M.C. Brouwer

Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis

Background: In this nationwide prospective cohort study, we evaluated the implementation of adjunctive dexamethasone therapy in Dutch adults with pneumococcal meningitis. Methods: From March 2006 through January 2009, all Dutch patients over 16 years old with community-acquired pneumococcal meningitis were prospectively evaluated. Outcome was classified as unfavorable (defined by a Glasgow Outcome Scale score of 1 to 4 points at discharge) or favorable (a score of 5). Clinical characteristics and outcome were compared with a similar nationwide cohort of 352 patients with pneumococcal meningitis from a previous period before guidelines recommended dexamethasone therapy (1998–2002). A multivariable prognostic model was used to adjust for differences in case mix between the 2 cohorts. Results: We evaluated 357 episodes with pneumococcal meningitis in 2006–2009. Characteristics on admission were comparable with the earlier cohort (1998–2002). Dexamethasone was started with or before the first dose of antibiotics in 84% of episodes in 2006–2009 and 3% in 1998–2002. At discharge, unfavorable outcome was present in 39% in 2006–2009 and 50% in 1998–2002 (odds ratio [OR] 0.63; 95% confidence interval [CI] 0.46–0.86; p = 0.002). Rates of death (20% vs 30%; p = 0.001) and hearing loss (12% vs 22%; p = 0.001) were lower in 2006–2009. Differences in outcome remained after adjusting for differences in case mix between cohorts. Conclusions: Dexamethasone therapy has been implemented on a large scale as adjunctive treatment of adults with pneumococcal meningitis in the Netherlands. The prognosis of pneumococcal meningitis on a national level has substantially improved after the introduction of adjunctive dexamethasone therapy. Classification of evidence: This study provides Class III evidence that dexamethasone (10 mg IV, given every 6 hours for 4 days started before or with the first dose of parenteral antibiotics) reduced the proportion of patients with unfavorable outcomes (Glasgow Outcome Scale score of 1 to 4) in the 2006–2009 cohort, as compared to the 1998–2002 cohort (39% vs 50%; OR 0.63; 95% CI 0.46–0.86; p = 0.002). Mortality rate (20% vs 30%; absolute risk difference 10%; 95% CI 4%–17%; p = 0.001) was also lower in 2006–2009.

Evidence that complement protein C1q interacts with C-reactive protein through its globular head region.

C1q acts as the recognition unit of the first complement component, C1, and binds to immunoglobulins IgG and IgM, as well as to non-Ig ligands, such as C-reactive protein (CRP). IgG and IgM are recognized via the globular head regions of C1q (C1qGR), whereas CRP has been postulated to interact with the collagen-like region (C1qCLR). In the present study, we used a series of nine mAbs to C1q, five directed against C1qGR and four against C1qCLR, to inhibit the interaction of C1q with CRP. The F(ab′)2 of each of the five mAbs directed against C1qGR inhibited binding of C1q to polymerized IgG. These five mAbs also successfully inhibited the interaction of C1q with CRP. Moreover, these five mAbs inhibited C1 activation by CRP as well as by polymerized IgG in vitro. In contrast, none of the four mAbs against C1qCLR inhibited C1q interaction with CRP or IgG, or could reduce activation of complement by CRP or polymerized IgG. These results provide the first evidence that the interaction of C1q with CRP or IgG involves sites located in the C1qGR, whereas sites in the CLR do not seem to be involved in the physiological interaction of C1q with CRP.

ESCMID guideline: diagnosis and treatment of acute bacterial meningitis

D. van de Beek, C. Cabellos, O. Dzupova, S. Esposito, M. Klein, A. T. Kloek, S. L. Leib, B. Mourvillier, C. Ostergaard, P. Pagliano, H. W. Pfister, R. C. Read, O. Resat Sipahi and M. C. Brouwer, for the ESCMID Study Group for Infections of the Brain (ESGIB) 1) Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands, 2) Department of Infectious Diseases, Hospital Universitari de Bellvitge, Barcelona, Spain, 3) Department of Infectious Diseases, Charles University, Third Faculty of Medicine, Prague, Czech Republic, 4) Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy, 5) Department of Neurology, Klinikum Großhadern, Munich, Germany, 6) Institute for Infectious Diseases, University of Bern, Bern, Switzerland, 7) Department of Intensive Care Medicine, Groupe Hospitalier Bichat-Claude Bernard, Paris, France, 8) Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark, 9) Department of Infectious Diseases, “D. Cotugno” Hospital, Naples, Italy, 10) Department of Infectious Diseases, Southampton General Hospital, Southampton, United Kingdom and 11) Department of Infectious Diseases and Clinical Microbiology, Ege University, Izmir, Turkey

Presence of the variant mannose-binding lectin alleles associated with slower progression to Aids

