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Neisseria infections associated with late complement component deficiency
B,cell function was studied by response to mitogens: In 9 out_ of !5 cases there was a subnormal prolifera-tire response without detectable immunoglobulin synthesis. In 5 cases, the cells underwent normal proliferation with intracellular immunoglobulin synthesis but did not secrete the immunoglobulin. In one case, the cells behaved normally in vitro when cultured in control media, but not when cultured in autologous serum. Furthermore, the serum of this patient inhibited allogenic B,cell antibody synthesis and inhibited T-cell proliferation to PHA. Ciccimarra (3) has postulated that in some cases the serum, immunoglobulin deficiency is due to a failure of immunoglobulin secretion, This may be secondary to a failure of heavy chain glycosy!ation, a required step prior .to excretion, A st~ppressor T, ce!! dysfunction has also been implicated, When studied by Wa!dman (13), cocu!|ures of lymphocy!es from patients with common variable !mmunodeficiency together with lymphocytes of normal individuals had abnormally low immunog!obu!in synthesis,
Thus, multiple etiologies of c0m-~ moo variable hypog-ammag!obu, !inemi-a are apparen..t, B ce!ls may be absent or unable to respond to .the normal stimuli. Immunoglobulin may be synthesized but not released. In addition, serum factors and suppressor cells may also have inhibitory effects on normal immunoglobulin synthesis,
References 1. Ament, M. E., and C. E. Rubin. 1972. Relation of giardiasis to abnormal intestinal structure and function in gas trointestina! immureddeficiency syndromes. Gast[o, ¢ntero!0gy 62:216-226. 2. Bruton, O, C, !952. A gammaglob, u!inemia. Pe_d!atrics 9;722-728. 3. Ciccimarra, F,, el a]. 1976. Failure of heavy chain, glyc0sy]afion of !gG !n some patients with common v~ai'iab!e agammaglobulinemia. J, Clin, I.~vest, 57;1386,!390, 4, Charache, P., F, S, _Rosen, and c. A, J.aneway, !965, Acqn!red agammaglobu!!nen3ia in siblings, Lancet I:234-237, 5, Geha, R. S,, et al. !974; Hete;o, geneitY of acqtfired or common v.ariable _agammaglobu!inem!a, N, Eng, J, M_ed, 291!!-6, 6. Gi!]ia, D,, W. _H, H!!zig, .and C, A. Janfway, 1956, M~ultip]eseru.m
protein deficiencies in congenital and C!in, I.nve.st, 35 1!99-!204, 7. Her_roans, P. E,, J, A. D!az,Bux o, and J. D, S!obo. |97& !diopathic Ia.te onset immun.oglobulin deficiency, Am, J. Med, 6h221.-237, 8, Hm'ow!tz, S, D.~ and R. Hone. !977, P, 48; The pathogen.esis and treat, ment " Karger ..... . . . . . . of . . .immunodeficiency. ........ .. S. AG, Basel, Sw!tzer!a.n.d, 9. Kersey, T. H,, B. D. Spector, .and R. A.. Good, !973. prim.a.ry!m.mt~nodeficiency diseases and cancer; The immunodgficiency-cancer regis.try, Br. J. Cancer 12:233-347. 10. P[.as.ad, A. S., E, Re!ner, .and .12. J. W.a~tson, ,1957. Sy0drorn_eof hypo~ gamm,aglcbuli~e~ia., sp!e~o.m.ega~].y and hypersp!enism. B]90.d 12; 927-9.32, !1, S_anford, J, P,, c, .B., Favour, and M, S. Trjbeman. !954, Absence of serum, ga!nmagl@u!in in ,an a~ol.t, .IX|, E.ng, J. ~eO, 250;|0.2%|029, !2. Twomey~ T: T,, A. H.. L.at~gh!er, .ana R, A. Good, 1970, The gastric d!s, order in immup.oglobu!!o de[~cient patients. Ann, !mern, ~e0, 72: 49%504, !3, Wa!dman, T. A., e! a]. !974: _Rc!e0.f SUPpressol"T ce[!s in. the pa!,h.0genes!s of comm0n variable .hyi~oga~maglobt~!ine.mia, Lancet _I!i609-6!3,
Case Reports
Neisseria Infections Associated with Late Complement Component Deficiency
Kathryn Kraus, M,D.* Monocomponent c omplement deficiencies have been discovered recently, Many of these have be e~ linked to clinical disorders, A c-ase of a ]ate complement component deficiency in association with Neisseria infection will be presented and discussed. A !6-year-old white male in good general health entered an emergency room wi.th complaints of malaise, headache, and abdominal pain of several hours duration, O n examination the patient was lethargic and *The universityaffiliationof Dr. Kraus can be found on p. 67.
