Properdin deficiency in a boy with fulminant meningococcal septic shock

Bacterial meningitis is a rare presentation for congenital immunodeficiency, but meningococcal invasive diseases and meningitis have been associated with late complement component deficiencies and properdin deficiency. A 5-y-old boy of non-consanguineous parents was admitted to our hospital with meningococcal septic shock. He had previously been suffering from recurrent respiratory infections. His 13-y-old brother had also been treated for meningococcal meningitis when he was 7 y old. Immunological studies, done after recovery, on the patient and his two brothers revealed normal immunoglobulin, IgG subclasses, C3, C4 and CH50 levels. Haemolytic activity of the alternative complement pathway could not be detected, and properdin concentrations were <0.01 mg/l in serum samples from the patient and his brothers. The patient and family members received quadrivalent polysaccharide meningococcal vaccine. The patient was discharged on penicillin prophylaxis, and he remained healthy during the ensuing year. Conclusion: Our findings stress that measurement of the haemolytic activity of the alternative complement pathway in addition to classical pathway haemolytic complement activity should be performed in patients with meningococcal disease to reveal various forms of complement deficiency. This is particularly important when there is a family history, or recurrences or infection due to uncommon serogroups. Deficient individuals and affected family members might be protected from infection by vaccination.     

Serum Haemolytic Classical and Alternative Pathways of Complement in Infancy: Age-Related Changes

Abstract. The haemolytic activity of complement was evaluated in the serum of healthy children from birth to 2 years of age using the kinetic method for the determination of the time needed to lyse 50 % of target red cells (t 1/2). No sex-linked differences were observed in any of the age groups studied and the lowest lytic activity levels for both complement pathways were detected in neonates. The two pathways, however, showed different maturation patterns, i. e., lytic activity levels similar to those of adults were reached between the 1st and 3rd month of life (classical pathway) and around the 13th month (alternative pathway). In the age group of 7 to 24 months, the lytic activity of the classical pathway was higher than in adults. The present data permitted us to establish normal ranges of t 1/2 values for the classical and alternative pathways in serum of healthy neonates and children aged 1 to 24 months.     

Serum haemolytic classical and alternative pathways of complement in infancy: age-related changes

The haemolytic activity of complement was evaluated in the serum of healthy children from birth to 2 years of age using the kinetic method for the determination of the time needed to lyse 50% of target red cells (t 1/2). No sex-linked differences were observed in any of the age groups studied and the lowest lytic activity levels for both complement pathways were detected in neonates. The two pathways, however, showed different maturation patterns, i.e., lytic activity levels similar to those of adults were reached between the 1st and 3rd month of life (classical pathway) and around the 13th month (alternative pathway). In the age group of 7 to 24 months, the lytic activity of the classical pathway was higher than in adults. The present data permitted us to establish normal ranges of t 1/2 values for the classical and alternative pathways in serum of healthy neonates and children aged 1 to 24 months.     

Evaluation of complement activation in premature newborn infants with hyaline membrane disease

Fifteen premature newborns with hyaline membrane disease causing acute respiratory distress were evaluated for complement activation. A high intrapulmonary right-to-left shunt and marked arterial-alveolar oxygen difference indicated the severity of the respiratory failure. Twenty preterm healthy infants served as controls. Total haemolytic activity, plasma concentrations of complement components and regulatory proteins (C3, C4, C1-inhibitor, factors H and I) as well as activation products (C3a, C3dg, C1rsC1-inhibitor, C3b(Bb)P) gave no evidence of significant complement activation. Functional activity of the ubiquitous regulatory protein C1-inhibitor was significantly reduced without impact on classical pathway activation. These data suggest that, in contrast to the adult form of respiratory distress syndrome, the low-pressure pulmonary oedema characterising hyaline membrane disease is not mediated by activation of the complement system.     

Complement activation in acute glomerulonephritis in children

Serial determinations of complement components (C1q, C4, C3, C5 and factor B) were performed in 32 children with acute glomerulonephritis. Low levels of C3 were found in 30 patients and low levels of C5 in 26. The findings of reduced C1q and/or C4 levels (25 patients) in the first days of the disease suggest activation of the classical pathway. Depressed Factor B levels were found rarely (4 patients). In all patients, the presence of a C3 splitting activity and/of a C3 nephritic factor-like activity was investigated. Both activities were demonstrated in 7 patients whereas in another patient, only C3 splitting activity was noted. A disappearance of both activities was observed in all patients. In 3 patients tested, the C3 nephritic factor-like activity was heat-labile and was therefore not related to true C3 nephritic factor. Both pathways are implicated in the early phases of the disease but continued C3 depression is probably through alternate pathway.     

