen a syndrome in which the patient provides a dramatic, plausible, but wholly false medical history. In 1977 Roy Meadow described two cases of parents "who, by falsification, caused their children innumerable harmful hospital procedures"1 and "Munchausen syndrome by proxy" was born. After brief flirtations with the now discredited "Polle syndrome"Z,3 and with "Meadow’s syndrome"’5 medical journals now seem to favour Munchausen by proxy.
As Meadow has pointed out,3 Munchausen was noted for his hospitality and ability as a raconteur. Unfortunately, the baron, like the children whose parents fabricate illness by proxy, was himself a victim of dishonesty. Rudolf Erich Raspe, the acknowledged author of Baron Munchausen’s Narrative of his Marvelous Travels and Campaigns in Russiawas a German living in exile in Britain after having embezzled from an antiquity collection of which he was curator. He wrote the stories based on previously published tales and perhaps on a few stories heard at the baron’s table. The book was written solely for the money and no name was attached to the 1785 version. The translation into German made Baron von Munchausen a legend in his homeland but with the stress of fame he grew embittered and morose. Hieronymus Karl Friederich Freiherr von Munchausen, who told astounding stories for the enjoyment and entertainment of his guests, was victimised by an exiled embezzler and died an unhappy man.
Of the 96 cases of suglottic stenosis 40 were recorded as acquired and only 3 as congenital. No cause was given for the other- 53. Ward 42,
University College Hospital, London WC1E 6AU
PENNY JENNINGS, Tracheostomy liaison sister
UVEITIS AFTER HEPATITIS B VACCINATION
SIR,-Vaccination against hepatitis B with purified hepatitis B antigen (HBsAg) particles became widespread in the prevention of hepatitis B infection in risk groups, such as hospital personnel. In over 200 000 vaccinations, only 6 serious side-effects
surface
reported.’ We have observed acute posterior uveitis which occurred after the first and second boost of a hepatitis B vaccination. A 20-year-old nurse was vaccinated against hepatitis B by ’Hevac B’ (Pasteur). 3 days after the first boost given 24 days after the basic immunisation, she complained about blurred vision, headache, and photophobia. Examination revealed a bilateral posterior uveitis. There was no history of eye diseases. Physical examination did not reveal any abnormality and chest X-ray was normal. Laboratory investigation showed normal values for alanine aminotransferase, alkaline phosphatase, red and white cell count, differential cell count, and urine sediment. Serological examination for syphilis was were
632
negative. No rheumatoid factor antibodies
were
detected.
or antinuclear or anti-DNA Antibodies against Toxoplasma, influenza and parainfluenza virus,
adenovirus, cytomegalovirus, respiratory syncytial virus, Mycoplasma pneumoniae, herpes simplex virus, Chlamydia psittaci, and Leptospira were not detected in
repeated serological investigations. HBs and HBe antigen (HbeAg) were negative; HBs antibodies were positive. 3 months after the first boost, after healing of the uveitis, the patient received the third dose of hevac B, against our advice. 4 days later she had the same symptoms as after the first boost, and bilateral
posterior uveitis was diagnosed again. No abnormal clinical and laboratory findings were found. Tests for rheumatoid factors and for antibodies against nuclei, mitochondria, and DNA were negative. The same antibodies tested after the first uveitis episode were again undetectable. Furthermore, no HIV antibody was found. HBsA was negative with an increased titre of HBs antibodies. HBeA and hepatitis B core antibodies were negative. Lymphocyte transformation tests (3H-thymidine incorporation) showed stimulated lymphocyte transformation by the vaccine. Similar results were observed in two other nurses immunised at the time with the same lot of vaccine. This is the first report of uveitis after hepatitis B vaccination. The causal relation with vaccination was shown by the re-exposure to the vaccine and renewed development of the eye disease. Bilateral uveitis occurred after both immunisations within a similar time, while known causes for uveitis could be excluded. The formation and peripheral deposition of immune complexes with complement activation is a major pathogenic mechanism in the development of uveitis in several infectious and systemic diseases.2 In our case, an immune complex disease was supported by the typical time interval of 3-4 days after antigen exposure while a cell-mediated immune response remained doubtful according to the results of the lymphocyte stimulation tests. Immune complex diseases such as cryoglobulinaemia and glomerulonephritis can be observed during chronic hepatitis B infection.3 The still unproven possibility that the hepatitis B virus could cause uveitis is suggested by the higher frequency of detectable HBsA and HBs antibodies in the blood of patients with uveitis,"and by a uveitis case with hepatitis B infection. We would suggest that the surface antigen of the vaccine and HBs antibodies of the immune response after vaccination formed immune complexes which initiated bilateral uveitis in our case. Thus, the surface antigen of the hepatitis virus could be responsible for the development of uveitis both after vaccination with HBsAg and during the course of hepatitis B infection. same
