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Recurrent meningococcal meningitis due to partial complement defects and poor anti-meningococcal antibody response
Journal of Infection (I983) 6, 55-60
Recurrent meningococcal meningitis due to partial c o m p l e m e n t defects and poor anti-meningococcal antibody response Elja Herva, Maija Leinonen,* Helena K/iyhty,t P. Helena M/ikel/i t and Sanna-Liisa V e t o n i e m i - K o r h o n e n ~
National Public Health Institute, Oulu *Department of Medical Microbiology, University of Oulu ~fNational Public Health Institute, Helsinki ~Department of Medicine, University of Oulu, Finland Summary An otherwise healthy young man had three episodes of meningococcal meningitis within three years. The last episode was caused by group A, and occurred four weeks after the patient received group A vaccine, thus representing one of the very few failures of this vaccine. The specific susceptibility to meningococcal infections was connected with half-normal levels of several components of the complement system (C3, C4, C9, factor B, properdin), and reduced antibody responses to group A and group C meningococcal polysaccharides, but not to several other polysaccharide or protein antigens.
Introduction W e still do not k n o w w h y few people develop meningitis as a result of meningococcal infection while m a n y m o r e remain asymptomatic. S e r u m antibodies certainly play a role : polysaccharide vaccines protect efficiently against infection, 1 whereas subjects lacking bactericidal antibodies are susceptible. 2 C o m p l e m e n t defects also predispose to the d e v e l o p m e n t of meningitis; the fact that those with defects of the late c o m p l e m e n t c o m p o n e n t s C6, C7 or C8 are especially prone to infections caused b y Neisseria meningitidis and N. gonorrhoeae suggests that a n t i b o d y - and c o m p l e m e n t - m e d i a t e d killing of bacteria is an important defence against neisserial infections, a-6 Because of the generally low incidence of meningococcal disease, repeated attacks are likely to indicate special susceptibility, and help towards u n d e r standing the basis of it. W e present here our findings in a y o u n g man, w h o had three episodes o f meningococcal meningitis within three years, and has multiple b u t incomplete defects in b o t h his c o m p l e m e n t system and his i m m u n e response to two meningococcal polysaccharide antigens.
Case report First episode in February I973 M K , an 18-year-old farmer's son admitted to the University Central Hospital of O u l u had clinically typical purulent meningitis, with a leucocyte count of Requests for reprints: P. Helena Mfikel~i, National Public Health Institute, Mannerheimintie I66, SF-oo28o Helsinki 28, Finland. oi63-4453/83/oioo55 +06 $o2.oo/o
© ~983 The British Society for the Study of Infection
56
E. HERVA
ET AL.
65O0 x 106 per litre (85 per cent polymorphonuclears) in the cerebrospinal fluid (CSF). Culture from CSF yielded Neisseria meningitidis, which was not tested further. T h e patient responded well to intravenous penicillin plus cephalotine and was discharged after 16 days. S e c o n d e p i s o d e in O c t o b e r 1974
]QIK was admitted to the same hospital because of fever, vomiting, headache and respiratory symptoms but in good general condition with no nuchal rigidity or rash. His CSF had a leucocyte count of 389 x lO6 per litre (IOO per cent polymorphonuclears). N. meningitidis of serogroup C was isolated both from CSF and blood. T h e patient responded well to intravenous penicillin and was discharged after IO days. T h i r d e p i s o d e in N o v e m b e r 1975 M K had started his military service in Oulu on IO October 1975, and received on 15 October the usual 5o #g dose of group A meningococcal polysaccharide vaccine (Meningovax A ®, Merck, Sharp and Dohme, West Point, Pennsylvania) given in 1975 to all recruits to the Finnish Armed Forces. 7 On I I November, four weeks after the vaccination, he fell ill with the typical symptoms of meningococcal meningitis including a petechial rash; his general condition was good. T h e CSF contained 35ox lO6 leucocytes per litre (68 per cent polymorphonuclears). N. meningitidis of group A and resistant to > 5o # g / m l of sulphonamide was isolated from his CSF and nasopharynx. T h e patient became symptomfree after four days of penicillin plus gentamicin treatment and was discharged IO days after admission. Further information
According to both M K and his parents the episode of meningitis in 1973 was his first serious illness requiring admission to hospital, although he was described as always having been prone to febrile infections. After the third meningitis episode he was discharged from military service and has since been in good health, with no febrile infections, working as a farmer. His parents and three siblings had not shown special liability to infectious diseases. Specific i n v e s t i g a t i o n s
No organic predisposing factors were revealed in a thorough neurological and otorhinological examination after the third episode. Tests for phagocyte functions (response to chemotactic stimuli and engulfment plus intracellular killing of Staphylococcus aureus, kindly tested by D r P. Ruutu, Department of Bacteriology and Immunology, University of Helsinki) performed four weeks after the third episode gave normal results. T h e immunoglobulin levels 8 of several serum samples of M K taken before, during, and up to ~o months after the third episode were within normal range with IgA and I g M perhaps slightly elevated (Table I). By contrast, several components of the complement system were reduced in the serum of M K as compared to normal control sera of the same sex and age (Table I). Thus, the mean value of his C3 (o'23 g/l) was about ~5 per cent of normal, and that of
Recurrent meningococcal meningitis Table I
Immunoglobulin and complement levels in patient M K
(g/l)* IgM IgA IgG C3 C4 (% of normal)]Factor B Properdin Properdin converted (units/ml)~: C3
C4 C5 C6 C7 C8 C9 C3-C9
57
Patient MK, range
Controls, mean (+ 3 x s.d.)