Objective:To examine the association between mannose-binding lectin (MBL) polymorphism and progression to AIDS and death in HIV-1 infection. Design and methods:In 131 HIV-1-infected homosexual seroconverters, survival analyses were performed to determine both the association between MBL genotype and time from HIV-1 seroconversion to AIDS and death, and time from AIDS to death. Results:Of the 131 seroconverters, of whom 61 developed AIDS, 76 were typed as homozygous wild-type and 55 as carriers of variant alleles (52 heterozygous and three homozygous variant alleles). A Survival analyses suggested that HIV-1-infected men with the variant alleles progressed somewhat slower to AIDS [relative hazard (RH), 0.62; 95% confidence interval (CI), 0.36–1.10] and death (RH, 0.73; 95% CI, 0.42–1.25). Interestingly, CD4+ T-cell count determined at the moment of AIDS was found to be significantly lower among persons with the mutation (97 × 106/l versus 204 × 106/l; P = 0.03). Furthermore, when AIDS-free times before the diagnosis of an opportunistic infection were compared with those preceding a diagnosis of Kaposis sarcoma, Kaposis sarcoma diagnosis was more postponed than that of an opportunistic infection (RH, 0.21; 95% CI, 0.05–0.95; versus RH, 0.67; 95% CI, 0.35–1.27). Conclusion:Indications for a weak pre-AIDS protective effect of variant MBL alleles were demonstrated.

Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis.

Objective: To report an unusual clinical course in 6 patients with community-acquired acute bacterial meningitis and to compare clinical features with cases reported in the literature. Methods: Case series from Dutch hospitals from 2003 to 2008. Results: Five out of six patients were male, age ranged from 30 to 73 years (mean age, 47 years). All patients had pneumococcal meningitis, received adjunctive dexamethasone treatment on admission, and made a good or excellent initial recovery. After 7 to 19 days, patients suddenly deteriorated, developing headache, fever, a decreased level of consciousness, brainstem signs, or hemiparesis. Imaging studies showed infarctions involving the thalamus or brainstem in all patients. Repeated lumbar puncture showed a pleocytosis, but CSF cultures were sterile. Five patients were treated with high-dose steroids on deterioration. Outcome was poor: 4 patients died and 2 remained disabled. Autopsies, performed in 2 patients, showed infarctions predominantly involving the posterior circulation territory, thrombosis in penetrating arteries, but no evidence of vasculitis. We identified 5 meningitis cases with delayed vasculopathy in the literature, but these patients did not exactly resemble the clinical course of our patients. Conclusions: Delayed cerebral thrombosis may occur in patients with excellent recovery from pneumococcal meningitis. All patients were treated initially with adjunctive dexamethasone therapy, suggesting a dexamethasone-associated effect. Pathology suggests an immunologic reaction targeting cerebral blood vessels.

Hearing loss in adults surviving pneumococcal meningitis is associated with otitis and pneumococcal serotype

We assessed the incidence of hearing loss and its relationship with clinical characteristics and pneumococcal serotypes in adults surviving pneumococcal meningitis. We analysed hearing loss in 531 adults surviving pneumococcal meningitis included in two prospective nationwide cohort studies performed from April 1998 through to October 2002 and March 2006 through to January 2009. Hearing loss was evaluated on admission and discharge for all patients. Severe hearing loss was assessed by pure tone average on audiology and corrected for age, or by the combination of hearing loss on discharge and a score on the Glasgow Outcome Scale below 5, which could not be explained by other neurological sequelae. A total of 531 episodes of pneumococcal meningitis with non-lethal outcome were included. Predisposing conditions for pneumococcal meningitis were present in the majority of patients (64%), most commonly otitis (36%). Hearing loss was present at discharge in 116 patients (22%) and was classified as mild in 53% and severe in 47%. Hearing loss was related to otitis (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.66-4.02; p < 0.001) and inversely related to serotype 23 F infection (OR, 0.36; 95% CI, 0.13-0.98; p = 0.025), but not with parameters of disease severity or indicators of cerebrospinal fluid inflammation severity. Meningitis due to pneumococcal serotype 3 was associated with the highest rate of hearing loss. Hearing loss frequently complicates pneumococcal meningitis. Risk factors for hearing loss were infection with pneumococcal serotype 23 F and otitis, but not disease severity. Otitis and resulting perilympathic inflammation contribute to meningitis-associated hearing loss.