hypotensive; a purpuric rash was noted over .the arms, legs, and .trpnk, Meningismps was absent, penicillin therapy was begun immediately, while blood and cerebrospinal fluid (CSF) cultures were not done url.t!! !he patient was .transferred to another hospi.tal. CSF ~examioati0n r_eveaLed a whffe blood copn.t of 2oO/mm ~ (a!l neutrophi!s), a red blood count of 222/mm', and slightly eleva.t.ed proLei0, NO 0rganisms were seen. Couoterimmunoe]ectrophor_esis for antigens of Neisseria meningi¢idis, Haemophi!us influenza¢ -and Sfrep: t.ococclts pneltlnoMae was negative. past medical histc~'y is significan.t only for dissemin.ated meningococ.cemia, .culture,positive, -at age !4. Family hbtory includes an aider brother who died suddenly at age !8 following 12 hours of malaise, fever,
and r~!sh over his entire body, T!aere is on history of inf_ect!ons or of cop, nec¢ive tissue diseases in o.ther f~ami!y members, The pafi¢0t did we!! wit• _co~a.t!nued p enici]lin .t.her-apy, co!t0res were negative, CH,0 assay was 10 u / m | (normal 40-85), A ssBy for c5, c6, c7, and C8 r ev~ea!ed abse.nce of C7, Family C7 sLudies were co0sjs.tent with an -au.tosomma!codominan.t pattern, TILe .-asso_ciati0nof )at_e co.m_p]e,m,ep..t compo,n,ept cl_eficiency and ,Neisseria infect!0n was first reporte.d in 1974 by Leddy (6) in on !8--year,9!d b!~a.c.k female wi!h syrup.toms of .Ray0aud's phe.n0m_en0n, p0!y~r.th_-a!gigswi.t.h swe!!i.ng of .the s.ma!] join.ts of .the hand.s and feet, and hemorrhagic infarc.ts of .the fingers, To eva!!Jate the possibilities of gonococcal ar-. 69
thritis and systemic lupus erythematosis, multiple synovial fluid cultures, tests for antinuclear antibodies, and serum complement assays were performed. The diagnosis proved to be gonococcal arthritis. The CHs0 assay was 5 U / m l (normal 80-160), provoking assays for individual complement components, which revealed absence o f C6. Complement levels were determined in members o f the patient's family. The alleles controlling the quantity of C6 appeared to be autosomal codominant. A patient with an undetectable level o f this component is homozygous for two abnormal genes, with the parents therefore being heterozygous; o f the stbs o f the propositus, one-quarter will be normal, one-half will be heterozygous but asymptomatic carriers of the abnormal allele, and one-quarter will be homozygous with two abnormal alleles. Secondly, in comparing the CH,0 and C6 levels, the 50070 C6 level o f the heterozygous state results in a normal CH~0. Therefore, as a screening test, CHso will only detect the complete deficiency state and will not determine the heterozygote. It was subsequently determined that any C6 level greater than 10070 o f normal is sufficient to allow a normal CHs0. A second case relating disseminated Neisseria infcctions to latc complement disorders is strikingly similar to the first one (I I). A 23-year-old female, again presenting with arthritis, was cvaluated for possible lupus. The patient proved to have disseminated gonococcus, her second documented episode, but the CHs0 titer was zero. Further studies documented a C8 deficiency. Again, family studies were consistent with an autosomal codominant trait. Other studies of this patient showed normal opsonization and chemotaxis. Bactericidal activity against staphylococcus was normal, but was lacking against Neisseria gonorrhoeae. This, however, could be corrected with addition o f purified C8. A third case report concerned a six-year-old boy who had three
70
Table 1 Summary of Nine Cases of Complement Deficiency Associated with Gonococcai (N.G.) or Meningococcal (N.M.) Infection
Reference Leddy (6) Petersen (11) Lira (8) McCarty (9) Lee (7) Gold (3) Clough (2)
Age
Sex
Frequency and Type o f Infection
18 23 6 21 27 29 6 5 15
F F M F M F M M M
N.G. x 2 N.G. x 2 N.M. x3 N.G. x 5 N.G. endocarditis x I N.G., N.M. x 1 (?) N.M.x l N.M.x I N.M. x 1
