Jean Henrik Braconier

Hereditary C2 Deficiency in Sweden: Frequent Occurrence of Invasive Infection, Atherosclerosis, and Rheumatic Disease.

Abstract: Although frequently asymptomatic, homozygous C2 deficiency (C2D) is known to be associated with severe infections and rheumatic disease. We describe the clinical findings in 40 persons with C2D from 33 families identified in Sweden over 25 years. Medical records covering 96% of the accumulated person-years were reviewed, giving a mean observation time of 39 years (range, 1-77 yr). Severe infection was the predominant clinical manifestation in the cohort: 23 patients had a past history of invasive infections, mainly septicemia or meningitis caused by Streptococcus pneumoniae, and 12 patients had repeated infections of this kind. Nineteen patients had at least 1 episode of pneumonia, and recurrent pneumonia was documented in 10 patients. Repeated infections occurred mainly during infancy and childhood. Systemic lupus erythematosus was found in 10 patients. Another 7 patients had undifferentiated connective tissue disease (n = 4) or vasculitis (n = 3). We found no correlation between susceptibility to invasive infection and rheumatologic disease. Cardiovascular disease occurred at a high rate, with a total of 10 acute myocardial infarctions and 5 cerebrovascular episodes in 6 patients. Causes of death among the C2D patients were infection (n = 5), acute myocardial infarction (n = 3), and cancer (n = 1). We suggest that severe infection may be the principal clinical manifestation of C2D. We also provide novel evidence for a possible role of C2D in the development of atherosclerosis consistent with findings in mannan-binding deficiency and experimental C3 deficiency. In addition, we confirm the well-known association between C2D and systemic lupus erythematosus. Abbreviations: ACR = American College of Rheumatology, AMI = acute myocardial infarction, ANA = antinuclear antibodies, C2D = homozygous C2 deficiency, MASP = MBL-associated serine protease, MBL = mannan-binding lectin, MHC = major histocompatibility complex, PCR = polymerase chain reaction, SLE = systemic lupus erythematosus.

Interference ofStaphylococcus aureus lipase with human granulocyte function

The influence of purifiedStaphylococcus aureus lipase on granulocyte function and morphology was studied. The lipase itself was strongly chemotactic; in addition preincubation of granulocytes with low concentrations of lipase enhanced the directed movement, as assayed in the agarose system. Higher concentrations of lipase, in contrast, gave a progressive reduction of granulocyte chemotaxis; at 12µg lipase per ml, cells were almost immobilized. Phagocytic killing ofStaphylococcus aureus by granulocytes preincubated with lipase was reduced in a dose-dependent manner. At 12µg lipase per ml almost no staphylococcal killing occurred. This was mainly accounted for by a reduction of bacterial uptake, but some decrease in intragranulocytic killing was also noted. These functional alterations, which can all be ascribed to an interference with membrane functions, were associated with marked changes of the granulocyte surface structure, which was denuded and lacked normal microvilli. The effects of lipase were partly retained after heat inactivation of lipase activity, indicating that the effects of staphylococcal lipase on granulocyte function are not due to enzymatic activity alone. These effects of lipase may be an important virulence factor and contribute to the preferential location of lipase-productingStaphyloccus aureus strains at deep sites of infection.

Combined Alpha-interferon and Ribavirin Treatment in Chronic Hepatitis C: A Pilot Study

16 patients with chronic hepatitis C virus (HCV) infection were treated with a combination of interferon-alpha and ribavirin for 24 weeks in an open study. One patient declined further treatment due to depression after week 16 and did not complete further follow-up. A moderate decline was observed in hemoglobin and an increase in bilirubin level both reversible after discontinuing the treatment. 24 weeks after treatment cessation 9/15 (60%) evaluable patients had complete clearance of HCV-RNA as measured with PCR. HCV genotype did not seem to be correlated with response, but patients with sustained response to treatment had a significantly reduced number of HCV RNA copies/ml serum at treatment start compared with the other patients. These findings support the promising results of this combination therapy noted in other pilot studies.

Comparison of 3 Quantitative HCV RNA Assays - Accuracy of Baseline Viral Load to Predict Treatment Outcome in Chronic Hepatitis C

The correlation between 3 assays for hepatitis C virus (HCV) RNA quantification and their respective accuracy in predicting the response to interferon and interferon/ribavirin therapy was evaluated by analysing pre-treatment sera from 100 patients. A total of 97%, 100%, and 98% of the patients tested positive by the branched DNA 2.0 assay (Quantiplex), a multi-cycle reversed transcriptase polymerase chain reaction quantitative assay (Superquant) and the Roche Amplicor Monitor assay, respectively. The correlations between the assays, in all patients and in the major genotypes 1, 2, and 3, were significant, although the levels detected by the Amplicor Monitor assay were more than 1 log lower than by the other assays. Sustained virological responders to interferon therapy, but not to combination therapy, had lower baseline viral levels than long-term non-responders (p = 0.002 by Quantiplex 2.0; p = 0.008 by Superquant; p = 0.06 by Roche Amplicor Monitor). Pre-treatment viral load greater than 3 x 10(6) Eq or copies/ml by the Quantiplex 2.0 and Superquant assays and greater than 100,000 copies/ml by the Amplicor Monitor assay predicted long-term non-response in 94%, 93% and 91% of the interferon treated patients, respectively. In conclusion, acceptable correlations between available commercial quantitative assays were found. High baseline viral load predicted long-term non-response to interferon monotherapy, whereas it did not to interferon/ribavirin combination therapy.

