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Meningococcaemia: Current concepts in prophylaxis
Journal of Infection (1980) 2, 316-319
REVIEW
Meningococcaemia: current concepts in prophylaxis A. P. Ball
Infectious Diseases Unit, Cameron Hospital, Windygates, Fife KY8 5RR, Scotland
Nasopharyngeal carriage of virulent meningococci is common in the community rising from 2-4-5.4 per cent in children (Gold, Goldschneider, Lepow, Draper and Randolph, 1978; Marks, Frasch and Shapera, 1979) to 21 per cent in mixed populations (Fraser, Bailey, Abbott, Gill and Walker, 1973). In young military recruits in overcrowded barracks carriage rates may rise from 30 per cent to 70 per cent within a few months (Fraser, Bailey, Abbott, Gill and Walker, 1973) and acquisition rates of 60 per cent over a period of three months have been reported in similar student populations (Melton, Edwards and Devine, 1977). The attack rate of disease amongst contacts of sporadic cases is small in comparison. The Meningococcal Disease Surveillance Group (1976a,b) have reported secondary attack rates in family contacts of 0.22-0.42 per cent. In epidemics casual contacts are at no greater risk than the general population, but the risk to close family contacts has varied from 1.6-5.9 per cent (Munford, Taunay, De Morais, Fraser and Feldman, 1974; Kaiser, Hennekens, Saslaw, Hayes and Bennett, 1974). The paradox of the difference between the incidence of acquisition and carriage, and the much lower incidence of clinical disease is beginning to be explained. Protection is partly the result of natural immunity acquired through carriage of low virulence strains, but may also result from childhood carriage of the closely related, but weakly pathogenic, Neisseria lactamica. Acquisition of this organism (by up to 20 per cent of infants) results in the development of IgG antibody active against group A, B and/or C meningococci in two-thirds, bactericidal titres being present in 40 per cent (Gold, Goldschneider, Lepow, Draper and Randolph, 1978). Conversely, various immune defects including classical agammaglobulinaemia, familial IgM deficiency (Hobbs, Milner and Watt, 1967), failure of antibody synthesis (Whittle, Oduloju, Evans-Jones and Greenwood, 1976) and complement component deficiencies (Lambert, Thompson, Jones and Fleck, 1979; Haeney, Ball and Thompson, 1979) have been shown to predispose to meningococcal disease. 01634453/80/040316 + 04 $01.00/0
© 1980 The British Society for the Study of Infection
Meningococcaemia
317
The risk of potentially fatal disease in close contacts and in predisposed individuals in the community is a powerful argument for prophylaxis. Sulphonamide chemoprophylaxis has been used successfully in the past, but increasing bacterial resistance, reports of development of resistance during prophylaxis (Holten, Vaage, Neess, Midtveldt and Jyssum, 1969) and poor eradicative results (Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman, 1974) question its use in the future. Minocycline and rifampicin have been investigated as alternatives. Minocycline alone achieved eradication rates of 67-83 per cent using dosage regimes of 200 mg, 12 hourly, for 48 hours (Devine, Johnson, Hagerman, Pierce, Rhode and Peckinpaugh, 1971) and 200 mg, stat, plus 100 mg, 12 hourly, for 72 hours (Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman, 1974) respectively, but unwanted effects, including abdominal symptoms and dizziness, were noted in 18-36 per cent of subjects. Rifampicin alone (600 mg, 12 hourly, for 48 hours) produced clearance rates of 91 per cent, but rifampicin-resistant organisms were encountered (Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman, 1974). These drugs have been used more successfully in combination. A sequential regime (Devine, Pollard, Krumpe, Hoy, Mammen, Miller and Peckinpaugh, 1973) eradicated carriage in all but seven (0.5 per cent) of 1258 subjects and Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman (1974) cleared all of 70 carriers who received minocycline and rifampicin simultaneously. Whether chemoprophylaxis equates with protection is not entirely clear, but the Meningococcal Disease Surveillance Group (1976) found no secondary cases amongst 693 contacts who received appropriate chemoprophylaxis as against five in 1179 untreated or improperly treated contacts, a highly significant difference. The demonstration of high immunogenicity and low reactogenicity of type A and C meningococcal vaccines (Goldschneider, Lepow