episodes o f meningococcal meningitis over several months (8). An extensive immunologic workup was initiated, but the only abnormality defined was a complete deficiency of C6. After a prolonged course of antibiotics, the patient recovered. Since 1976, six additional cases linking complement deficiency and Neisseria infections have been reported in the literature (1, 3, 7, 9). These are summarized in Table 1. Five had documented gonococcal infections and four had meningococcal disease. Deficiencies o f C5, 6, 7, and 8 have been noted, with C6 deficiency being the most frequent. Typically, the patients are young, with ages ranging from 6 to 29. This finding reflects the generally young population affected by these diseases. In all cases described, the patients were previously in good health and did not suffer from recurrent infections with other organisms. Most responded promptly to antibiotic therapy; no deaths were reported in these cases. The incidence of complement deficiency alone or associated with Neisseria infection is difficult to determine; obviously the combination is uncommon. In a Swiss study by Hassig (4), 41,000 healthy military recruits were screened ~with CHs0 tests; 14 had zero or near-zero levels, yielding an incidence of 0.034°7o for all complement deficiencies. In a study of 23 consecutive cases of dis-
Complement Deficiency 6 8 6 5 8 7 6 6 7
seminated Neisseria infections, Lee (7) discovered one case o f C6 and one case o f C7 deficiency. Thus, in a select population, late complement deficiencies may not be rare, perhaps warranting CH,0 screening o f this population. Petersen (10) summarized 24 cases with known deficiency o f C6, 7, or 8. Thirteen o f these had had at least one episode of Neisseria infection. The defect allowing Neisseria to proliferate appears to be related solely to the complement system. Antibody titers to Neisseria and bacterial opsonization are normal. Complement-mediated chemotaxis is also normal. The abnormality appears to lie in complementmediated cell lysis against Neisseria organisms. In most cases addition o f the deficient complement component will restore this function. Although lysis o f other gram-negative organisms may also be impaired, there is no increased incidence of infection with these organisms. Therefore, it could be postulated that the C5, 6, 7, 8, 9 " m e m b r a n e attack" unit is uniquely important in the defense against Neisseria infections. Finally, what can be offered to these patients? Clinically there is little to be done in the nonacute setting. Perhap the most important aspect o f care in these patients is advising them of their problem and stressing the importance o f immediate care if symptoms compatible with a Neis-
seria infection are noted. Meningococcal vaccine may be o f some value, although specific antibody production appears normal in these patients. Prophylactic penicillin therapy has not been evaluated. This, of course, would risk selection of a penicillinresistant organism. With acute Neisseria infection, prompt antibiotic treatment is essential. In an acutely ill patient, fresh-frozen plasma to replace the deficient component might be warranted. In summary, an absence of C5, C6, C7, or C8 predisposes to disseminated Neisseria meningococcal or gonococcal infections through an unknown mechanism. Although a rare disorder, patients presenting with these diseases should be screened for a complement deficiency. This deficiency is inherited with an autosomal codominant pattern. Treatment is limited to antibiotic therapy for the infecting organism. C o m m o n Variable H y p o g a m m a globulinemia
Kathryn Kraus, M.D. Bruce S. Rabin, M.D., Ph.D.* The patient is a 4.5-year-old white female with a history of frequent upper respiratory infections (URI) since several months of age. As a child, she developed chronic sinusitus and frequent urinary infections. Vitiligo was noted at age 7. Cystoscopy performed to evaluate urinary tract infections (UTI) at age 10 was normal, except for positive cultures of Staphylococcus attreus and S. epidermidis. Several congenital bony abnormalities were noted, including scoliosis with fusion of thoracic vertebrae 9, I0, and II, spina bifida occulta, and shortened fifth metacarpals. At age 20, serum protein electrophoresis revealed an absence of gamma globulins, and the patient was begun on monthly gamma globulin injections with a good clinical response (5). Serial gamma globulins are shown in Table 2. *The university affiliation of Drs. Rabin and Kraus can be found on p. 67.
