Werner Zenz

Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease

Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D<E), P = 2.2 × 10−11) and in CFH-related protein 3 (CFHR3)(rs426736, P = 4.6 × 10−13). N. meningitidis is known to evade complement-mediated killing by the binding of host CFH to the meningococcal factor H–binding protein (fHbp). Our study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen.

Recombinant Tissue Plasminogen Activator Restores Perfusion in Meningococcal Purpura Fulminans

Objective: To investigate whether an Infusion of recombinant tissue plasminogen activator would dissolve microvascular thromboses and improve organ perfusion in a patient with fulminant meningococcemia. Design: Descriptive case report. Setting: Fifteen-bed pediatric intensive care unit (ICU) in a university hospital. Patient: A 4-month-old male with fulminant meningococcemia, refractory shock, and multiple organ failure. Interventions: In addition to standard aggressive ICU care, the patient received a recombinant tissue plasminogen activator infusion at a total dose of 1.25 mglkg over 4 hrs. Measurements and Main Results: Heart rate, arterial blood pressure, urine output, and base deficit (as a reflection of severity of metabolic acidosis) were recorded immediately before the recombinant tissue plasminogen activator infusion and 4 hrs later, after completion of the recombinant tissue plasminogen activator infusion. The amount of exogenous vasopressor and inotropic support required to maintain the patients hemodynamic status before and after recombinant tissue plasminogen activator infusion were also compared. Subjective observations regarding the patients peripheral perfusion status were also noted. The patient showed a dramatic improvement in hemodynamics, urine output, and metabolic acidosis, as well as a perceived increase in skin perfusion after recombinant tissue plasminogen activator infusion. Conclusions: In this patient, recombinant tissue plasminogen activator infusion resulted in improved organ perfusion and cardiac performance. Selective use of recombinant tissue plasminogen activator in the treatment of fulminant meningococcemia merits further investigation.

4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia

Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor-1 (PAI-1) is a characteristic feature of meningococcal sepsis. Previously, an association between mortality and the functional 4G/5G promoter polymorphism of the PAI-1gene in a cohort of UK and Dutch children with meningococcal sepsis was reported. We carried out a prospective, multicentre study to investigate the association of the 4G/5G PAI-1 polymorphism, diagnosis, and outcome in meningococcal disease in a Central European and UK population. Blood samples and clinical information of 347 previously healthy children with meningococcal infection were collected from 95 paediatric hospitals in Germany, Switzerland, Italy, the United Kingdom, and Austria from 2000 until 2002. Mortality was significantly associated with the 4G/4G genotype (12 of 90 (13%) vs. 15 of 240 (6%), P =0.037), resulting in an odds ratio of 2.31. The diagnosis of sepsis (independent of symptoms of meningitis) was significantly more frequent in carriers of the 4G/4G genotype (P =0.01), resulting in an odds ratio of 2.21 to develop sepsis. Meningitis was not associated with the PAI-1 4G/5G polymorphism, and allele frequencies were similar in patient and control groups. Conclusion:Our data show a correlation between the 4G/4G genotype in the plasminogen activator inhibitor-1 gene and poor outcome in children with meningococcal infection. In addition, 4G homozygous patients were prone to develop sepsis. We found no influence of the plasminogen activator inhibitor-1 polymorphism on the susceptibility to invasive meningococcal infection.

Use of recombinant tissue plasminogen activator in children with meningococcal purpura fulminans: a retrospective study.

Objective:Meningococcal disease causes septic shock with associated disseminated intravascular coagulation and hemorrhagic skin necrosis. In severe cases, widespread vascular thrombosis leads to gangrene of limbs and digits and contributes to morbidity and mortality. Uncontrolled case reports have suggested that thrombolytic therapy may prevent some complications, and the use of tissue plasminogen activator (t-PA) has been widespread. Our aim was to summarize the clinical outcome and adverse effects where systemic t-PA has been used to treat children with fulminant meningococcemia. Design:International, multiple-center, retrospective, observational case note study between January 1992 and June 2000. Setting:Twenty-four different hospitals in seven European countries and Australia. Patients:A total of 62 consecutive infants and children with severe meningococcal sepsis in whom t-PA was used for the treatment of predicted amputations and/or refractory shock (40 to treat severe ischemia, 12 to treat shock, and ten to treat both). Interventions:t-PA was administered with a median dose of 0.3 mg·kg−1·hr−1 (range, 0.008–1.13) and a median duration of 9 hrs (range, 1.2–83). Main Results:Twenty-nine of 62 patients died (47%; 95% confidence interval, 28–65). Seventeen of 33 survivors had amputations (11 below knee/elbow or greater loss; six less severe). In 12 of 50 patients to whom t-PA was given for imminent amputation, no amputations were observed. Five developed intracerebral hemorrhages (five of 62, 8%; 95% confidence interval, 0.5–16). Of these five, three died, one developed a persistent hemiparesis, and one recovered completely. Conclusions:The high incidence of intracerebral hemorrhage in our study raises concerns about the safety of t-PA in children with fulminant meningococcemia. However, due to the absence of a control group in such a severe subset of patients, whether t-PA is beneficial or harmful cannot be answered from the unrestricted use of the drug that is described in this report. Our experience highlights the need to avoid strategies that use experimental drugs in an uncontrolled fashion and to participate in multiple-center trials, which are inevitably required to study rare diseases.