Outpatient Clinic and Division of Gastroenterology,
University Hospital, CH-4031 Basel, Switzerland
M. FRIED D. CONEN M. CONZELMANN E. STEINEMANN
1. Anonymous. The safety of hepatius B virus vaccine. MMWR 1983; 32: 134-36. 2. Rahi AHS, Holborow EJ, Perkins ES, Gungen YY, Dinning WJ. Immunological investigations in uveitis. Trans Ophthalmol Soc UK 1976; 96: 113. 3. London WT. Hepatitis B virus and antigen-antibody complex diseases. N Engl J Med 1977; 26: 1528-29. 4. Grob PJ, Martenet AC, Witmer R. Nonspecific immune parameters and hepatitis B antigens in patients with uveitis. Mod Probl Ophthalmol 1976; 16: 254-58. 5. Murray PI, Prasad J, Rahi AH. Status of hepatitis B virus in the aetiology of uveitis in Great Britain. Br J Ophthalmol 1983; 67: 685-87. 6. Farthing CF, Howard RS, Thin RN Papillitis and hepatitis B. Br Med J 1986; 292: 1712.
DETOXIFICATION OF PERTUSSIS VACCINES
SIR,-Dr Cameron (June 20, p 1427) does not refer to much of recent discussion about whole cell pertussis vaccines and their replacement by acellular vaccines. The presence in whole cell vaccines of histamine-sensitising factor (HSF) and lymphocytosispromoting factor (LPF) activities, now known to be properties of pertussis toxin,’ has been recognised for years. So too has the link between HSF activity and vaccine potency;’ indeed a small amount of active pertussis toxin will greatly enhance the potency of a variety of preparations in the intracerebral protection test.3 This has been a major problem in the development of acellular pertussis vaccines,
the
for which the aim has been to detoxify the toxin as completely as possible, precluding the use of the conventional potency assay. The need for thorough and irreversible detoxification follows from the recognition that this toxin has the potential to affect many physiological systems and might cause major reactions within the central nervous system. The precise mechanisms whereby this might happen, the dose of active pertussis toxin needed, and the involvement of other factors are all areas of conjecture. Agents used to detoxify pertussis toxin include formaldehyde and glutaraldehyde, which are well-tried for other bacterial toxins. However, the many variables in methodology can lead to products differing with regard to completeness of detoxification and stability. One cannot simply extrapolate from experience with other toxins because of differences in structure, (and hence reactivity with the detoxifying agent), molecular mechanism of action, and purity. Completeness of detoxification is usually assayed by the most sensitive
tests
available-ie, histamine sensitisation of mice and
clumping of Chinese hamster ovary (CHO) cells. Reversion to toxicity can be tested by incubating a vaccine for a long time at 4-37°C and then reassaying for active toxin. For the acellular pertussis vaccine developed at this centre, it is a requirement that active pertussin toxin should not be detectable in the vaccine before or after such incubations. Any acellular vaccine containing detoxified pertussis toxin should similarly be shown to be as completely and irreversibly detoxified as possible. In our experience whole cell vaccines fail this requirement since active toxin is readily detected by the histamine sensitisation test and, in contrast to Cameron’s findings, by the CHO cell assay also. The pertussin toxin content of whole cell vaccine in our previous. report’ was a crude estimate measured as LPF in mice; the content of inactive toxin could not be assessed. We now know that the ELISA for pertussis toxin does not work after this antigen has been subjected to the rigorous detoxification procedures used for acellular vaccines. Despite this apparent loss of ELISA antigenicity, the detoxified substance is a potent immunogen, giving rise to toxin-neutralising antibodies.5 In the future, inactive pertussin toxin or fragments thereof will probably be produced by techniques of molecular genetics or peptide synthesis, and chemical detoxification will become unnecessary. For the present, however, the procedures used ensure irreversible detoxification. This, together with the reduced endotoxin content, enables acellular vaccines to contain higher levels of toxin per dose (eg, the CAMR vaccine contains 10 Jlg detoxified pertussis toxin per dose besides 10 ng each of filamentous haemagglutinin and agglutinogens). Consequently, enhanced levels of serum antibody to PT are induced in comparison with the whole cell vaccine and this may allow a reduction in the number of doses required to induce full immunity.6 Experimental Pathology and Vaccine Research and Production Laboratories, Public Health Laboratory Service, Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire SP4 0JG