Table 2 Summary of l m m u n o g l o b u l i n Levels (mg/dl)
Date 1970 2/72 12/73" 7/74 1/75 11/78 3/79 1/80 8/80
IgG
IgM
20 72 40 65 103 48 84 150 150
0 105 49 0 0 0 0 22 0
IgA 13 20 38 24 9 11.2 I1 16 14
*two weeks after gamma globulin injection In 1962, an episode of acute aplastic anemia followed chloramphenicol treatment for a UTI. The patient's hemoglobin fell to 5.5 g. Frequent transfusions, prednisone, and an anabolic steroid were required for the next six years. Diarrhea became a problem in 1969. Evaluation in 1970 (l) indicated malabsorption, with a fecal fat o f 10 g in 24 hr and a carotene of 45 ug/dl. Small bowel biopsy showed Giardia infection, and the patient was treated with metronidazole, with clinical improvement. At this time, the patient's vitiligo progressed to complete loss o f pigmentation of the skin and hair. Her hemoglobin and hematocrit were 10.1/29.7 with a mean corpuscular volume (MCV) of 102. Pernicious anemia was diagnosed by the Schilling test, and monthly vitamin B12 injections were begun. Since this time, the patient has received monthly injections o f human globulin and vitamin Bl2. However, she has had multiple hospital admissions for diarrhea, pulmonary infections, and urinary tract infections. In 1980, several minutes after receiving a gamma globulin injection, the patient suffered an anaphylactoid reaction of itching, wheezing and mild hypotension. She responded to treatment of solumedrol and benadryl. Anti-lgA and rheumatoid factor tests were negative. The patient has done well without gamma globulin for the past three months. A final diagnosis of common variable hypogammaglobulinemia was reached.
References 1. Ament, M. E., and C. E. Rubin. 1972. Relation of giardiasis to abnormal intestinal structure and function in gastrointestinal immunodeficiency syndromes. Gastroenterology 62:216-226. 2. Clough, J. D., el al. 1980. Familial late complement deficiency with chronic meningococcemia. Arch. Intern. Med. 140:929-933. 3. Gold, R. 1978. Absence of the sixth component of complement in a child with chronic meningococcemia. Pediatr. Res. 12:480. 4. Hassig, V. A., el al. 1964. Essential hypokomplementamie. Pathol. Microbiol. (Basel) 27:542-547. 5. Kuhns, W.J., and I. A. Solow. 1957. Agammaglobulinemia in a young female. Penn. Med. J. 60:621-623. 6. Leddy, J. P., et al. 1974. Hereditary deficiency of the sixth component of complement in man. J. Ciin. Invest. 53:544-553. 7. Lee, T. J., el al. 1978. Familial deficiency of the seventh component of complement associated with recurrent bacteremic infections due to Neisseria. J. Infect. Dis. 138:159-368. 8. Lim, D., et al. 1976. Absence of the sixth component of complement in a patient with repeated episodes of meningococeal meningitis. J. Pediatr. 89:42-47. 9. McCarty, G. A. 1978. Isolated deficiencies of the fifth and eighth components of complement in two families. J. lmmunol. 120(ii):1799. 10. Petersen, B. H., et al. 1979. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7 or C8 deficiency. Ann. Intern. Med. 90:917-920. 11. Petersen, B. H., J. A. Graham, and G. F. Brooks. 1976. Human deficiency of the eighth component of complement. J. Clin. Invest. 57:283-290.