I'9C-2"85 3"lO-4'25 IO'8O--I4"2o o- 12-o.28 o. I2--o.zo
I'33 (_+ I'O5) 2"39 (-+ 4"I I) I2"84 (-+4"95) 0'86 (+0'45) o'3I (_+0"33)
46-66 53-5o 83-83
82 (+ 26) 84 (_+24) 88 (_+27)
29--11o 597o-1174 ° 825-974
300 3oooo ( -+20oo0) 1ooo I9oo 6oo 95o 3 IOO 15° ( _ 50)
I552--1688
654-718 9o9-I I24 1378-r347 16--64
* Samples 4 to 9 (Table II), immunochemical determination 8with plates and standards from Behringwerke, Marburg Lahn, West Germany. t Samples 8 and 9 (Table II), immunochemical determination kindly performed by R. E. Spitzer, Department of Pediatrics, Upstate Medical Center, Syracuse, New York. Samples 8 and 9 (Table II), haemolytic titres kindly determined by R. E. Spitzer, Department of Pediatrics, Upstate Medical Center, Syracuse, New York. C4 (o" I7 g/l), a b o u t 50 p e r cent o f normal. E q u a l l y low values were obt ai ned w h e n these c o m p o n e n t s w e r e d e t e r m i n e d as haem ol yt i c units, and the total h a e m o l y t i c titre varied f r o m I x to 43 pe r cent o f normal. F u r t h e r m o r e , a b o u t h alf n o r m a l values were m e a s u r e d for C9, factor B and p r o p e r d i n , whereas the o t h e r late c o m p l e m e n t c o m p o n e n t s , C5, C6, C7 and C8 as well as p r o p e r d i n convertase were nor m al . T h e r e d u c e d values were consistently seen in several s e r u m samples taken u p to r8 m o n t h s after the meningitis. Specific antibodies to the g r o u p A m e n i n g o c o c c a l capsular polysaccharide m e a s u r e d b y r a d i o i m m u n o a s s a y ( T a b l e II) were very low in a n u m b e r of M K s e r u m samples taken after g r o u p A vaccination b u t before the g r o u p A meningitis or at various times after the meningitis. At each time t hey were b elo w the 95 p e r cent limits o f controls after vaccination or r e c o v e r i n g f r o m meningitis. 9-11 A n increase in the s e r u m antibodies was actually seen in M K sera only t h r e e to f o u r m o n t h s after the meningitis, and only at this time was th er e significant antigen b i n d i n g capacity in the I g G fraction. N o r m a l l y , I g G is the p r e d o m i n a n t class o f a n t i b o d y f o u n d t hree weeks after m eni ngococcal vaccination. 9 R e v a c c i n a t i o n with g r o u p A + C m e n i n g o c o c c a l polysaccharide vaccine 19 m o n t h s after t he last meningitis episode resulted in only a m i ni m al rise in an ti- A antibodies. T h e a n t i - g r o u p C p o l y s a c c h a r i d e a n t i b o d y levels in the M K sera f r o m I975