Significance of immune complexes in children with severe hemophilia A in substitution treatment with factor VIII concentrates

Sera and EDTA-Plasma of patients with severe Haemophilia A were analysed for immune complexes and the hemolytic activity of complement in relation to Factor VIII replacement, in order to confirm or possibly exclude a relationship to allergic reactions. Immune complexes were isolated by PEG precipitation and quantitated. In addition a solid phase ELISA assay was used to detect complement-binding complexes. Total hemolytic complement activity of the classical and the alternate pathway was measured in addition to the C3 splitproduct C3d. The results obtained from 12 patients with severe Haemophilia A showed slightly increased immune complex titers, no changes of the immune complex levels during Factor VIII replacement and no alteration of the complement system following the infusions. One patient developed an allergic reaction without evidence of complement activation.     

Familial deficiency of the seventh component of complement associated with recurrent meningococcal infections

We describe an 11-year-old girl suffering from recurrent meningitis with a complete absence of the seventh component of complement (C7). Diagnosis was established by haemolytic titration and western blotting. The patient's serum lacked the 85 kDa C7 chain. Haemolytic activity of serum was reconstituted with either pooled normal human serum or with purified C7. The relatives (parents and one sister) had halfnormal levels of both immunochemically and functionally determined C7, indicating a heterozygous state for C7 deficiency.Abbreviation C7 seventh component of complement     

Deficient alternative complement pathway activity in newborn sera.

Neonatal susceptibility to overwhelming bacterial infection is commonly attributed to a relative deficiency in serum opsonic activity. However, few studies have compared the functional capacity of the classical complement pathway with that of the alternative complement pathway in the neonate. The opsonic activity of nine maternal infant serum pairs were studied by determining percent uptake of radiolabeled Escherichia coli. Seven mother-infant paired sera were studied using E. coli strains known to be opsonized via the alternative complement pathway: the mean percent uptake of E. coli opsonized in neonatal sera was 16.8%; of those opsonized in maternal sera, 54%; and of those opsonized in control sera, 45% (P less than 0.005). Two E. coli strains requiring the classical complement pathway for opsonization were phagocytized equally well in maternal and infant sera of seven mother-infant pairs. Determination of anti-O hemagglutination inhibition (HI) antibody titers in six maternal sera for one classical complement pathway activating and one alternative complement pathway strain showed no correlation between percent phagocytosis and HI antibody titer. These data would suggest that serum levels of classical pathway components are probably adequate for opsonization of E. coli via the classical pathway, but that low alternative complement pathway activity in neonatal sera may contribute to the newborn's increased susceptibility to bacterial sepsis.     

Defective yeast opsonisation and functional deficiency of complement in sickle cell disease.

Opsonisation of heat-killed baker''s yeast, functional activity of the total alternative pathway of complement, and factor B detected functionally and immunochemically were significantly reduced in 72 children with sickle cell disease compared with 40 age-matched black control children. There was significant correlation between functional activity of the total alternative pathway and functionally measured factor B, but not between factor B measured functionally and immunochemically. The opsonisation defect could be corrected in vitro by normal serum, and factor B-depleted serum, and was qualitatively similar to that seen in patients with primary yeast opsonisation deficiency. Serial studies showed that these serum defects were persistent. Reduction in the activity of components of the alternative pathway of complement and opsonisation was found in 4 patients who had recovered from pneumococcal meningitis and in one who developed osteomyelitis. Defects of yeast opsonisation and complement which are common in patients with sickle cell disease, may partly explain the children''s increased susceptibility to infection, and might help to identify individuals especially at risk.     