71
Thus, multiple etiologies of c0m-~ moo variable hypog-ammag!obu, !inemi-a are apparen..t, B ce!ls may be absent or unable to respond to .the normal stimuli. Immunoglobulin may be synthesized but not released. In addition, serum factors and suppressor cells may also have inhibitory effects on normal immunoglobulin synthesis,
References 1. Ament, M. E., and C. E. Rubin. 1972. Relation of giardiasis to abnormal intestinal structure and function in gas trointestina! immureddeficiency syndromes. Gast[o, ¢ntero!0gy 62:216-226. 2. Bruton, O, C, !952. A gammaglob, u!inemia. Pe_d!atrics 9;722-728. 3. Ciccimarra, F,, el a]. 1976. Failure of heavy chain, glyc0sy]afion of !gG !n some patients with common v~ai'iab!e agammaglobulinemia. J, Clin, I.~vest, 57;1386,!390, 4, Charache, P., F, S, _Rosen, and c. A, J.aneway, !965, Acqn!red agammaglobu!!nen3ia in siblings, Lancet I:234-237, 5, Geha, R. S,, et al. !974; Hete;o, geneitY of acqtfired or common v.ariable _agammaglobu!inem!a, N, Eng, J, M_ed, 291!!-6, 6. Gi!]ia, D,, W. _H, H!!zig, .and C, A. Janfway, 1956, M~ultip]eseru.m
protein deficiencies in congenital and C!in, I.nve.st, 35 1!99-!204, 7. Her_roans, P. E,, J, A. D!az,Bux o, and J. D, S!obo. |97& !diopathic Ia.te onset immun.oglobulin deficiency, Am, J. Med, 6h221.-237, 8, Hm'ow!tz, S, D.~ and R. Hone. !977, P, 48; The pathogen.esis and treat, ment " Karger ..... . . . . . . of . . .immunodeficiency. ........ .. S. AG, Basel, Sw!tzer!a.n.d, 9. Kersey, T. H,, B. D. Spector, .and R. A.. Good, !973. prim.a.ry!m.mt~nodeficiency diseases and cancer; The immunodgficiency-cancer regis.try, Br. J. Cancer 12:233-347. 10. P[.as.ad, A. S., E, Re!ner, .and .12. J. W.a~tson, ,1957. Sy0drorn_eof hypo~ gamm,aglcbuli~e~ia., sp!e~o.m.ega~].y and hypersp!enism. B]90.d 12; 927-9.32, !1, S_anford, J, P,, c, .B., Favour, and M, S. Trjbeman. !954, Absence of serum, ga!nmagl@u!in in ,an a~ol.t, .IX|, E.ng, J. ~eO, 250;|0.2%|029, !2. Twomey~ T: T,, A. H.. L.at~gh!er, .ana R, A. Good, 1970, The gastric d!s, order in immup.oglobu!!o de[~cient patients. Ann, !mern, ~e0, 72: 49%504, !3, Wa!dman, T. A., e! a]. !974: _Rc!e0.f SUPpressol"T ce[!s in. the pa!,h.0genes!s of comm0n variable .hyi~oga~maglobt~!ine.mia, Lancet _I!i609-6!3,
Case Reports
Neisseria Infections Associated with Late Complement Component Deficiency
Kathryn Kraus, M,D.* Monocomponent c omplement deficiencies have been discovered recently, Many of these have be e~ linked to clinical disorders, A c-ase of a ]ate complement component deficiency in association with Neisseria infection will be presented and discussed. A !6-year-old white male in good general health entered an emergency room wi.th complaints of malaise, headache, and abdominal pain of several hours duration, O n examination the patient was lethargic and *The universityaffiliationof Dr. Kraus can be found on p. 67.
