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Recurrent meningococcal septicaemia and properdin deficiency
Journal of Infection (1995) 31, 67-68
CASE REPORT
Recurrent Meningococcal Septicaemia and Properdin Deficiency N. A. Cunliffe 1, N. Snowden 2, E. M. DunbaP and M. R. Haeney 2 1The Department of Infectious Diseases and Tropical Medicine, (Monsall Unit) North Manchester General Hospital, Crumpsall, Manchester and 2Department of Immunology, Hope Hospital, Eccles Old Road, Salford, U.K. Accepted for publication 24 November 1994 A 32-year-old male presented with two episodes of meningococcal septicaemia, each of which was caused by a different serogroup of Neisseria meningitidis. Examination of the alternative pathway of complement revealed the rare X-linked disorder properdin deficiency (PD). Meningococcal infection in complement deficiency states is discussed and the unusual features of this case are highlighted.
Introduction Individuals with complement deficiency are at increased risk of developing systemic infection with encapsulated bacteria, with up to 82% infections caused by Neisseria species, especially Neisseria meningitidis. ~-3 Properdin forms part of the alternative pathway of the complement cascade. Properdin deficiency (PD) is inherited as an Xlinked recessive trait and affected individuals are at risk of developing overwhelming meningococcal infection. This typically does not recur, explained in part by the high mortality in the initial episode. 2
Case Report A previously healthy 32-year-old Caucasian male gardener was admitted in February 1990 with an 18 h history of severe headache, vomiting and photophobia. On admission he was drowsy with a temperature of 40°C and generalised purpuric rash. Neck stiffness was present. Blood cultures grew N. meningitidis serogroup B. He made a rapid and uneventful recovery with i.v. benzylpenicillin. He was subsequently discharged from clinic and remained well until September 1992 when he was re-admitted with a 24 h history of headache and vomiting. On examination he was extremely unwell, with a temperature of 3 7.7°C and generalised purpuric rash again evident. Neck stiffness was present. Clotting studies revealed evidence of DIC. He subsequently developed aspiration pneumonia and was ventilated for 4 days. Blood cultures grew
N. meningitidis serogroup W135. Intravenous benzylpenicillin was given and he made a complete recovery. He was discharged on chemoprophylaxis with sulphadimidine i g bd. Prophylactic immunisation with meningococcal vaccines A and C was given. He has since remained well and is to remain on lifelong prophylactic antibiotics. Investigations of the complement system showed normal total classical pathway activity (therefore excluding deficiency of complement components C1-C9). In contrast, alternative pathway lytic activity (assessed by the method of Platts-Mills and Ishizaka 4) was completely absent. Factors B, D, H and I were detected by Ouchterlony double diffusion but no properdin could be detected by either double diffusion (Professor R.A. Thompson, Birmingham, U.K.) or ELISA (Professor K. Whaley, Leicester, U.K.). There was no family history of serious bacterial infections. Screening of the patient's parents and 24year-old brother revealed normal alternative pathway complement activity. Further screening of the mother's family is proposed.