58
E. HERVA E T A L .
T a b l e II Specific antibodies to the meningococcal group A capsular polysaccharide
in patient M K and vaccinated controls Anti-group A polysaccharide #g/ml (predominant Ig class)t Sample Time of number sampling I 2 3 4 5 6 7 8 9
27 Oct. I975 14 Nov. 1975 22 Nov. i975 2 Dec. 1975 9 Jan. 1976 io Feb. 1976 11 Nov. 1976 3 June 1977 28 June 1977
In relation to meningitis* Before 3 days after 1I days after 2I days after 2 months after 3 months after 1 year after I~ years after 1~ years after
In relation to vaccination 2 weeks after:~ 4 weeks after 5 weeks after ~ weeks after 3 months after 4 months after 1 year after I½ years after 4 weeks after revaccinations§
Patient 3.64 1.6o (IgA) 3"IO (IgA) 3'I4 (IgM) 5'82 (IgG) 8-00 4'9o (IgA, M) 4"1o 5"80
Controls --
19"55 (IgG)
II'74 (IgG) w
* Caused by N. meningitidis group A. ~f Antibody determination by radioimmunoassay for total antigen binding capacity11and for antigen binding by Ig classes A, M, and G; 9 controls were 3o0 recruits to the Finnish Armed Forces9,11 who had received the group A meningococcal vaccine. ~: Group A meningococcal polysaccharide vaccine. § Group A + C meningococcal polysaccharide vaccine. to 1977, one to three years after the previous meningitis caused by group C meningococci, were low (o.8 to 2.o # g / m l ) , close to the m e a n (o'5 # g / m l ) in a normal population w i t h o u t previous group C infection. Vaccination in J u n e 1977 resulted in a response to the level of 11-o9 # g / m l while 86 per cent of recruits who have received the same vaccine m o u n t a higher response (K~iyhty, m a n u s c r i p t in preparation). T h e patient had shown no other identified susceptibility to infections. Consistent with this, we f o u n d n o r m a l levels of antibodies to several p n e u m o coccal polysaccharides (measured by r a d i o i m m u n e assay 1~ to types I, 2, 3, 4, 7F, 8, 9N, I 2 F , I4, IBC, I 9 F , 23F and 25) and a normal response to vaccination with the I4-valent pneumococcal polysaccharide vaccine (Pneumovax ®, Merck, Sharp and D o h m e , R a h w a y , Pa) and an influenza virus vaccine (kindly measured by R. Pyh/il/i, Central Public H e a l t h L a b o r a t o r y , Helsinki, F i n l a n d , by the haemagglutination inhibition technique to strains o f antigenic types H s w l N I and H 3 N 2 ). T h e parents and three siblings of M K showed none of the abnormalities of M K , and were not prone to infections. T h e C3 level in their sera varied between o'7o and 1.o8 g / l , and they all had relatively high pre-vaccination levels of antigroup A polysaccharide antibodies (mean 5"16 # g / m l ; normal m e a n 2 # g / m l ) and r e s p o n d e d well to vaccination. Discussion
T h e patient M K described appears to have a peculiarly selective increased susceptibility to meningococcal infections. His initial episode was caused by
Recurrent meningococcal meningitis
59
group A at a time of a group A meningococcal epidemic in the country; however, in I975 all recruits to the A r m e d Forces received the group A vaccine, and only two cases were seen among 3000o men. M K was one of them, the other had severe h y p o g a m m a g l o b u l i n a e m i a (H. Peltola, H. K/iyhty, and P. H. Mfikel/i, m a n u s c r i p t in preparation). T h e two previous meningitis episodes of M K were unrelated to epidemics. W e f o u n d b o t h r e d u c e d levels of several c o m p o n e n t s of the c o m p l e m e n t system and r e d u c e d responses to some bacterial polysaccharides in the patient. T h e c o m p l e m e n t defects were, however, only partial, which is surprising since increased susceptibility to infections has usually been linked with a more or less complete lack of a c o m p l e m e n t component, C3 TM 14 or C6 to 83-5, whereas persons with half-normal values have been healthy. 