hypotensive; a purpuric rash was noted over .the arms, legs, and .trpnk, Meningismps was absent, penicillin therapy was begun immediately, while blood and cerebrospinal fluid (CSF) cultures were not done url.t!! !he patient was .transferred to another hospi.tal. CSF ~examioati0n r_eveaLed a whffe blood copn.t of 2oO/mm ~ (a!l neutrophi!s), a red blood count of 222/mm', and slightly eleva.t.ed proLei0, NO 0rganisms were seen. Couoterimmunoe]ectrophor_esis for antigens of Neisseria meningi¢idis, Haemophi!us influenza¢ -and Sfrep: t.ococclts pneltlnoMae was negative. past medical histc~'y is significan.t only for dissemin.ated meningococ.cemia, .culture,positive, -at age !4. Family hbtory includes an aider brother who died suddenly at age !8 following 12 hours of malaise, fever,
and r~!sh over his entire body, T!aere is on history of inf_ect!ons or of cop, nec¢ive tissue diseases in o.ther f~ami!y members, The pafi¢0t did we!! wit• _co~a.t!nued p enici]lin .t.her-apy, co!t0res were negative, CH,0 assay was 10 u / m | (normal 40-85), A ssBy for c5, c6, c7, and C8 r ev~ea!ed abse.nce of C7, Family C7 sLudies were co0sjs.tent with an -au.tosomma!codominan.t pattern, TILe .-asso_ciati0nof )at_e co.m_p]e,m,ep..t compo,n,ept cl_eficiency and ,Neisseria infect!0n was first reporte.d in 1974 by Leddy (6) in on !8--year,9!d b!~a.c.k female wi!h syrup.toms of .Ray0aud's phe.n0m_en0n, p0!y~r.th_-a!gigswi.t.h swe!!i.ng of .the s.ma!] join.ts of .the hand.s and feet, and hemorrhagic infarc.ts of .the fingers, To eva!!Jate the possibilities of gonococcal ar-. 69
thritis and systemic lupus erythematosis, multiple synovial fluid cultures, tests for antinuclear antibodies, and serum complement assays were performed. The diagnosis proved to be gonococcal arthritis. The CHs0 assay was 5 U / m l (normal 80-160), provoking assays for individual complement components, which revealed absence o f C6. Complement levels were determined in members o f the patient's family. The alleles controlling the quantity of C6 appeared to be autosomal codominant. A patient with an undetectable level o f this component is homozygous for two abnormal genes, with the parents therefore being heterozygous; o f the stbs o f the propositus, one-quarter will be normal, one-half will be heterozygous but asymptomatic carriers of the abnormal allele, and one-quarter will be homozygous with two abnormal alleles. Secondly, in comparing the CH,0 and C6 levels, the 50070 C6 level o f the heterozygous state results in a normal CH~0. Therefore, as a screening test, CHso will only detect the complete deficiency state and will not determine the heterozygote. It was subsequently determined that any C6 level greater than 10070 o f normal is sufficient to allow a normal CHs0. A second case relating disseminated Neisseria infcctions to latc complement disorders is strikingly similar to the first one (I I). A 23-year-old female, again presenting with arthritis, was cvaluated for possible lupus. The patient proved to have disseminated gonococcus, her second documented episode, but the CHs0 titer was zero. Further studies documented a C8 deficiency. Again, family studies were consistent with an autosomal codominant trait. Other studies of this patient showed normal opsonization and chemotaxis. Bactericidal activity against staphylococcus was normal, but was lacking against Neisseria gonorrhoeae. This, however, could be corrected with addition o f purified C8. A third case report concerned a six-year-old boy who had three
70
Table 1 Summary of Nine Cases of Complement Deficiency Associated with Gonococcai (N.G.) or Meningococcal (N.M.) Infection
Reference Leddy (6) Petersen (11) Lira (8) McCarty (9) Lee (7) Gold (3) Clough (2)
Age
Sex
Frequency and Type o f Infection
18 23 6 21 27 29 6 5 15
F F M F M F M M M
N.G. x 2 N.G. x 2 N.M. x3 N.G. x 5 N.G. endocarditis x I N.G., N.M. x 1 (?) N.M.x l N.M.x I N.M. x 1