L. A. E. ASHWORTH A. ROBINSON
JJ, Arai H, Bergman RK, Sadowski PL. Biological activities of crystalline pertussigen from Bordetella pertussis. Infect Immun 1981; 33: 820-26. 2. Pittman M. Comparison of the histamine-sensitising property with the protective activity of pertussis vaccines for mice. J Infect Dis 1951; 89: 300-04. 3. Robinson A, Irons LI. Synergistic effect of Bordetella pertussis lymphocytosis promoting factor on protective activities of isolated Bordetella antigens in mice. Infect Immun 1983; 40: 523-48. 4. Ashworth LAE, Robinson A, Irons LI, Morgan CP, Isaacs D. Antigens in whooping cough vaccine and antibody levels induced by vaccination of children. Lancet 1983; 1. Munoz
ii: 878-81. 5. Rutter DA, Ashworth LAE, Day A, Funnell S, Lovell F, Robinson A Tnal ofa new acellular pertussis vaccine in healthy adult volunteers. Vaccine (in press). 6. Olin P. Clinical results obtained to date in the Swedish trials. In. Workshop on acellular pertussis vaccines (sponsored by Interagency Group to Monitor Vaccine Development, Production and Usages, Bethesda, Maryland, September 1986): 106-10.
CRYPTOSPORIDIUM AND DRINKING WATER
SIR,-We read with interest the speculations on water-borne infection presented by Isaac-Renton and Cryptosporidium colleagues. Suspected water-borne cryptosporidiosis has been reported previously. 2,3
attention from the "socioeconomic and political inequalities that sustain poverty". He challenges our statement that the intervention was relatively modest and inexpensive. Between 1 and 21 % of young children in developing countries2 suffer from severe malnutrition, and most are destined to develop poorly owing to a combination of malnutrition and sociocultural deprivation. Very little attention has been paid to treatment after the acute stage. Is your correspondent suggesting that we abandon attempts to rehabilitate these children? Money must be spent on the prevention of malnutrition, but it is precisely because the roots of malnutrition are based in social and economic inequalities that prevention is so difficult. Malnutrition is not going to be eradicated in the near future and for years to come millions of children will survive malnutrition and face a dismal future. We showed that malnourished children responded to modest treatment-the use of home visitors with readily available skills and home-made toys. The approach was inexpensive compared with most interventions reported on in child development. I agree that many poor communities could not afford the programme we described, and we are now exploring the effects of less frequent and shorter visits. The important point was to establish that children would respond to treatment and families would cooperate. However, some developing countries have primary health care networks which include paraprofessionals visiting homes, and the intervention was designed to be attached to this type of service. Programmes are already underway in other countries based on similar designs. I cannot accept the principle that when a means for preventing a disease is known, research on treatment or rehabilitation should cease, even though millions of cases are still occurring. Such a suggestion could be applied to many other diseases, such as cholera, malaria, and AIDS. It is sensible, humane, and good medicine to continue research into improving methods of treatment and
rehabilitation, as well as prevention, until numbers of malnourished children.
we no
Tropical Metabolism Research Unit, University of the West Indies, Mona, Kingston 7, Jamaica, WI 1
longer
see
large
The recognition of Munchausen syndrome by proxy is a milestone in child protection, and the increasing number of these tragic case-reports is a testimony to the astute observations of Dr S. R. Meadow. I suggest that "Meadow’s syndrome" be used in future reports not only as a tribute to Dr Meadow’s work but also in recognition of the fact that Baron von Munchausen never harmed a child. 13629 Hartsbourne Drive, Germantown, Maryland 20874, USA
STEPHEN LAZORITZ
1. Meadow R. Munchausen syndrome by proxy-the hinterland of child abuse. Lancet 1977; i: 343-45. 2. Strassburg H, Peuckert W. Not "Polle syndrome", please. Lancet 1984; i: 166. 3. Meadow R, Lennert T. Munchausen by proxy or Polle syndrome: which term is correct? Pediatrics 1984; 74: 554-56. 4. Editorial. Meadow’s and Munchausen. Lancet 1983; i: 456. 5. Warner J, Hathaway M. Allergic form of Meadow’s syndrome. Arch Dis’ Child 1984;
59: 151-56. 6.