Decoding the Human Immunoglobulin G-Glycan Repertoire Reveals a Spectrum of Fc-Receptor- and Complement-Mediated-Effector Activities

Glycosylation of the immunoglobulin G (IgG)-Fc tail is required for binding to Fc-gamma receptors (FcγRs) and complement-component C1q. A variety of IgG1-glycoforms is detected in human sera. Several groups have found global or antigen-specific skewing of IgG glycosylation, for example in autoimmune diseases, viral infections, and alloimmune reactions. The IgG glycoprofiles seem to correlate with disease outcome. Additionally, IgG-glycan composition contributes significantly to Ig-based therapies, as for example IVIg in autoimmune diseases and therapeutic antibodies for cancer treatment. The effect of the different glycan modifications, especially of fucosylation, has been studied before. However, the contribution of the 20 individual IgG glycoforms, in which the combined effect of all 4 modifications, to the IgG function has never been investigated. Here, we combined six glyco-engineering methods to generate all 20 major human IgG1-glycoforms and screened their functional capacity for FcγR and complement activity. Bisection had no effect on FcγR or C1q-binding, and sialylation had no- or little effect on FcγR binding. We confirmed that hypo-fucosylation of IgG1 increased binding to FcγRIIIa and FcγRIIIb by ~17-fold, but in addition we showed that this effect could be further increased to ~40-fold for FcγRIIIa upon simultaneous hypo-fucosylation and hyper-galactosylation, resulting in enhanced NK cell-mediated antibody-dependent cellular cytotoxicity. Moreover, elevated galactosylation and sialylation significantly increased (independent of fucosylation) C1q-binding, downstream complement deposition, and cytotoxicity. In conclusion, fucosylation and galactosylation are primary mediators of functional changes in IgG for FcγR- and complement-mediated effector functions, respectively, with galactose having an auxiliary role for FcγRIII-mediated functions. This knowledge could be used not only for glycan profiling of clinically important (antigen-specific) IgG but also to optimize therapeutic antibody applications.

Antibodies to IgG4 hinge can be found in rheumatoid arthritis patients during all stages of disease and may exacerbate chronic antibody-mediated inflammation.

In rheumatoid arthritis (RA), autoantibodies such as anti–citrullinated protein antibodies (ACPAs) develop in response to neoepitopes that are formed under conditions of chronic inflammation. These autoantibodies may subsequently be fragmented by inflammation‐associated proteases, leading to the formation of F(ab′)2 fragments. The hinge of F(ab′)2 fragments can serve as a neoepitope, and so‐called antihinge antibodies (AHAs) can be found in RA patients, which might modulate the function of (fragmented) autoantibodies. We undertook this study to investigate the presence and specificities of AHAs in different stages of RA and to study their function.

Bacterial meningitis in pregnancy: report of six cases and review of the literature

Few cases of bacterial meningitis during pregnancy have been reported in the literature, and the causative microorganisms and prognosis of bacterial meningitis during pregnancy are unclear. In a 6-year period we identified six cases of bacterial meningitis in pregnant women. All were multigravida and gestational age at presentation ranged from 5 to 39 weeks. Predisposing factors were present in five patients and consisted of otitis in four patients. The causative organism was Streptococcus pneumoniae in all patients. Two patients died, both due to florid septic shock and brain herniation. Foetal outcome was good in five cases; one woman had a miscarriage 3 weeks after the episode of bacterial meningitis. We reviewed the literature on bacterial meningitis during pregnancy and identified 42 cases of bacterial meningitis. Twenty-five of these patients had pneumococcal meningitis and seven had meningitis caused by L. monocytogenes. We found that pneumococcal meningitis during pregnancy can be rapidly fatal and is associated with foetal death, especially in the first trimester. L. monocytogenes meningitis was associated with a high rate of neonatal deaths.

Benzalkonium tolerance genes and outcome in Listeria monocytogenes meningitis

Objectives Listeria monocytogenes is a food-borne pathogen that can cause meningitis. The listerial genotype ST6 has been linked to increasing rates of unfavourable outcome over time. We investigated listerial genetic variation and the relation with clinical outcome in meningitis. Methods We sequenced 96 isolates from adults with listerial meningitis included in two prospective nationwide cohort studies by whole genome sequencing, and evaluated associations between bacterial genetic variation and clinical outcome. We validated these results by screening listerial genotypes of 445 cerebrospinal fluid and blood isolates from patients over a 30-year period from the Dutch national surveillance cohort. Results We identified a bacteriophage, phiLMST6 co-occurring with a novel plasmid, pLMST6, in ST6 isolates to be associated with unfavourable outcome in patients (p 2.83e-05). The plasmid carries a benzalkonium chloride tolerance gene, emrC, conferring decreased susceptibility to disinfectants used in the food-processing industry. Isolates harbouring emrC were growth inhibited at higher levels of benzalkonium chloride (median 60 mg/L versus 15 mg/L; p <0.001), and had higher MICs for amoxicillin and gentamicin compared with isolates without emrC (both p <0.001). Transformation of pLMST6 into naive strains led to benzalkonium chloride tolerance and higher MICs for gentamicin. Conclusions These results show that a novel plasmid, carrying the efflux transporter emrC, is associated with increased incidence of ST6 listerial meningitis in the Netherlands. Suggesting increased disease severity, our findings warrant consideration of disinfectants used in the food-processing industry that select for resistance mechanisms and may, inadvertently, lead to increased risk of poor disease outcome.