episodes o f meningococcal meningitis over several months (8). An extensive immunologic workup was initiated, but the only abnormality defined was a complete deficiency of C6. After a prolonged course of antibiotics, the patient recovered. Since 1976, six additional cases linking complement deficiency and Neisseria infections have been reported in the literature (1, 3, 7, 9). These are summarized in Table 1. Five had documented gonococcal infections and four had meningococcal disease. Deficiencies o f C5, 6, 7, and 8 have been noted, with C6 deficiency being the most frequent. Typically, the patients are young, with ages ranging from 6 to 29. This finding reflects the generally young population affected by these diseases. In all cases described, the patients were previously in good health and did not suffer from recurrent infections with other organisms. Most responded promptly to antibiotic therapy; no deaths were reported in these cases. The incidence of complement deficiency alone or associated with Neisseria infection is difficult to determine; obviously the combination is uncommon. In a Swiss study by Hassig (4), 41,000 healthy military recruits were screened ~with CHs0 tests; 14 had zero or near-zero levels, yielding an incidence of 0.034°7o for all complement deficiencies. In a study of 23 consecutive cases of dis-
Complement Deficiency 6 8 6 5 8 7 6 6 7
seminated Neisseria infections, Lee (7) discovered one case o f C6 and one case o f C7 deficiency. Thus, in a select population, late complement deficiencies may not be rare, perhaps warranting CH,0 screening o f this population. Petersen (10) summarized 24 cases with known deficiency o f C6, 7, or 8. Thirteen o f these had had at least one episode of Neisseria infection. The defect allowing Neisseria to proliferate appears to be related solely to the complement system. Antibody titers to Neisseria and bacterial opsonization are normal. Complement-mediated chemotaxis is also normal. The abnormality appears to lie in complementmediated cell lysis against Neisseria organisms. In most cases addition o f the deficient complement component will restore this function. Although lysis o f other gram-negative organisms may also be impaired, there is no increased incidence of infection with these organisms. Therefore, it could be postulated that the C5, 6, 7, 8, 9 " m e m b r a n e attack" unit is uniquely important in the defense against Neisseria infections. Finally, what can be offered to these patients? Clinically there is little to be done in the nonacute setting. Perhap the most important aspect o f care in these patients is advising them of their problem and stressing the importance o f immediate care if symptoms compatible with a Neis-
seria infection are noted. Meningococcal vaccine may be o f some value, although specific antibody production appears normal in these patients. Prophylactic penicillin therapy has not been evaluated. This, of course, would risk selection of a penicillinresistant organism. With acute Neisseria infection, prompt antibiotic treatment is essential. In an acutely ill patient, fresh-frozen plasma to replace the deficient component might be warranted. In summary, an absence of C5, C6, C7, or C8 predisposes to disseminated Neisseria meningococcal or gonococcal infections through an unknown mechanism. Although a rare disorder, patients presenting with these diseases should be screened for a complement deficiency. This deficiency is inherited with an autosomal codominant pattern. Treatment is limited to antibiotic therapy for the infecting organism. C o m m o n Variable H y p o g a m m a globulinemia
Kathryn Kraus, M.D. Bruce S. Rabin, M.D., Ph.D.* The patient is a 4.5-year-old white female with a history of frequent upper respiratory infections (URI) since several months of age. As a child, she developed chronic sinusitus and frequent urinary infections. Vitiligo was noted at age 7. Cystoscopy performed to evaluate urinary tract infections (UTI) at age 10 was normal, except for positive cultures of Staphylococcus attreus and S. epidermidis. Several congenital bony abnormalities were noted, including scoliosis with fusion of thoracic vertebrae 9, I0, and II, spina bifida occulta, and shortened fifth metacarpals. At age 20, serum protein electrophoresis revealed an absence of gamma globulins, and the patient was begun on monthly gamma globulin injections with a good clinical response (5). Serial gamma globulins are shown in Table 2. *The university affiliation of Drs. Rabin and Kraus can be found on p. 67.