Discussion
The association of complement deficiency states with systemic infection is well recognised, 1-3 and affected individuals may develop life threatening disease particularly with encapsulated bacteria. Individuals with deficiency of one of the classical pathway components (C1, C4 or C2) experience systemic infection in approximately 20% of cases, usually early in life. The most common infecting organisms are Streptococcus pneumoniae, N. meningitidis Address correspondenceto: Dr. N. A. Cunliffe,Registrar in Microbiology, Department of Medical Microbiology,Universityof Edinburgh, Medical and Haemophilus influenzae. 2 Although recurrent otitis School, TeviotPlace, Edinburgh EH8 9AG, U.K. and sinusitis are common, recurrent systemic infection 0163-4453/95/040067+02 $08.00/0
© 1995 The British Societyfor the Study of Infection
68
Meningococcal Septicaemia and Properdin Deficiency
by the same organism is unusual. Individuals with C3 deficiency experience severe infection in 70% cases, often early in life and caused particularly by N. meningitidis and S. pneumoniae; recurrent infection is common. 2 Those with a deficiency of one of the late complement components (C5-9) have a 5 0 - 6 0 % incidence of meningococcal disease, characteristically presenting as meningitis with a low mortality (1.5%) and a high recurrence rate (41%). 2 Properdin is a serum protein belonging to the alternative pathway of the complement cascade, its function is to stabilise the inherently labile C3 convertase. A recent historical review of the structure and function of properdin has been published. 5 The properdin structural locus is located on the short arm of the X-chromosome, and families with multiple male members who have meningococcal infection secondary to PD have been described. 6-s Although PD is considered rare, prevalence data is scarce. In a study from Israel, two patients with PD among 101 who survived meningococcal disease were found. 9 A further study from Norway of 98 survivors of meningococcal disease found none of complete PD, although median properdin concentration was significantly lower in the disease group compared with a control population. 1° The prevalence of PD may vary according to the ethnic origins of the population studied. ~: Individuals with PD have approximately a 50% incidence of meningococcal disease, and, as in those with late complement component deficiency (LCCD), infection often occurs initially in the mid-teenage years. 2 Infection with unusual serogroups is common in both LCCD and PD. However, in contrast to individuals with LCCD, individuals with PD characteristically develop fulminating septicaemia (mortality up to 50%) with a low recurrence rate (<2%). 2 Chronic meningococcaemia and less fulminant meningococcal disease are recognised as occurring in association with PD. T M The case of meningococcal infection secondary to PD reported here is unusual. Firstly, the patient survived and had a further non-fatal episode of meningococcal septicaemia. Secondly, the age of this patient at first presentation is older than is usually found. Finally, there was no family history of death from severe bacterial infection to give a clue as to the diagnosis. Since antibody formation is not impaired, it is to be
expected that immunity would develop to the serogroup of meningococcus involved following an episode of nonfatal septicaemia, and this report shows that the serogroup was different in each episode. It is suggested that patients with PD may be able to reduce their susceptibility to overwhelming meningococcal infection by production of protective antibody following vaccination.7 The patient described here has now been vaccinated against serogroups A and C and has survived infection with groups B and W135. It might be hoped that he will now have some degree of protection against all common serotypes.
Acknowledgements The authors would like to thank Professor K. Whaley and Professor R. A. Thompson for confirming properdin deficiency in this case.
References 1 Ross SC, Densen P. Complement deficiency states and infection; epidemiology, pathogenesis and consequences of Neisserial and other infections in an immune deficiency. Medicine (Baltimore) 1984; 63: 243-273. 2 Figueroa JE, Densen E Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 1991; 4: 359-395. 3 Densen P. Complement deficiencies and meningococcal disease. Clin Exp Immunol 1991; 86 (8uppl 1) 57-62. 4 Platts-Mills TAE, Ishizaka K. Activation of the alternative pathway of complement by rabbit cells. J Immunol 1974; 113: 348-351. 5 Mares KK, Weiler JM. Properdin: approaching four decades of research. Immunol Res 1993; 12: 233-243. 6 Sj0holm AG, Braconier ]H, S6derstr6m C. Properdin deficiency in a family with fulminant meningococcal infections. Clin Exp Immunol 1982; 50: 291-297. 7 Densen P, Weiler JM, Grifiss JM, Hoffmann LG. Familial properdin
8 9 10 11 12
deficiency and fatal meningococcaemia. Correction of the bactericidal defectby vaccination.New Erie] Med 1987; 316:922-926. Nielsen HE, Koch C. Congenital properdin deficiency and meningococcal infection. Clin Immunol Immunopathol 1987; 44: 134139. Schlesinger M, Nave Z, LevyY, Slater PE, Fishelson Z. Prevalence of hereditary properdin, C7 and C8 deficiencies in patients with meningococcalinfections. Clin Exp Immunol 1990; 81: 423-427. HogfisenK, Michaelsen T, Mellbye OJ, Bjune G. Low prevalence of complement deficiencies among patients with meningococcaldisease in Norway. Scand] Immunol 1993; 37: 487-489. SchlesingerM, Mashal U, Levy], Fishelson Z. Hereditary properdin deficiencyin three families ofTunisian Jews. Acta Paedicatrica 1993; 82: 744-747. Nielsen HE, Koch C, Mansa B, Magnussen E Bergmann O]. Complement and immunoglobulin studies in 15 cases of chronic meningococcaemia: properdin deficiency and hypogammaglobulinaemia. Scand ] Infect Dis 1990: 22:31-36.