Raspe RE Singular campaigns and adventures of Baron Munchausen (Carswell J, ed). London: Cresset Press, 1948: ix-xlv.
IATROGENIC SUBGLOTTIC STENOSIS LEADING TO TRACHEOSTOMY IN CHILDHOOD
SIR,--Children with tracheostomies generate a considerable workload, both in hospital and in the community. Over the past twenty years an increasing proportion of such tracheostomies have been done on infants with subglottic stenosis acquired as a result of neonatal intensive care. However, there are no data on the prevalence and aetiology of tracheostomy among children in the UK. I therefore undertook a survey in September, 1986. The 455 members of the British Association of Otolaryngologists were circulated with a questionnaire and 262 (58%) responded. This apparently low response can be explained in part by the fact that some surgeons replied on behalf of several centres and by the fact that the questionnaire indicated that those who had retired from clinical practice and senior registrars need not reply. A follow-up survey of a random 20 of the non-responders showed only 1 (5 %) to be caring for a child with a tracheostomy. On this basis I estimate that this survey missed about 10 children or 4% of the total, which 225. Indications for
was
SALLY MCGREGOR
tracheostomy were:
Grantham-McGregor SM, Schofield W, Powell C. Development of severely malnourished children who received psychosocial stimulation six year follow-up. Pediatrics 1987; 79: 247-54.
2. Grant JP. The state of the world’s children. New York: 3. Blaxter K. Future hunger? Lancet 1987; i: 309-13.
UNICEF,
1987.
MUNCHAUSEN BY PROXY OR MEADOW’S SYNDROME?
SiR,—In 1951, Richard Asher dedicated to Baron von Munchausen a syndrome in which the patient provides a dramatic, plausible, but wholly false medical history. In 1977 Roy Meadow described two cases of parents "who, by falsification, caused their children innumerable harmful hospital procedures"1 and "Munchausen syndrome by proxy" was born. After brief flirtations with the now discredited "Polle syndrome"Z,3 and with "Meadow’s syndrome"’5 medical journals now seem to favour Munchausen by proxy.
As Meadow has pointed out,3 Munchausen was noted for his hospitality and ability as a raconteur. Unfortunately, the baron, like the children whose parents fabricate illness by proxy, was himself a victim of dishonesty. Rudolf Erich Raspe, the acknowledged author of Baron Munchausen’s Narrative of his Marvelous Travels and Campaigns in Russiawas a German living in exile in Britain after having embezzled from an antiquity collection of which he was curator. He wrote the stories based on previously published tales and perhaps on a few stories heard at the baron’s table. The book was written solely for the money and no name was attached to the 1785 version. The translation into German made Baron von Munchausen a legend in his homeland but with the stress of fame he grew embittered and morose. Hieronymus Karl Friederich Freiherr von Munchausen, who told astounding stories for the enjoyment and entertainment of his guests, was victimised by an exiled embezzler and died an unhappy man.
Of the 96 cases of suglottic stenosis 40 were recorded as acquired and only 3 as congenital. No cause was given for the other- 53. Ward 42,
University College Hospital, London WC1E 6AU
PENNY JENNINGS, Tracheostomy liaison sister
UVEITIS AFTER HEPATITIS B VACCINATION
SIR,-Vaccination against hepatitis B with purified hepatitis B antigen (HBsAg) particles became widespread in the prevention of hepatitis B infection in risk groups, such as hospital personnel. In over 200 000 vaccinations, only 6 serious side-effects
surface
reported.’ We have observed acute posterior uveitis which occurred after the first and second boost of a hepatitis B vaccination. A 20-year-old nurse was vaccinated against hepatitis B by ’Hevac B’ (Pasteur). 3 days after the first boost given 24 days after the basic immunisation, she complained about blurred vision, headache, and photophobia. Examination revealed a bilateral posterior uveitis. There was no history of eye diseases. Physical examination did not reveal any abnormality and chest X-ray was normal. Laboratory investigation showed normal values for alanine aminotransferase, alkaline phosphatase, red and white cell count, differential cell count, and urine sediment. Serological examination for syphilis was were
632
negative. No rheumatoid factor antibodies
were
detected.