and Gotschlich, 1972; Monto, Brandt and Artenstein, 1973) has offered immunoprophylaxis as an alternative. Antibody responses in adults are excellent, but the response in children relates to age, small babies responding poorly (Monto, Brandt and Artenstein, 1973). However, infants of vaccinated mothers retain significant antibody levels during the first few months of life following passive placental transfer (Carvalho, Giampaglia, Kimura, Pereira, Farhat, Neves, Prandini, Carvalho and Zarvos, 1977). Field studies in epidemics in Nigeria have demonstrated the protective value of group A vacccine in at-risk family contacts (Greenwood, Hassan-King and Whittle, 1978) and fears that vaccines might encourage an increase in disease due to other serotypes have not been confirmed (Makela and Peltola, 1978). Type A and C mono/divalent vaccines are now licensed in the U.S.A. with recommendations for use as an adjunct to chemoprophylaxis in close contacts and to control outbreaks. However, vaccines do not eradicate carriage (Greenwood, Hassan-King and Whittle, 1978) and unfortunately Type A/C vaccines are likely to be of lesser use in the U.K. as they are ineffective
318
A . P . Ball
against the T y p e B meningococcus which p r e d o m i n a t e s in sporadic outbreaks. A t t e m p t s at production of T y p e B vaccines have b e e n h a m p e r e d by the p o o r immunogenicity of the serotype, but recent studies of vaccines derived from neisserial m e m b r a n e proteins have d e m o n s t r a t e d active protection in mice and satisfactory antibody responses in h u m a n volunteers (ZO1linger, Mandrell, Altieri, Berman, L o w e n t h a l and Artenstein, 1978). Active immunoprophylaxis of T y p e B infection may t h e r e f o r e be available in the future. In the U.K. therapy is currently limited to chemoprophylaxis. The literature q u o t e d in this review suggests that prophylaxis combining rifampicin and minocycline has advantages over the use of either sulphonamides or minocycline alone. H o w e v e r minocycline may cause tooth staining in children and vestibular and gastro-intestinal upsets in up to a third of patients, and the e m e r g e n c e of resistance during rifampicin prophylaxis m a y detract from the usefulness of this d r u g . N o ideal chemoprophylactic agent is currently available and, although the conclusion that secondary disease in at-risk contacts can and should be p r e v e n t e d b y ' a d e q u a t e prophylaxis' is not in doubt, the definition o f ' adequate prophylaxis' remains a subject for d e b a t e and further clinical trial.
References
Carvalho, A. De A., Giampaglia, C. M. S., Kimura, H., Pereira, O. A. De C., Frahat, C. K., Neves, J. C., Prandini, R., Carvalho, E. Da S. and Zarvos, A. M. (1977). Maternal and infant antibody response to meningococcal vaccination in pregnancy. Lancet, ii, 809. Devine, L. F., Johnson, D. P., Hagerman, C. R., Pierce, W. E., Rhode, S. L. and Peckinpaugh, R. O. (1971). The effect of minocycline on meningococcal nasopharyngeal carrier state in naval personnel. American Journal of Epidemiology, 93, 337. Devine, L. F., Pollard, R. B., Krumpe, P. E., Hoy, E. S., Mammen, R. E., Miller, C. H. and Peckinpaugh, R. O. (1973). Field trial of the efficacy of a previously proposed regimen using minocycline and rifampicin sequentially for the elimination of meningococci from healthy carriers. American Journal of Epidemiology, 97, 394. Fraser, P. K., Bailey, G. K., Abbott, J. D., Gill, J. B. and Walker, D. J. C. (1973). The meningococcal carrier rate. Lancet, i, 1235. Gold, R., Goldschneider, I., Lepow, M. L., Draper, T. F. and Randolph, M. (1978). Carriage of Neisseria meningitidis and Neisseria lactamica in infants and children. Journal of Infectious Diseases, 137, 112. Goldschneider, I., Lepow, M. L. and Gotschlich, E. C. (1972). Immunogenicity of the Group A and Group C meningococcal polysaccharides in children. Journal oflnfectious Diseases, 125, 509. Greenwood, B. M., Hassan-King, M. and Whittle, H. C. (1978). Prevention of secondary cases of meningococcal disease in household contacts by vaccination. British Medical Journal, i, 1317. Haeney, M. R., Ball, A. P. and Thompson, R. A. (1979). Recurrent bacterial meningitis due to genetic deficiencies of terminal complement components (C5 and C6). Zeitschrifi fur lmmunitatsforschung (in press). Hobbs, J. R., Milner, R. D. G. and Watt, P. J. (1967). Gamma-M deficiency predisposing to meningococcal septicaemia. British Medical Journal, iv, 583.