13 H o w e v e r , the patient described b y T h o m p s o n and L a c h m a n n 6 w h o suffered episodes of b o t h p n e u m o c o c c a l and meningococcal meningitis had approximately one third of normal s e r u m hemolytic capacity and one third of normal C3, which are values not far from those in our patient. T h e i r patient also had other abnormalities of the c o m p l e m e n t system: r e d u c e d factor B and p r o p e r d i n (like our patient), as well as r e d u c e d C5 and C7 and absent C 3 b inhibitor ( K A F ) which was t h o u g h t to be the p r i m a r y defect. O u r patient had normal C5 and C7 b u t r e d u c e d C4 and C9; C 3 b inhibitor was not measured. In b o t h these patients the susceptibility to infection was selective. T h e impaired ability of our patient to m o u n t an i m m u n e response to the capsular polysaccharides of meningococci either after infection or vaccination suggests a possible mechanism of his restricted susceptibility. Because c o m p l e m e n t and antibody act together in phagocytosis as well as in direct killing of bacteria, which is possibly m o r e important in meningococcal infections, a relative deficiency of b o t h could have a synergistic effect on the anti-infectious defence. T h o m p s o n and L a c h m a n n ' s patient was s h o w n to lack anti-meningococcal activity in convalescent serum, m e a s u r e d b y a less sensitive c o m p l e m e n t fixation assay. 6 An interesting question is whether our patient's poor antibody response was causally related to his c o m p l e m e n t defect and w h e t h e r this w o u l d account for only some a n t i b o d y specificities being affected. C o m p l e m e n t , especially C3, has indeed been implicated as participating in the induction of i m m u n e responses. 23 (This study was partially supported by United States Public Health Service contract No. I AI 52502 from the National Institute of Allergy and Infectious Diseases, U.S.A. We wish to thank Drs Harry Feldman and Roger E. Spitzer, SUNY for kind advice and help.) References
I. WHO Study Group. Cerebrospinal meningitis control. WHO TechRep Ser I976; 588 : 1-29. 2. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. II. Development of natural immunity. J. Exp Med I969; Iz9: I327-I348. 3. Lira D, Gewurz A, Lint TF, Ghaze M, Sepheri B, Gewurz H. Absence of the sixth component of complement in a patient with repeated episodes of meningococcal meningitis. J Pediatr I976; 89:42-47 • 4. Lambert HP, Thompson RA, Jones DM, Fleck DG. Absence of the seventh complement component (C7) in a patient with recurrent meningococcal meningitis. J Infect I979; x: I9I-I94.
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E. HERVA E T A L .
5. Peterson BH, Lee TJ, Snyderman R, Brooks GF. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Ailed 1979; 9o : 917-92o. 6. Thompson RA, Lachmann PJ. A second case of human C3b inhibitor (KAF) deficiency. Clin Exp Immunol 1977; 27: 23-29. 7. M/ikel/i PH, K/iyhty H, Weckstr6m P, Sivonen A, Renkonen OV. Effect of group A meningococcal vaccine in army recruits in Finland. Lancet 1975; 2: 883-886. 8. Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. I n t J Immunochem I965; 2: 235-254. 9. K/iyhty H, Jousimies-Somer H, Peltola H, M/ikel/i PH. Antibody response to capsular polysaccharides of groups A and C Neisseria meningitidis and Haemophilus influenzae type b during bacteremic disease. J Infect Dis 1981 ; I43: 32-4I. IO. Kfiyhty H, Karanko V, Peltola H, Sarna S, Mfikelfi PH. Serum antibodies to capsular polysaccharide vaccine of group A Neisseria meningitidis followed for three years in infants and children. J. Infect Dis 198o; i42: 861-868. I i. M~ikel~iPH, Peltola H, Kfiyhty H. Polysaccharide vaccine of group A Neisseria meningitidis and Haemophilus influenzae type b: a field trial in Finland. J Infect Dis 1977; I36 (Suppl): $43-5o. 12. Schiffman G, Douglas RM, Bonner MJ, Robbins M, Austrian R. A radioimmunoassay for immunologic phenomena in pneumococcal disease and for the antibody response to pneumococcal vaccines. I. Method for the radioimmunoassay ofanticapsular antibodies and comparison with other techniques. J Immunol Methods 198o; 33: 133-144. I3. Grace HJ, Brereton-Stiles GG, Vos GH, Schonland M. A family with partial and total deficiency of complement C3. S Afr M e d J I976; 5o: I39-I4 o. 14. Alper CA, Abramson N, Johnston RB Jr, Jandl JH, Rosen FS. Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3). N EnglJ Med 197o; 282: 349-354. I5. Dukor P, Dietrich FM, Gisler RH, Schumann G, Bitter-Suermann D. Possible targets of complement action in B-cell triggering. In: Brent L, Holborow J, eds. Progress in immunology II, Vol. 3. Amsterdam: North-Holland Publishing Co., 1974: 99-1o9.