CASE REPORT
Recurrent Meningococcal Septicaemia and Properdin Deficiency N. A. Cunliffe 1, N. Snowden 2, E. M. DunbaP and M. R. Haeney 2 1The Department of Infectious Diseases and Tropical Medicine, (Monsall Unit) North Manchester General Hospital, Crumpsall, Manchester and 2Department of Immunology, Hope Hospital, Eccles Old Road, Salford, U.K. Accepted for publication 24 November 1994 A 32-year-old male presented with two episodes of meningococcal septicaemia, each of which was caused by a different serogroup of Neisseria meningitidis. Examination of the alternative pathway of complement revealed the rare X-linked disorder properdin deficiency (PD). Meningococcal infection in complement deficiency states is discussed and the unusual features of this case are highlighted.
Introduction Individuals with complement deficiency are at increased risk of developing systemic infection with encapsulated bacteria, with up to 82% infections caused by Neisseria species, especially Neisseria meningitidis. ~-3 Properdin forms part of the alternative pathway of the complement cascade. Properdin deficiency (PD) is inherited as an Xlinked recessive trait and affected individuals are at risk of developing overwhelming meningococcal infection. This typically does not recur, explained in part by the high mortality in the initial episode. 2
Case Report A previously healthy 32-year-old Caucasian male gardener was admitted in February 1990 with an 18 h history of severe headache, vomiting and photophobia. On admission he was drowsy with a temperature of 40°C and generalised purpuric rash. Neck stiffness was present. Blood cultures grew N. meningitidis serogroup B. He made a rapid and uneventful recovery with i.v. benzylpenicillin. He was subsequently discharged from clinic and remained well until September 1992 when he was re-admitted with a 24 h history of headache and vomiting. On examination he was extremely unwell, with a temperature of 3 7.7°C and generalised purpuric rash again evident. Neck stiffness was present. Clotting studies revealed evidence of DIC. He subsequently developed aspiration pneumonia and was ventilated for 4 days. Blood cultures grew
N. meningitidis serogroup W135. Intravenous benzylpenicillin was given and he made a complete recovery. He was discharged on chemoprophylaxis with sulphadimidine i g bd. Prophylactic immunisation with meningococcal vaccines A and C was given. He has since remained well and is to remain on lifelong prophylactic antibiotics. Investigations of the complement system showed normal total classical pathway activity (therefore excluding deficiency of complement components C1-C9). In contrast, alternative pathway lytic activity (assessed by the method of Platts-Mills and Ishizaka 4) was completely absent. Factors B, D, H and I were detected by Ouchterlony double diffusion but no properdin could be detected by either double diffusion (Professor R.A. Thompson, Birmingham, U.K.) or ELISA (Professor K. Whaley, Leicester, U.K.). There was no family history of serious bacterial infections. Screening of the patient's parents and 24year-old brother revealed normal alternative pathway complement activity. Further screening of the mother's family is proposed.
Discussion
The association of complement deficiency states with systemic infection is well recognised, 1-3 and affected individuals may develop life threatening disease particularly with encapsulated bacteria. Individuals with deficiency of one of the classical pathway components (C1, C4 or C2) experience systemic infection in approximately 20% of cases, usually early in life. The most common infecting organisms are Streptococcus pneumoniae, N. meningitidis Address correspondenceto: Dr. N. A. Cunliffe,Registrar in Microbiology, Department of Medical Microbiology,Universityof Edinburgh, Medical and Haemophilus influenzae. 2 Although recurrent otitis School, TeviotPlace, Edinburgh EH8 9AG, U.K. and sinusitis are common, recurrent systemic infection 0163-4453/95/040067+02 $08.00/0
© 1995 The British Societyfor the Study of Infection
68
Meningococcal Septicaemia and Properdin Deficiency