Meningococcaemia
319
Holten, E., Vaage, L., Neess, C., Midveldt, T. and Jyssum, K. (1969). Sulphonamide-resistant meningococci after sulphonamide prophylaxis among naval recruits in Norway. Scandinavian Journal of Infectious Diseases, l, 185. Lambert, H. P., Thompson, R. A., Jones, D. M. and Fleck, D. G. (1979). Absence of the seventh complement component (C7) in a patient with recurrent meningococcal meningitis. Journal of Infection, 1, 191. Kaiser, A. B., Hennekens, C. H., Saslaw, M. S., Hayes, P. S. and Bennett, J. V. (1974). Seroepidemiology and chemoprophylaxis of disease due to sulphonamide-resistant Neisseria meningitidis in a civilian population. Journal of Infectious Diseases, 130, 217. Makela, P. H. and Peltola, H. (1978)• Group specific meningococcal vaccination and epidemics caused by other groups of meningococei. Lancet, ii, 780. Marks, M. I., Frasch, C. E. and Shapera, R. M. (1979). Meningococcal colonization and infection in children and their household contacts. American Journal of Epidemiology, 109, 563. Meningococcal Disease Surveillance Group (1976a). Analysis of endemic meningococcal disease by sero~xoup and evaluation of chemoprophylaxis. JDurnal of Infectious Diseases. Menlngoeoccal Disease Surveillance Group (1976b). M~nmgococcal disease: ~eecondary attack rate and chemoprophylaxis in the United States, 1974. Journal of the American Medical Association, 235, 261• Melton, L. J., Edwards, E. A. and Devine, L. F. (1977). Differences between sexes in the nasopharyngeal carriage of Neisseria meningitidis. American Journal of Epidemiology, 106, 215• Monto, A. S., Brandt, B. L. and Artenstein, M. S. (1973). Response of children to Neisseria meningitidis polysaccharide vaccines. Journal of Infectious Diseases, 127, 394• Munford, R. S., Taunay, A. De E., De Morais, J. S., Fraser, D. W. and Feldman, R. A. (1974). Spread of meningococcal infection within households. Lancet, i, 1275. Munford, R. S., De Vasconcelos, Z. J. S., Phillips, C. J., Gelli, D. S., Gorman; G. W., Risi, J. B. and Feldman, R. A. (1974). Eradication of carriage ofNeisseria meningitidis in families: A study in Brazil. Journal of Infectious Diseases, 129, 644. Whittle, H. C., Oduloju, A., Evans-Jones, G. and Greenwood, B. M. (1976). Evidence for familial immune defect in meningococcal meningitis. British Medical Journal, i, 1247. Zollinger, W. D., Mandrell, R. E., Altieri, P., Berman, S., Lowenthal, J. and Artenstein, M. S. (1978). Safety and immunogenicity of a Neisseria meningitidis type 2 protein vaccine in animals and humans. Journal of Infectious Diseases, 137, 728.