or antinuclear or anti-DNA Antibodies against Toxoplasma, influenza and parainfluenza virus,
adenovirus, cytomegalovirus, respiratory syncytial virus, Mycoplasma pneumoniae, herpes simplex virus, Chlamydia psittaci, and Leptospira were not detected in
repeated serological investigations. HBs and HBe antigen (HbeAg) were negative; HBs antibodies were positive. 3 months after the first boost, after healing of the uveitis, the patient received the third dose of hevac B, against our advice. 4 days later she had the same symptoms as after the first boost, and bilateral
posterior uveitis was diagnosed again. No abnormal clinical and laboratory findings were found. Tests for rheumatoid factors and for antibodies against nuclei, mitochondria, and DNA were negative. The same antibodies tested after the first uveitis episode were again undetectable. Furthermore, no HIV antibody was found. HBsA was negative with an increased titre of HBs antibodies. HBeA and hepatitis B core antibodies were negative. Lymphocyte transformation tests (3H-thymidine incorporation) showed stimulated lymphocyte transformation by the vaccine. Similar results were observed in two other nurses immunised at the time with the same lot of vaccine. This is the first report of uveitis after hepatitis B vaccination. The causal relation with vaccination was shown by the re-exposure to the vaccine and renewed development of the eye disease. Bilateral uveitis occurred after both immunisations within a similar time, while known causes for uveitis could be excluded. The formation and peripheral deposition of immune complexes with complement activation is a major pathogenic mechanism in the development of uveitis in several infectious and systemic diseases.2 In our case, an immune complex disease was supported by the typical time interval of 3-4 days after antigen exposure while a cell-mediated immune response remained doubtful according to the results of the lymphocyte stimulation tests. Immune complex diseases such as cryoglobulinaemia and glomerulonephritis can be observed during chronic hepatitis B infection.3 The still unproven possibility that the hepatitis B virus could cause uveitis is suggested by the higher frequency of detectable HBsA and HBs antibodies in the blood of patients with uveitis,"and by a uveitis case with hepatitis B infection. We would suggest that the surface antigen of the vaccine and HBs antibodies of the immune response after vaccination formed immune complexes which initiated bilateral uveitis in our case. Thus, the surface antigen of the hepatitis virus could be responsible for the development of uveitis both after vaccination with HBsAg and during the course of hepatitis B infection. same
Outpatient Clinic and Division of Gastroenterology,
University Hospital, CH-4031 Basel, Switzerland
M. FRIED D. CONEN M. CONZELMANN E. STEINEMANN
1. Anonymous. The safety of hepatius B virus vaccine. MMWR 1983; 32: 134-36. 2. Rahi AHS, Holborow EJ, Perkins ES, Gungen YY, Dinning WJ. Immunological investigations in uveitis. Trans Ophthalmol Soc UK 1976; 96: 113. 3. London WT. Hepatitis B virus and antigen-antibody complex diseases. N Engl J Med 1977; 26: 1528-29. 4. Grob PJ, Martenet AC, Witmer R. Nonspecific immune parameters and hepatitis B antigens in patients with uveitis. Mod Probl Ophthalmol 1976; 16: 254-58. 5. Murray PI, Prasad J, Rahi AH. Status of hepatitis B virus in the aetiology of uveitis in Great Britain. Br J Ophthalmol 1983; 67: 685-87. 6. Farthing CF, Howard RS, Thin RN Papillitis and hepatitis B. Br Med J 1986; 292: 1712.