Recurrent meningococcal meningitis due to partial c o m p l e m e n t defects and poor anti-meningococcal antibody response Elja Herva, Maija Leinonen,* Helena K/iyhty,t P. Helena M/ikel/i t and Sanna-Liisa V e t o n i e m i - K o r h o n e n ~
National Public Health Institute, Oulu *Department of Medical Microbiology, University of Oulu ~fNational Public Health Institute, Helsinki ~Department of Medicine, University of Oulu, Finland Summary An otherwise healthy young man had three episodes of meningococcal meningitis within three years. The last episode was caused by group A, and occurred four weeks after the patient received group A vaccine, thus representing one of the very few failures of this vaccine. The specific susceptibility to meningococcal infections was connected with half-normal levels of several components of the complement system (C3, C4, C9, factor B, properdin), and reduced antibody responses to group A and group C meningococcal polysaccharides, but not to several other polysaccharide or protein antigens.
Introduction W e still do not k n o w w h y few people develop meningitis as a result of meningococcal infection while m a n y m o r e remain asymptomatic. S e r u m antibodies certainly play a role : polysaccharide vaccines protect efficiently against infection, 1 whereas subjects lacking bactericidal antibodies are susceptible. 2 C o m p l e m e n t defects also predispose to the d e v e l o p m e n t of meningitis; the fact that those with defects of the late c o m p l e m e n t c o m p o n e n t s C6, C7 or C8 are especially prone to infections caused b y Neisseria meningitidis and N. gonorrhoeae suggests that a n t i b o d y - and c o m p l e m e n t - m e d i a t e d killing of bacteria is an important defence against neisserial infections, a-6 Because of the generally low incidence of meningococcal disease, repeated attacks are likely to indicate special susceptibility, and help towards u n d e r standing the basis of it. W e present here our findings in a y o u n g man, w h o had three episodes o f meningococcal meningitis within three years, and has multiple b u t incomplete defects in b o t h his c o m p l e m e n t system and his i m m u n e response to two meningococcal polysaccharide antigens.
Case report First episode in February I973 M K , an 18-year-old farmer's son admitted to the University Central Hospital of O u l u had clinically typical purulent meningitis, with a leucocyte count of Requests for reprints: P. Helena Mfikel~i, National Public Health Institute, Mannerheimintie I66, SF-oo28o Helsinki 28, Finland. oi63-4453/83/oioo55 +06 $o2.oo/o
© ~983 The British Society for the Study of Infection
56
E. HERVA
ET AL.
65O0 x 106 per litre (85 per cent polymorphonuclears) in the cerebrospinal fluid (CSF). Culture from CSF yielded Neisseria meningitidis, which was not tested further. T h e patient responded well to intravenous penicillin plus cephalotine and was discharged after 16 days. S e c o n d e p i s o d e in O c t o b e r 1974
]QIK was admitted to the same hospital because of fever, vomiting, headache and respiratory symptoms but in good general condition with no nuchal rigidity or rash. His CSF had a leucocyte count of 389 x lO6 per litre (IOO per cent polymorphonuclears). N. meningitidis of serogroup C was isolated both from CSF and blood. T h e patient responded well to intravenous penicillin and was discharged after IO days. T h i r d e p i s o d e in N o v e m b e r 1975 M K had started his military service in Oulu on IO October 1975, and received on 15 October the usual 5o #g dose of group A meningococcal polysaccharide vaccine (Meningovax A ®, Merck, Sharp and Dohme, West Point, Pennsylvania) given in 1975 to all recruits to the Finnish Armed Forces. 7 On I I November, four weeks after the vaccination, he fell ill with the typical symptoms of meningococcal meningitis including a petechial rash; his general condition was good. T h e CSF contained 35ox lO6 leucocytes per litre (68 per cent polymorphonuclears). N. meningitidis of group A and resistant to > 5o # g / m l of sulphonamide was isolated from his CSF and nasopharynx. T h e patient became symptomfree after four days of penicillin plus gentamicin treatment and was discharged IO days after admission. Further information
According to both M K and his parents the episode of meningitis in 1973 was his first serious illness requiring admission to hospital, although he was described as always having been prone to febrile infections. After the third meningitis episode he was discharged from military service and has since been in good health, with no febrile infections, working as a farmer. His parents and three siblings had not shown special liability to infectious diseases. Specific i n v e s t i g a t i o n s
No organic predisposing factors were revealed in a thorough neurological and otorhinological examination after the third episode. Tests for phagocyte functions (response to chemotactic stimuli and engulfment plus intracellular killing of Staphylococcus aureus, kindly tested by D r P. Ruutu, Department of Bacteriology and Immunology, University of Helsinki) performed four weeks after the third episode gave normal results. T h e immunoglobulin levels 8 of several serum samples of M K taken before, during, and up to ~o months after the third episode were within normal range with IgA and I g M perhaps slightly elevated (Table I). By contrast, several components of the complement system were reduced in the serum of M K as compared to normal control sera of the same sex and age (Table I). Thus, the mean value of his C3 (o'23 g/l) was about ~5 per cent of normal, and that of
Recurrent meningococcal meningitis Table I
Immunoglobulin and complement levels in patient M K
(g/l)* IgM IgA IgG C3 C4 (% of normal)]Factor B Properdin Properdin converted (units/ml)~: C3
C4 C5 C6 C7 C8 C9 C3-C9
57
Patient MK, range
Controls, mean (+ 3 x s.d.)