Fatal pneumococcal meningitis in a 1-year-old child with homozygous C2 deficiency

The 1-year old girl died of recurrent bacterial meningitis. Streptococcus pneumoniae was isolated from the cerebrospinal fluid. The analysis of the immune system revealed only a defect of the complement system. The following results were obtained: 1. No function of the classical complement pathway. 2. Reduced function of the alternative complement pathway. 3. No functional C2 activity. 4. No C2 protein. The parents had half normal C2 titers. HLA typing was only possible for the parents with the following results: A1, A32(w19), B18, DR2, DRw11(5) (father) and A3, A10, B18, B7, DR2 (mother). These data are compatible with a B18, DR2 haplotype of the child which is found in most cases of homozygous C2 deficiency. Our patient list another example for the high risk of recurrent severe infectious diseases in persons with a total complement defect.     

Activity of classical and alternative pathways of complement in preterm and small for gestational age infants

Complement activity was compared in 50 low birth weight infants divided into appropriate and small for gestational age groups; the influence of birth weight and gestational age on complement development was also investigated. CH50 and kinetics (tH50) of both classical and alternative pathway activity of complement, C3, and Factor B levels were significantly higher in small for gestational age infants (classical pathway CH50, 630 HU/ml +/- 184 SD; CP tH50, 77 min +/- 47; aternative pathway CH50, 44.8 HU/ml +/- 11.3; AP tH50, 56 min +/- 43; C3, 73.98 mg/dl +/- 12.68; and Factor B, 13.17 mg/dl +/- 3.67) than in weight-matched appropriate for gestational age infants (CP CH50, 523 HU/ml +/- 152; CP tH50, 105 min +/- 49; AP CH50, 38.8 HU/ml +/- 13; AP tH50, 90 min +/- 53; C3, 58.14 mg/dl +/- 9.43; and Factor B, 9.32 mg/dl +/- 1.73). Complement values were lower in low birth weight infants than in adult controls (P less than 0.001 in all cases). All complement parameters were mainly correlated with gestational age; CH50 values of the classical and alternative pathways were also highly correlated with each other (r = 0.64; P less than 0.001). Low birth weight infants, especially preterm infants, have an important defect of complement activity. Complement factors increase gradually during gestation and intrauterine growth retardation does not affect complement development. Classical and alternative complement pathway activities have a similar development pattern.     

Opsonic activity in serum from septic infants treated with intravenous immunoglobulin.

Thirteen infants with staphylococcal sepsis and reduced opsonic activity received infusions of acid treated immunoglobulin together with antibiotics. Opsonic activity (using Staphylococcus aureus (type 42D) as the test organism), haemolytic activity of complement, and concentrations of complement C3 and IgG were measured in serum prepared before and after three days of treatment with immunoglobulin at a dose of 250-300 mg/kg/day. There was increased ingestion of S aureus by normal human granulocytes in the presence of fresh serum prepared after infusion of immunoglobulin and significantly increased opsonic activity of heat inactivated serum after treatment with immunoglobulin. The haemolytic activity of complement and concentrations of complement C3 were not influenced, and serum concentrations of IgG increased as the result of receiving a total of 800-900 mg/kg immunoglobulin over a period of three days. This study shows that administration of acid treated IgG to septic infants leads to functionally increased opsonisation.     

Lyme Disease in a 12-year-old Girl

ABSTRACT. We report the case of a 12-year-old girl with erythema chronicum migrans, aseptic meningitis and knee arthralgia. Rise of specific antibody titre against an Ixodes ricinus spirochaete was demonstrated. Circulating immune complexes and high levels of Clr-Cis-CIIA complexes indicating activation of the complement system via the classical pathway were found. The clinical features and the laboratory findings warranted a diagnosis of Lyme disease.     

Lyme disease in a 12-year-old girl

We report the case of a 12-year-old girl with erythema chronicum migrans, aseptic meningitis and knee arthralgia. Rise of specific antibody titre against an Ixodes ricinus spirochaete was demonstrated. Circulating immune complexes and high levels of C1r-C1s-C1IA complexes indicating activation of the complement system via the classical pathway were found. The clinical features and the laboratory findings warranted a diagnosis of Lyme disease.     

Serum complement and immunoconglutinin in malnutrition.

Serum haemolytic complement activity and C3 were significantly decreased in 35 malnourished children. The changes were more pronounced in those with infection. Electrophoretically altered forms of complement C were detected in 14. There was an inverse correlation between C3 levels and immunoconglutinin titres. Nutritional rehabilitation and eradication of infection reversed the abnormalities. It is suggested that reduced complement function in malnutrition is the combined result of impaired synthesis, complement activation in vivo, and changes in plasma volume, and that it may contribute to an increased susceptibility to infection in undernourished individuals.     