,
REVIEW
Meningococcaemia: current concepts in prophylaxis A. P. Ball
Infectious Diseases Unit, Cameron Hospital, Windygates, Fife KY8 5RR, Scotland
Nasopharyngeal carriage of virulent meningococci is common in the community rising from 2-4-5.4 per cent in children (Gold, Goldschneider, Lepow, Draper and Randolph, 1978; Marks, Frasch and Shapera, 1979) to 21 per cent in mixed populations (Fraser, Bailey, Abbott, Gill and Walker, 1973). In young military recruits in overcrowded barracks carriage rates may rise from 30 per cent to 70 per cent within a few months (Fraser, Bailey, Abbott, Gill and Walker, 1973) and acquisition rates of 60 per cent over a period of three months have been reported in similar student populations (Melton, Edwards and Devine, 1977). The attack rate of disease amongst contacts of sporadic cases is small in comparison. The Meningococcal Disease Surveillance Group (1976a,b) have reported secondary attack rates in family contacts of 0.22-0.42 per cent. In epidemics casual contacts are at no greater risk than the general population, but the risk to close family contacts has varied from 1.6-5.9 per cent (Munford, Taunay, De Morais, Fraser and Feldman, 1974; Kaiser, Hennekens, Saslaw, Hayes and Bennett, 1974). The paradox of the difference between the incidence of acquisition and carriage, and the much lower incidence of clinical disease is beginning to be explained. Protection is partly the result of natural immunity acquired through carriage of low virulence strains, but may also result from childhood carriage of the closely related, but weakly pathogenic, Neisseria lactamica. Acquisition of this organism (by up to 20 per cent of infants) results in the development of IgG antibody active against group A, B and/or C meningococci in two-thirds, bactericidal titres being present in 40 per cent (Gold, Goldschneider, Lepow, Draper and Randolph, 1978). Conversely, various immune defects including classical agammaglobulinaemia, familial IgM deficiency (Hobbs, Milner and Watt, 1967), failure of antibody synthesis (Whittle, Oduloju, Evans-Jones and Greenwood, 1976) and complement component deficiencies (Lambert, Thompson, Jones and Fleck, 1979; Haeney, Ball and Thompson, 1979) have been shown to predispose to meningococcal disease. 01634453/80/040316 + 04 $01.00/0
© 1980 The British Society for the Study of Infection
Meningococcaemia
317
The risk of potentially fatal disease in close contacts and in predisposed individuals in the community is a powerful argument for prophylaxis. Sulphonamide chemoprophylaxis has been used successfully in the past, but increasing bacterial resistance, reports of development of resistance during prophylaxis (Holten, Vaage, Neess, Midtveldt and Jyssum, 1969) and poor eradicative results (Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman, 1974) question its use in the future. Minocycline and rifampicin have been investigated as alternatives. Minocycline alone achieved eradication rates of 67-83 per cent using dosage regimes of 200 mg, 12 hourly, for 48 hours (Devine, Johnson, Hagerman, Pierce, Rhode and Peckinpaugh, 1971) and 200 mg, stat, plus 100 mg, 12 hourly, for 72 hours (Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman, 1974) respectively, but unwanted effects, including abdominal symptoms and dizziness, were noted in 18-36 per cent of subjects. Rifampicin alone (600 mg, 12 hourly, for 48 hours) produced clearance rates of 91 per cent, but rifampicin-resistant organisms were encountered (Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman, 1974). These drugs have been used more successfully in combination. A sequential regime (Devine, Pollard, Krumpe, Hoy, Mammen, Miller and Peckinpaugh, 1973) eradicated carriage in all but seven (0.5 per cent) of 1258 subjects and Munford, De Vasconcelos, Phillips, Gelli, Gorman, Risi and Feldman (1974) cleared all of 70 carriers who received minocycline and rifampicin simultaneously. Whether chemoprophylaxis equates with protection is not entirely clear, but the Meningococcal Disease Surveillance Group (1976) found no secondary cases amongst 693 contacts who received appropriate chemoprophylaxis as against five in 1179 untreated or improperly treated contacts, a highly significant difference. The demonstration of high immunogenicity and low reactogenicity of type A and C meningococcal vaccines (Goldschneider, Lepow and Gotschlich, 1972; Monto, Brandt and Artenstein, 1973) has