I'9C-2"85 3"lO-4'25 IO'8O--I4"2o o- 12-o.28 o. I2--o.zo
I'33 (_+ I'O5) 2"39 (-+ 4"I I) I2"84 (-+4"95) 0'86 (+0'45) o'3I (_+0"33)
46-66 53-5o 83-83
82 (+ 26) 84 (_+24) 88 (_+27)
29--11o 597o-1174 ° 825-974
300 3oooo ( -+20oo0) 1ooo I9oo 6oo 95o 3 IOO 15° ( _ 50)
I552--1688
654-718 9o9-I I24 1378-r347 16--64
* Samples 4 to 9 (Table II), immunochemical determination 8with plates and standards from Behringwerke, Marburg Lahn, West Germany. t Samples 8 and 9 (Table II), immunochemical determination kindly performed by R. E. Spitzer, Department of Pediatrics, Upstate Medical Center, Syracuse, New York. Samples 8 and 9 (Table II), haemolytic titres kindly determined by R. E. Spitzer, Department of Pediatrics, Upstate Medical Center, Syracuse, New York. C4 (o" I7 g/l), a b o u t 50 p e r cent o f normal. E q u a l l y low values were obt ai ned w h e n these c o m p o n e n t s w e r e d e t e r m i n e d as haem ol yt i c units, and the total h a e m o l y t i c titre varied f r o m I x to 43 pe r cent o f normal. F u r t h e r m o r e , a b o u t h alf n o r m a l values were m e a s u r e d for C9, factor B and p r o p e r d i n , whereas the o t h e r late c o m p l e m e n t c o m p o n e n t s , C5, C6, C7 and C8 as well as p r o p e r d i n convertase were nor m al . T h e r e d u c e d values were consistently seen in several s e r u m samples taken u p to r8 m o n t h s after the meningitis. Specific antibodies to the g r o u p A m e n i n g o c o c c a l capsular polysaccharide m e a s u r e d b y r a d i o i m m u n o a s s a y ( T a b l e II) were very low in a n u m b e r of M K s e r u m samples taken after g r o u p A vaccination b u t before the g r o u p A meningitis or at various times after the meningitis. At each time t hey were b elo w the 95 p e r cent limits o f controls after vaccination or r e c o v e r i n g f r o m meningitis. 9-11 A n increase in the s e r u m antibodies was actually seen in M K sera only t h r e e to f o u r m o n t h s after the meningitis, and only at this time was th er e significant antigen b i n d i n g capacity in the I g G fraction. N o r m a l l y , I g G is the p r e d o m i n a n t class o f a n t i b o d y f o u n d t hree weeks after m eni ngococcal vaccination. 9 R e v a c c i n a t i o n with g r o u p A + C m e n i n g o c o c c a l polysaccharide vaccine 19 m o n t h s after t he last meningitis episode resulted in only a m i ni m al rise in an ti- A antibodies. T h e a n t i - g r o u p C p o l y s a c c h a r i d e a n t i b o d y levels in the M K sera f r o m I975