by the same organism is unusual. Individuals with C3 deficiency experience severe infection in 70% cases, often early in life and caused particularly by N. meningitidis and S. pneumoniae; recurrent infection is common. 2 Those with a deficiency of one of the late complement components (C5-9) have a 5 0 - 6 0 % incidence of meningococcal disease, characteristically presenting as meningitis with a low mortality (1.5%) and a high recurrence rate (41%). 2 Properdin is a serum protein belonging to the alternative pathway of the complement cascade, its function is to stabilise the inherently labile C3 convertase. A recent historical review of the structure and function of properdin has been published. 5 The properdin structural locus is located on the short arm of the X-chromosome, and families with multiple male members who have meningococcal infection secondary to PD have been described. 6-s Although PD is considered rare, prevalence data is scarce. In a study from Israel, two patients with PD among 101 who survived meningococcal disease were found. 9 A further study from Norway of 98 survivors of meningococcal disease found none of complete PD, although median properdin concentration was significantly lower in the disease group compared with a control population. 1° The prevalence of PD may vary according to the ethnic origins of the population studied. ~: Individuals with PD have approximately a 50% incidence of meningococcal disease, and, as in those with late complement component deficiency (LCCD), infection often occurs initially in the mid-teenage years. 2 Infection with unusual serogroups is common in both LCCD and PD. However, in contrast to individuals with LCCD, individuals with PD characteristically develop fulminating septicaemia (mortality up to 50%) with a low recurrence rate (<2%). 2 Chronic meningococcaemia and less fulminant meningococcal disease are recognised as occurring in association with PD. T M The case of meningococcal infection secondary to PD reported here is unusual. Firstly, the patient survived and had a further non-fatal episode of meningococcal septicaemia. Secondly, the age of this patient at first presentation is older than is usually found. Finally, there was no family history of death from severe bacterial infection to give a clue as to the diagnosis. Since antibody formation is not impaired, it is to be
expected that immunity would develop to the serogroup of meningococcus involved following an episode of nonfatal septicaemia, and this report shows that the serogroup was different in each episode. It is suggested that patients with PD may be able to reduce their susceptibility to overwhelming meningococcal infection by production of protective antibody following vaccination.7 The patient described here has now been vaccinated against serogroups A and C and has survived infection with groups B and W135. It might be hoped that he will now have some degree of protection against all common serotypes.
Acknowledgements The authors would like to thank Professor K. Whaley and Professor R. A. Thompson for confirming properdin deficiency in this case.
References 1 Ross SC, Densen P. Complement deficiency states and infection; epidemiology, pathogenesis and consequences of Neisserial and other infections in an immune deficiency. Medicine (Baltimore) 1984; 63: 243-273. 2 Figueroa JE, Densen E Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 1991; 4: 359-395. 3 Densen P. Complement deficiencies and meningococcal disease. Clin Exp Immunol 1991; 86 (8uppl 1) 57-62. 4 Platts-Mills TAE, Ishizaka K. Activation of the alternative pathway of complement by rabbit cells. J Immunol 1974; 113: 348-351. 5 Mares KK, Weiler JM. Properdin: approaching four decades of research. Immunol Res 1993; 12: 233-243. 6 Sj0holm AG, Braconier ]H, S6derstr6m C. Properdin deficiency in a family with fulminant meningococcal infections. Clin Exp Immunol 1982; 50: 291-297. 7 Densen P, Weiler JM, Grifiss JM, Hoffmann LG. Familial properdin
8 9 10 11 12
deficiency and fatal meningococcaemia. Correction of the bactericidal defectby vaccination.New Erie] Med 1987; 316:922-926. Nielsen HE, Koch C. Congenital properdin deficiency and meningococcal infection. Clin Immunol Immunopathol 1987; 44: 134139. Schlesinger M, Nave Z, LevyY, Slater PE, Fishelson Z. Prevalence of hereditary properdin, C7 and C8 deficiencies in patients with meningococcalinfections. Clin Exp Immunol 1990; 81: 423-427. HogfisenK, Michaelsen T, Mellbye OJ, Bjune G. Low prevalence of complement deficiencies among patients with meningococcaldisease in Norway. Scand] Immunol 1993; 37: 487-489. SchlesingerM, Mashal U, Levy], Fishelson Z. Hereditary properdin deficiencyin three families ofTunisian Jews. Acta Paedicatrica 1993; 82: 744-747. Nielsen HE, Koch C, Mansa B, Magnussen E Bergmann O]. Complement and immunoglobulin studies in 15 cases of chronic meningococcaemia: properdin deficiency and hypogammaglobulinaemia. Scand ] Infect Dis 1990: 22:31-36.