offered immunoprophylaxis as an alternative. Antibody responses in adults are excellent, but the response in children relates to age, small babies responding poorly (Monto, Brandt and Artenstein, 1973). However, infants of vaccinated mothers retain significant antibody levels during the first few months of life following passive placental transfer (Carvalho, Giampaglia, Kimura, Pereira, Farhat, Neves, Prandini, Carvalho and Zarvos, 1977). Field studies in epidemics in Nigeria have demonstrated the protective value of group A vacccine in at-risk family contacts (Greenwood, Hassan-King and Whittle, 1978) and fears that vaccines might encourage an increase in disease due to other serotypes have not been confirmed (Makela and Peltola, 1978). Type A and C mono/divalent vaccines are now licensed in the U.S.A. with recommendations for use as an adjunct to chemoprophylaxis in close contacts and to control outbreaks. However, vaccines do not eradicate carriage (Greenwood, Hassan-King and Whittle, 1978) and unfortunately Type A/C vaccines are likely to be of lesser use in the U.K. as they are ineffective
318
A . P . Ball
against the T y p e B meningococcus which p r e d o m i n a t e s in sporadic outbreaks. A t t e m p t s at production of T y p e B vaccines have b e e n h a m p e r e d by the p o o r immunogenicity of the serotype, but recent studies of vaccines derived from neisserial m e m b r a n e proteins have d e m o n s t r a t e d active protection in mice and satisfactory antibody responses in h u m a n volunteers (ZO1linger, Mandrell, Altieri, Berman, L o w e n t h a l and Artenstein, 1978). Active immunoprophylaxis of T y p e B infection may t h e r e f o r e be available in the future. In the U.K. therapy is currently limited to chemoprophylaxis. The literature q u o t e d in this review suggests that prophylaxis combining rifampicin and minocycline has advantages over the use of either sulphonamides or minocycline alone. H o w e v e r minocycline may cause tooth staining in children and vestibular and gastro-intestinal upsets in up to a third of patients, and the e m e r g e n c e of resistance during rifampicin prophylaxis m a y detract from the usefulness of this d r u g . N o ideal chemoprophylactic agent is currently available and, although the conclusion that secondary disease in at-risk contacts can and should be p r e v e n t e d b y ' a d e q u a t e prophylaxis' is not in doubt, the definition o f ' adequate prophylaxis' remains a subject for d e b a t e and further clinical trial.
References
Carvalho, A. De A., Giampaglia, C. M. S., Kimura, H., Pereira, O. A. De C., Frahat, C. K., Neves, J. C., Prandini, R., Carvalho, E. Da S. and Zarvos, A. M. (1977). Maternal and infant antibody response to meningococcal vaccination in pregnancy. Lancet, ii, 809. Devine, L. F., Johnson, D. P., Hagerman, C. R., Pierce, W. E., Rhode, S. L. and Peckinpaugh, R. O. (1971). The effect of minocycline on meningococcal nasopharyngeal carrier state in naval personnel. American Journal of Epidemiology, 93, 337. Devine, L. F., Pollard, R. B., Krumpe, P. E., Hoy, E. S., Mammen, R. E., Miller, C. H. and Peckinpaugh, R. O. (1973). Field trial of the efficacy of a previously proposed regimen using minocycline and rifampicin sequentially for the elimination of meningococci from healthy carriers. American Journal of Epidemiology, 97, 394. Fraser, P. K., Bailey, G. K., Abbott, J. D., Gill, J. B. and Walker, D. J. C. (1973). The meningococcal carrier rate. Lancet, i, 1235. Gold, R., Goldschneider, I., Lepow, M. L., Draper, T. F. and Randolph, M. (1978). Carriage of Neisseria meningitidis and Neisseria lactamica in infants and children. Journal of Infectious Diseases, 137, 112. Goldschneider, I., Lepow, M. L. and Gotschlich, E. C. (1972). Immunogenicity of the Group A and Group C meningococcal polysaccharides in children. Journal oflnfectious Diseases, 125, 509. Greenwood, B. M., Hassan-King, M. and Whittle, H. C. (1978). Prevention of secondary cases of meningococcal disease in household contacts by vaccination. British Medical Journal, i, 1317. Haeney, M. R., Ball, A. P. and Thompson, R. A. (1979). Recurrent bacterial meningitis due to genetic deficiencies of terminal complement components (C5 and C6). Zeitschrifi fur lmmunitatsforschung (in press). Hobbs, J. R., Milner, R. D. G. and Watt, P. J. (1967). Gamma-M deficiency predisposing to meningococcal septicaemia. British Medical Journal, iv, 583.