58
E. HERVA E T A L .
T a b l e II Specific antibodies to the meningococcal group A capsular polysaccharide
in patient M K and vaccinated controls Anti-group A polysaccharide #g/ml (predominant Ig class)t Sample Time of number sampling I 2 3 4 5 6 7 8 9
27 Oct. I975 14 Nov. 1975 22 Nov. i975 2 Dec. 1975 9 Jan. 1976 io Feb. 1976 11 Nov. 1976 3 June 1977 28 June 1977
In relation to meningitis* Before 3 days after 1I days after 2I days after 2 months after 3 months after 1 year after I~ years after 1~ years after
In relation to vaccination 2 weeks after:~ 4 weeks after 5 weeks after ~ weeks after 3 months after 4 months after 1 year after I½ years after 4 weeks after revaccinations§
Patient 3.64 1.6o (IgA) 3"IO (IgA) 3'I4 (IgM) 5'82 (IgG) 8-00 4'9o (IgA, M) 4"1o 5"80
Controls --
19"55 (IgG)
II'74 (IgG) w
* Caused by N. meningitidis group A. ~f Antibody determination by radioimmunoassay for total antigen binding capacity11and for antigen binding by Ig classes A, M, and G; 9 controls were 3o0 recruits to the Finnish Armed Forces9,11 who had received the group A meningococcal vaccine. ~: Group A meningococcal polysaccharide vaccine. § Group A + C meningococcal polysaccharide vaccine. to 1977, one to three years after the previous meningitis caused by group C meningococci, were low (o.8 to 2.o # g / m l ) , close to the m e a n (o'5 # g / m l ) in a normal population w i t h o u t previous group C infection. Vaccination in J u n e 1977 resulted in a response to the level of 11-o9 # g / m l while 86 per cent of recruits who have received the same vaccine m o u n t a higher response (K~iyhty, m a n u s c r i p t in preparation). T h e patient had shown no other identified susceptibility to infections. Consistent with this, we f o u n d n o r m a l levels of antibodies to several p n e u m o coccal polysaccharides (measured by r a d i o i m m u n e assay 1~ to types I, 2, 3, 4, 7F, 8, 9N, I 2 F , I4, IBC, I 9 F , 23F and 25) and a normal response to vaccination with the I4-valent pneumococcal polysaccharide vaccine (Pneumovax ®, Merck, Sharp and D o h m e , R a h w a y , Pa) and an influenza virus vaccine (kindly measured by R. Pyh/il/i, Central Public H e a l t h L a b o r a t o r y , Helsinki, F i n l a n d , by the haemagglutination inhibition technique to strains o f antigenic types H s w l N I and H 3 N 2 ). T h e parents and three siblings of M K showed none of the abnormalities of M K , and were not prone to infections. T h e C3 level in their sera varied between o'7o and 1.o8 g / l , and they all had relatively high pre-vaccination levels of antigroup A polysaccharide antibodies (mean 5"16 # g / m l ; normal m e a n 2 # g / m l ) and r e s p o n d e d well to vaccination. Discussion
T h e patient M K described appears to have a peculiarly selective increased susceptibility to meningococcal infections. His initial episode was caused by
Recurrent meningococcal meningitis
59
group A at a time of a group A meningococcal epidemic in the country; however, in I975 all recruits to the A r m e d Forces received the group A vaccine, and only two cases were seen among 3000o men. M K was one of them, the other had severe h y p o g a m m a g l o b u l i n a e m i a (H. Peltola, H. K/iyhty, and P. H. Mfikel/i, m a n u s c r i p t in preparation). T h e two previous meningitis episodes of M K were unrelated to epidemics. W e f o u n d b o t h r e d u c e d levels of several c o m p o n e n t s of the c o m p l e m e n t system and r e d u c e d responses to some bacterial polysaccharides in the patient. T h e c o m p l e m e n t defects were, however, only partial, which is surprising since increased susceptibility to infections has usually been linked with a more or less complete lack of a c o m p l e m e n t component, C3 TM 14 or C6 to 83-5, whereas persons with half-normal values have been healthy. 