DETOXIFICATION OF PERTUSSIS VACCINES
SIR,-Dr Cameron (June 20, p 1427) does not refer to much of recent discussion about whole cell pertussis vaccines and their replacement by acellular vaccines. The presence in whole cell vaccines of histamine-sensitising factor (HSF) and lymphocytosispromoting factor (LPF) activities, now known to be properties of pertussis toxin,’ has been recognised for years. So too has the link between HSF activity and vaccine potency;’ indeed a small amount of active pertussis toxin will greatly enhance the potency of a variety of preparations in the intracerebral protection test.3 This has been a major problem in the development of acellular pertussis vaccines,
the
for which the aim has been to detoxify the toxin as completely as possible, precluding the use of the conventional potency assay. The need for thorough and irreversible detoxification follows from the recognition that this toxin has the potential to affect many physiological systems and might cause major reactions within the central nervous system. The precise mechanisms whereby this might happen, the dose of active pertussis toxin needed, and the involvement of other factors are all areas of conjecture. Agents used to detoxify pertussis toxin include formaldehyde and glutaraldehyde, which are well-tried for other bacterial toxins. However, the many variables in methodology can lead to products differing with regard to completeness of detoxification and stability. One cannot simply extrapolate from experience with other toxins because of differences in structure, (and hence reactivity with the detoxifying agent), molecular mechanism of action, and purity. Completeness of detoxification is usually assayed by the most sensitive
tests
available-ie, histamine sensitisation of mice and
clumping of Chinese hamster ovary (CHO) cells. Reversion to toxicity can be tested by incubating a vaccine for a long time at 4-37°C and then reassaying for active toxin. For the acellular pertussis vaccine developed at this centre, it is a requirement that active pertussin toxin should not be detectable in the vaccine before or after such incubations. Any acellular vaccine containing detoxified pertussis toxin should similarly be shown to be as completely and irreversibly detoxified as possible. In our experience whole cell vaccines fail this requirement since active toxin is readily detected by the histamine sensitisation test and, in contrast to Cameron’s findings, by the CHO cell assay also. The pertussin toxin content of whole cell vaccine in our previous. report’ was a crude estimate measured as LPF in mice; the content of inactive toxin could not be assessed. We now know that the ELISA for pertussis toxin does not work after this antigen has been subjected to the rigorous detoxification procedures used for acellular vaccines. Despite this apparent loss of ELISA antigenicity, the detoxified substance is a potent immunogen, giving rise to toxin-neutralising antibodies.5 In the future, inactive pertussin toxin or fragments thereof will probably be produced by techniques of molecular genetics or peptide synthesis, and chemical detoxification will become unnecessary. For the present, however, the procedures used ensure irreversible detoxification. This, together with the reduced endotoxin content, enables acellular vaccines to contain higher levels of toxin per dose (eg, the CAMR vaccine contains 10 Jlg detoxified pertussis toxin per dose besides 10 ng each of filamentous haemagglutinin and agglutinogens). Consequently, enhanced levels of serum antibody to PT are induced in comparison with the whole cell vaccine and this may allow a reduction in the number of doses required to induce full immunity.6 Experimental Pathology and Vaccine Research and Production Laboratories, Public Health Laboratory Service, Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire SP4 0JG
L. A. E. ASHWORTH A. ROBINSON
JJ, Arai H, Bergman RK, Sadowski PL. Biological activities of crystalline pertussigen from Bordetella pertussis. Infect Immun 1981; 33: 820-26. 2. Pittman M. Comparison of the histamine-sensitising property with the protective activity of pertussis vaccines for mice. J Infect Dis 1951; 89: 300-04. 3. Robinson A, Irons LI. Synergistic effect of Bordetella pertussis lymphocytosis promoting factor on protective activities of isolated Bordetella antigens in mice. Infect Immun 1983; 40: 523-48. 4. Ashworth LAE, Robinson A, Irons LI, Morgan CP, Isaacs D. Antigens in whooping cough vaccine and antibody levels induced by vaccination of children. Lancet 1983; 1. Munoz
ii: 878-81. 5. Rutter DA, Ashworth LAE, Day A, Funnell S, Lovell F, Robinson A Tnal ofa new acellular pertussis vaccine in healthy adult volunteers. Vaccine (in press). 6. Olin P. Clinical results obtained to date in the Swedish trials. In. Workshop on acellular pertussis vaccines (sponsored by Interagency Group to Monitor Vaccine Development, Production and Usages, Bethesda, Maryland, September 1986): 106-10.
CRYPTOSPORIDIUM AND DRINKING WATER
SIR,-We read with interest the speculations on water-borne infection presented by Isaac-Renton and Cryptosporidium colleagues. Suspected water-borne cryptosporidiosis has been reported previously. 2,3