Complement in cystic fibrosis

Quantitative and functional assessments were made of both the classical and alternative pathways of complement activation in sera from 23 patients with cystic fibrosis. The classical pathway functioned similarly in patients and controls as measured by CH50 titre. Alternative pathway function, initiated in patient sera by incubation with inulin, was equal to that of controls as determined by cleavage of Factor B and C3, and by the consumption of terminal components. Factor B, however, was more readily activated in patient than in control sera. This rapid alteration of Factor B did not lead to accelerated or more extensive activation of the terminal complement components via the alternative pathway when assessed by C3 cleavage and the consumption of terminal components. Thus, a complement deficiency was not found. The importance of the easily activated Factor B is undefined.     

Yeast opsonisation and complement in children with liver disease. Analysis of 69 cases

Opsonisation of heat-killed bakers yeast and C3 and C4 concentrations were determined in sera from 69 children with liver disease and 39 controls as simple screening procedures for abnormalities in the complement system. Where significant defects in these moieties were encountered, the activity of the following was measured: total haemolytic complement, C4, C5, total alternative pathway, factor B and D activities were measured. Complement activation was detected by the presence of C3d in EDTA plasma samples. Yeast opsonisation, C3 and C4 concentrations and activities of all complement components measured were significantly (P less than 0.001) reduced in all of 10 children with fulminant hepatic failure (FHF) and six with chronic active hepatitis (CAH). There was no consistent relationship between complement deficiency and standard tests of liver function. C3 breakdown products were identified in plasma from five patients with CAH and complement deficiency but not in three patients with complement deficiencies associated with FHF. Complement concentration and activity improved in children recovering from FHF and in CAH treated by immunosuppressants. Yeast opsonisation index was raised significantly without parallel increase in C3 or C4 concentration in eight of nine children with biliary atresia before surgery and 11 of 13 with alpha-1-antitrypsin deficiency regardless of age or the presence of active liver disease. Yeast opsonisation indices became normal after successful surgery in patients with biliary atresia.     

Serum complement and immunoconglutinin in malnutrition

Serum haemolytic complement activity and C3 were significantly decreased in 35 malnourished children. The changes were more pronounced in those with infection. Electrophoretically altered forms of complement C were detected in 14. There was an inverse correlation between C3 levels and immunoconglutinin titres. Nutritional rehabilitation and eradication of infection reversed the abnormalities. It is suggested that reduced complement function in malnutrition is the combined result of impaired synthesis, complement activation in vivo, and changes in plasma volume, and that it may contribute to an increased susceptibility to infection in undernourished individuals.     

Defective activation of the alternative pathway of complement in patients with homozygous C2 deficiency: studies in two unrelated families

Selective homozygous deficiency of the second component of complement, C2, with increased susceptibility to infection was detected in five children of two unrelated families. Because the haemolytic activity of the alternative complement pathway (AP) was in the low normal range, we evaluated the AP activation pattern. Serum levels of factor B measured immunochemically and the haemolytic function of factor B were low normal. Levels of C3d were not increased. Activation products of factor B were undetectable indicating the absence of in vivo activation of AP. Activation of C3 in vitro by activators of the AP (zymosan A and lipopolysaccaride) was profoundly deficient in homozygous C2 deficiency while heterozygous carriers exhibited intermediate values. There was no correlation between serum levels of factor B and in vitro C3 activation. We conclude that defective AP activation may contribute to increased susceptibility to bacterial infections in some patients with homozygous C2 deficiency.     

Dynamics of inherent interactions between the classical and alternative pathways of complement activation in premature infants with suppurative-inflammatory diseases

Altogether 57 premature infants were examined. Of these, 15 presented with neonatal sepsis, 36 with local purulent infection (LPI) of different etiology, and 6 children were conventionally normal serving as control. Early activation of the alternative pathway of the complement system was shown by the patients as compared with control. The development of neonatal sepsis was attended by the increased role played by the classical pathway of complement activation. At the same time the course of LPI was characterized by differences in the degree of participation of the classical and alternative pathways in the antiinfectious defence of the neonates. It has been established that high activation of the alternative pathway seen in the premature children may be considered as a prognostic sign enabling one to classify them with the risk group in terms of the possibility of the development in them of an infectious process.