Interference of Antibody Production to Hepatitis B Surface Antigen in a Combination Hepatitis A/Hepatitis B Vaccine

A randomized trial comparing 3 manufacturing consistency lots of a combination hepatitis A/hepatitis B vaccine to each other and to hepatitis A vaccine and hepatitis B vaccine given separately and concurrently was done to evaluate safety, tolerability, and immunogenicity. Healthy volunteers >/=11 years of age were divided into 4 groups. Each of 3 groups received a separate consistency lot of the combination vaccine, and 1 group received separate but concurrent injections of hepatitis A and hepatitis B vaccines. Injections were given at weeks 0 and 24. The combination vaccine was generally well tolerated. The hepatitis A portion of the combination vaccine produced clinically acceptable high seropositivity rates 4 and 52 weeks after the first injection. The hepatitis B portion of the vaccine did not produce clinically acceptable seropositivity rates 4 weeks after the second injection. Lack of antibody production may be attributed, at least in part, to immunologic interference.

Homozygosity for the IgG2 Subclass Allotype G2M(n) Protects against Severe Infection in Hereditary C2 Deficiency

Homozygous C2 deficiency (C2D) is the most common deficiency of the classical complement pathway in Western countries. It is mostly found in patients with autoimmune disease or susceptibility to bacterial infections and in healthy persons. We wished to assess to what extent other immunological factors might explain differences of susceptibility to infections in C2D. For this reason, 44 Swedish patients with C2D were stratified with regard to the severity of documented infections. Investigations of IgG subclass levels, IgG subclass-specific GM allotypes, concentrations of factor B, properdin, and factor H, and polymorphisms of mannan-binding lectin and the Fc receptors FcγRIIa and FcγRIIIb were performed. Homozygosity for the G2M*n allele, which is known to promote Ab responses to polysaccharide Ags, was strongly associated with the absence of severe infections (p < 0.001) in the patients, suggesting a major protective role. The combination of mannan (or mannose)-binding lectin and C2 deficiency was found to be a minor susceptibility factor for invasive infection (p = 0.03). Low concentrations of IgG2 and factor B might sometimes contribute to susceptibility to infection. Other factors investigated did not appear to be important. In conclusion, the findings indicated that efficient Ab responses to polysaccharides are protective against severe infection in C2D. Implications with regard to vaccination should be considered.

Immune response to tetravalent meningococcal vaccine: opsonic and bactericidal functions of normal and properdin deficient sera.

Neisseria meningitidis serogroup W-135 appears to be a fairly common cause of infection associated with properdin deficiency or dysfunction, and anticapsular antibodies might be protective in these patients. For this reason, bactericidal and opsonophagocytic activities for serogroup W-135 were investigated before and four weeks after vaccination of two properdin-deficient adults with tetravalent meningococcal vaccine. In addition, the response of IgM, IgG and IgA class antibodies to the serogroups A, C, Y and W-135 was determined by ELISA. There was no evidence of poor antibody responses in the properdin-deficient persons. Vaccination promoted classical pathway-mediated killing in serum and opsonization of serogroup W-135 to the same extent as that seen in vaccinated controls. The increase of alternative pathway-mediated killing in the properdin-deficient sera was moderate, but vaccination clearly enhanced alternative pathway-mediated opsonophagocytosis in the sera. It was also shown that vaccination markedly reduced the requirement for properdin in alternative pathway-mediated killing of the meningococci.

Fulminant Course of Infectious Mononucleosis with Virus-associated Hemophagocytic Syndrome

A fatal case of infectious mononucleosis due to serologically verified Epstein-Barr virus infection in a previously healthy 30-year-old man is presented. The clinical course was characterized by severe prostration, persistently high spiking fever, and continuous development of enlarged lymph nodes. Hematologic examination revealed peripheral leukopenia and thrombocytopenia, and in the bone marrow an increased number of benign histiocytes showed marked hemophagocytosis. At autopsy abnormal lymphoid infiltrates were present in several tissues. The pathogenesis of this infection-associated hemophagocytic syndrome is discussed in terms of the possibility of an impaired immune response to infectious agents.

Immunoglobulin Deficiencies and Impaired Immune Response to Polysaccharide Antigens in Adult Patients with Recurrent Community-acquired Pneumonia

The frequency of humoral immunodeficiencies was analysed in 39 patients with a history of recurrent (> or = 3) episodes of community-acquired pneumonia. Total immunoglobulin levels and/or IgG subclass levels were low in 14 patients (36%), including eight patients with IgG or IgG2 deficiency. The specific antibody activity to pneumococcal capsular polysaccharides (serotypes 3, 6A, 19F, and 23F) and to phosphorylcholine was low in the IgG/IgG2-deficient patients compared to 36 healthy controls, and they also responded poorly to vaccination with a 23-valent pneumococcal capsular polysaccharide vaccine. The remaining 25 patients, with normal immunoglobulin and IgG subclass levels, had specific anti-pneumococcal antibody levels comparable to the healthy controls, and all but 3 responded to vaccination. We conclude that immunoglobulin deficiencies and the inability to respond to polysaccharide antigens are common risk factors for recurrent pneumonia in adult patients. Immunoglobulin levels (including IgG subclasses) and antibody response to polysaccharide antigens should be investigated in these patients.

Abdominal Aortitis and Infected Aneurysms Due to Salmonella

Three cases of salmonella aortitis with rupture of the abdominal aorta were admitted to hospitals in a limited area of Southern Sweden during 18 months. Two patients with secondarily infected aneurysms died. One patient with a non-aneurysmal aortitis and retroperitoneal abscess is alive but still hospitalized 13 months after the accomplishment of an axillo-femoral by-pass. All 3 patients were elderly males without a history of recent foreign travel. The majority of salmonella patients in the area during the same time period were younger and had acquired the infection abroad. The epidemiology, diagnosis and treatment of salmonella aortitis is reviewed.