13 H o w e v e r , the patient described b y T h o m p s o n and L a c h m a n n 6 w h o suffered episodes of b o t h p n e u m o c o c c a l and meningococcal meningitis had approximately one third of normal s e r u m hemolytic capacity and one third of normal C3, which are values not far from those in our patient. T h e i r patient also had other abnormalities of the c o m p l e m e n t system: r e d u c e d factor B and p r o p e r d i n (like our patient), as well as r e d u c e d C5 and C7 and absent C 3 b inhibitor ( K A F ) which was t h o u g h t to be the p r i m a r y defect. O u r patient had normal C5 and C7 b u t r e d u c e d C4 and C9; C 3 b inhibitor was not measured. In b o t h these patients the susceptibility to infection was selective. T h e impaired ability of our patient to m o u n t an i m m u n e response to the capsular polysaccharides of meningococci either after infection or vaccination suggests a possible mechanism of his restricted susceptibility. Because c o m p l e m e n t and antibody act together in phagocytosis as well as in direct killing of bacteria, which is possibly m o r e important in meningococcal infections, a relative deficiency of b o t h could have a synergistic effect on the anti-infectious defence. T h o m p s o n and L a c h m a n n ' s patient was s h o w n to lack anti-meningococcal activity in convalescent serum, m e a s u r e d b y a less sensitive c o m p l e m e n t fixation assay. 6 An interesting question is whether our patient's poor antibody response was causally related to his c o m p l e m e n t defect and w h e t h e r this w o u l d account for only some a n t i b o d y specificities being affected. C o m p l e m e n t , especially C3, has indeed been implicated as participating in the induction of i m m u n e responses. 23 (This study was partially supported by United States Public Health Service contract No. I AI 52502 from the National Institute of Allergy and Infectious Diseases, U.S.A. We wish to thank Drs Harry Feldman and Roger E. Spitzer, SUNY for kind advice and help.) References
I. WHO Study Group. Cerebrospinal meningitis control. WHO TechRep Ser I976; 588 : 1-29. 2. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. II. Development of natural immunity. J. Exp Med I969; Iz9: I327-I348. 3. Lira D, Gewurz A, Lint TF, Ghaze M, Sepheri B, Gewurz H. Absence of the sixth component of complement in a patient with repeated episodes of meningococcal meningitis. J Pediatr I976; 89:42-47 • 4. Lambert HP, Thompson RA, Jones DM, Fleck DG. Absence of the seventh complement component (C7) in a patient with recurrent meningococcal meningitis. J Infect I979; x: I9I-I94.
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5. Peterson BH, Lee TJ, Snyderman R, Brooks GF. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Ailed 1979; 9o : 917-92o. 6. Thompson RA, Lachmann PJ. A second case of human C3b inhibitor (KAF) deficiency. Clin Exp Immunol 1977; 27: 23-29. 7. M/ikel/i PH, K/iyhty H, Weckstr6m P, Sivonen A, Renkonen OV. Effect of group A meningococcal vaccine in army recruits in Finland. Lancet 1975; 2: 883-886. 8. Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. I n t J Immunochem I965; 2: 235-254. 9. K/iyhty H, Jousimies-Somer H, Peltola H, M/ikel/i PH. Antibody response to capsular polysaccharides of groups A and C Neisseria meningitidis and Haemophilus influenzae type b during bacteremic disease. J Infect Dis 1981 ; I43: 32-4I. IO. Kfiyhty H, Karanko V, Peltola H, Sarna S, Mfikelfi PH. Serum antibodies to capsular polysaccharide vaccine of group A Neisseria meningitidis followed for three years in infants and children. J. Infect Dis 198o; i42: 861-868. I i. M~ikel~iPH, Peltola H, Kfiyhty H. Polysaccharide vaccine of group A Neisseria meningitidis and Haemophilus influenzae type b: a field trial in Finland. J Infect Dis 1977; I36 (Suppl): $43-5o. 12. Schiffman G, Douglas RM, Bonner MJ, Robbins M, Austrian R. A radioimmunoassay for immunologic phenomena in pneumococcal disease and for the antibody response to pneumococcal vaccines. I. Method for the radioimmunoassay ofanticapsular antibodies and comparison with other techniques. J Immunol Methods 198o; 33: 133-144. I3. Grace HJ, Brereton-Stiles GG, Vos GH, Schonland M. A family with partial and total deficiency of complement C3. S Afr M e d J I976; 5o: I39-I4 o. 14. Alper CA, Abramson N, Johnston RB Jr, Jandl JH, Rosen FS. Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3). N EnglJ Med 197o; 282: 349-354. I5. Dukor P, Dietrich FM, Gisler RH, Schumann G, Bitter-Suermann D. Possible targets of complement action in B-cell triggering. In: Brent L, Holborow J, eds. Progress in immunology II, Vol. 3. Amsterdam: North-Holland Publishing Co., 1974: 99-1o9.