Meningococcaemia
319
Holten, E., Vaage, L., Neess, C., Midveldt, T. and Jyssum, K. (1969). Sulphonamide-resistant meningococci after sulphonamide prophylaxis among naval recruits in Norway. Scandinavian Journal of Infectious Diseases, l, 185. Lambert, H. P., Thompson, R. A., Jones, D. M. and Fleck, D. G. (1979). Absence of the seventh complement component (C7) in a patient with recurrent meningococcal meningitis. Journal of Infection, 1, 191. Kaiser, A. B., Hennekens, C. H., Saslaw, M. S., Hayes, P. S. and Bennett, J. V. (1974). Seroepidemiology and chemoprophylaxis of disease due to sulphonamide-resistant Neisseria meningitidis in a civilian population. Journal of Infectious Diseases, 130, 217. Makela, P. H. and Peltola, H. (1978)• Group specific meningococcal vaccination and epidemics caused by other groups of meningococei. Lancet, ii, 780. Marks, M. I., Frasch, C. E. and Shapera, R. M. (1979). Meningococcal colonization and infection in children and their household contacts. American Journal of Epidemiology, 109, 563. Meningococcal Disease Surveillance Group (1976a). Analysis of endemic meningococcal disease by sero~xoup and evaluation of chemoprophylaxis. JDurnal of Infectious Diseases. Menlngoeoccal Disease Surveillance Group (1976b). M~nmgococcal disease: ~eecondary attack rate and chemoprophylaxis in the United States, 1974. Journal of the American Medical Association, 235, 261• Melton, L. J., Edwards, E. A. and Devine, L. F. (1977). Differences between sexes in the nasopharyngeal carriage of Neisseria meningitidis. American Journal of Epidemiology, 106, 215• Monto, A. S., Brandt, B. L. and Artenstein, M. S. (1973). Response of children to Neisseria meningitidis polysaccharide vaccines. Journal of Infectious Diseases, 127, 394• Munford, R. S., Taunay, A. De E., De Morais, J. S., Fraser, D. W. and Feldman, R. A. (1974). Spread of meningococcal infection within households. Lancet, i, 1275. Munford, R. S., De Vasconcelos, Z. J. S., Phillips, C. J., Gelli, D. S., Gorman; G. W., Risi, J. B. and Feldman, R. A. (1974). Eradication of carriage ofNeisseria meningitidis in families: A study in Brazil. Journal of Infectious Diseases, 129, 644. Whittle, H. C., Oduloju, A., Evans-Jones, G. and Greenwood, B. M. (1976). Evidence for familial immune defect in meningococcal meningitis. British Medical Journal, i, 1247. Zollinger, W. D., Mandrell, R. E., Altieri, P., Berman, S., Lowenthal, J. and Artenstein, M. S. (1978). Safety and immunogenicity of a Neisseria meningitidis type 2 protein vaccine in animals and humans. Journal of Infectious Diseases, 137, 728.
,