Table 2 Summary of l m m u n o g l o b u l i n Levels (mg/dl)
Date 1970 2/72 12/73" 7/74 1/75 11/78 3/79 1/80 8/80
IgG
IgM
20 72 40 65 103 48 84 150 150
0 105 49 0 0 0 0 22 0
IgA 13 20 38 24 9 11.2 I1 16 14
*two weeks after gamma globulin injection In 1962, an episode of acute aplastic anemia followed chloramphenicol treatment for a UTI. The patient's hemoglobin fell to 5.5 g. Frequent transfusions, prednisone, and an anabolic steroid were required for the next six years. Diarrhea became a problem in 1969. Evaluation in 1970 (l) indicated malabsorption, with a fecal fat o f 10 g in 24 hr and a carotene of 45 ug/dl. Small bowel biopsy showed Giardia infection, and the patient was treated with metronidazole, with clinical improvement. At this time, the patient's vitiligo progressed to complete loss o f pigmentation of the skin and hair. Her hemoglobin and hematocrit were 10.1/29.7 with a mean corpuscular volume (MCV) of 102. Pernicious anemia was diagnosed by the Schilling test, and monthly vitamin B12 injections were begun. Since this time, the patient has received monthly injections o f human globulin and vitamin Bl2. However, she has had multiple hospital admissions for diarrhea, pulmonary infections, and urinary tract infections. In 1980, several minutes after receiving a gamma globulin injection, the patient suffered an anaphylactoid reaction of itching, wheezing and mild hypotension. She responded to treatment of solumedrol and benadryl. Anti-lgA and rheumatoid factor tests were negative. The patient has done well without gamma globulin for the past three months. A final diagnosis of common variable hypogammaglobulinemia was reached.
References 1. Ament, M. E., and C. E. Rubin. 1972. Relation of giardiasis to abnormal intestinal structure and function in gastrointestinal immunodeficiency syndromes. Gastroenterology 62:216-226. 2. Clough, J. D., el al. 1980. Familial late complement deficiency with chronic meningococcemia. Arch. Intern. Med. 140:929-933. 3. Gold, R. 1978. Absence of the sixth component of complement in a child with chronic meningococcemia. Pediatr. Res. 12:480. 4. Hassig, V. A., el al. 1964. Essential hypokomplementamie. Pathol. Microbiol. (Basel) 27:542-547. 5. Kuhns, W.J., and I. A. Solow. 1957. Agammaglobulinemia in a young female. Penn. Med. J. 60:621-623. 6. Leddy, J. P., et al. 1974. Hereditary deficiency of the sixth component of complement in man. J. Ciin. Invest. 53:544-553. 7. Lee, T. J., el al. 1978. Familial deficiency of the seventh component of complement associated with recurrent bacteremic infections due to Neisseria. J. Infect. Dis. 138:159-368. 8. Lim, D., et al. 1976. Absence of the sixth component of complement in a patient with repeated episodes of meningococeal meningitis. J. Pediatr. 89:42-47. 9. McCarty, G. A. 1978. Isolated deficiencies of the fifth and eighth components of complement in two families. J. lmmunol. 120(ii):1799. 10. Petersen, B. H., et al. 1979. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7 or C8 deficiency. Ann. Intern. Med. 90:917-920. 11. Petersen, B. H., J. A. Graham, and G. F. Brooks. 1976. Human deficiency of the eighth component of complement. J. Clin. Invest. 57:283-290.
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