Age-Dependent Association of Human Mannose-Binding Lectin Mutations With Susceptibility to Invasive Meningococcal Disease in Childhood

Background: Mannose-binding lectin (MBL) is an important factor of the innate immune system, and MBL-initiated complement activation is an important early defense mechanism against various bacterial infections, including invasive meningococcal disease. Methods: In a pediatric cohort (ages 2–215 months) with invasive meningococcal disease, we investigated the overall and age-stratified frequency of 3 MBL exon 1 variations (C154T, G161A, G170A), previously shown to result in markedly decreased MBL plasma concentrations, by allele specific fluorescent hybridization probe real-time PCR assays and direct sequencing. Healthy age-matched volunteers with the same ethnic background and no history of meningococcal disease served as a control group. Results: The overall frequency of a MBL exon 1 variant genotype was significantly higher in patients than in controls (31.8% vs. 8.2%, P < 0.001). In the patient group with disease onset less than 24 months of age, the prevalence of MBL structural variant genotype was further increased (39.3%; P < 0.001) and most pronounced in children with disease onset less than 12 months of age (57.1%; P < 0.001) when compared with healthy controls. Analysis of clinical severity and outcome revealed no significant difference between patients with wild-type and mutant alleles. Conclusions: Our data suggest that MBL exon 1 structural variants are significantly associated with susceptibility to childhood meningococcal disease in an age-dependent manner.

Tick-borne encephalitis in Styrian children from 1981 to 2005: a retrospective study and a review of the literature

Background: Tick‐borne encephalitis in children appears to be more benign than in adults and shows also a more favourable outcome. Only some authors report of sequelae like paralysis, paresis or seizures and behavioural abnormalities. The aim was to describe the clinical features of tick‐borne encephalitis in children with special attention to sequelae and to review the literature.

4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia

Summary.u2002 Background:u2002Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor‐1 (PAI‐1) is a characteristic feature of meningococcal sepsis. We and others have reported an association between mortality and the functional 4G/5G promoter polymorphism of the PAI‐1 gene in children with meningococcal sepsis. Objective:u2002Multicenter study to investigate the association of the 4G/5G PAI‐1 polymorphism and disseminated intravascular coagulation (DIC) in children with meningococcal disease in a Central European population. Patients/Methods:u2002Blood samples and clinical information of 326 previously healthy children with meningococcal infection were collected from 95 pediatric hospitals in Germany, Switzerland, Italy, and Austria from 2000 to 2002. Results:u2002DIC, defined as platelet counts below 100u2003Gu2003L−1, increased D‐dimer levels and prolonged prothrombin time, was significantly associated with the 4G4G genotype [31 of 63 (49%) vs. 55 of 175 (31%), Pu2003=u20030.014], resulting in a hazard ratio (HR) of 1.5 (95% confidence interval 1.1–2.1) to develop DIC. Carriers of the 4G4G genotype showed significantly lower platelet counts (183u2003Gu2003L−1 vs. 227u2003Gu2003L−1, Pu2003=u20030.009) on admission. Fibrinogen and C‐reactive protein levels were not associated with the PAI‐1 4G/5G polymorphism, nor were white blood cell counts. Conclusions:u2002Our data show a correlation between the 4G4G genotype of the PAI‐1 gene and development of DIC in meningococcal infection.

Tick-borne encephalitis in a 3-month-old child

Tick-borne encephalitis has not been reported in infants younger than 12 months of age. We report a 3.5-month-old child with a serologically proven tick-borne encephalitis. The infant had a history of a tick bite 3.5 weeks before the first symptoms of encephalitis appeared. The family lives in an endemic area of the disease. There were no prodromal signs and the course of the disease was monophasic. In an endemic area, prophylactic treatment with hyperimmunoglobulin after a tick bite should be considered even in very young infants, but in most children active immunization is probably not necessary because of infrequent exposure. Acitve immunization is still recommended after the 1st year of life.

Tick-borne encephalitis in children in Styria and Slovenia between 1980 and 2003.

Background: To describe the effect of the Austrian vaccination program against tick-borne encephalitis (TBE) on the incidence of this disease in children from Styria, an Austrian federal state, and to compare it with that in Slovenia, the neighboring country with a risk to acquire TBE similar to that of Styria. Methods: A retrospective population-based cohort study was performed with the use of discharge data from all Styrian pediatric hospitals and data from the Center for Communicable Diseases at the National Institute of Public Health in Ljubljana, Slovenia. Results: From January 1980 to December 2003, 139 cases of TBE in children younger than 16 years were observed in Styria. The annual incidence of TBE/100,000 Styrian children declined from 2.5–9.3 cases between 1980 and 1986 to 0–2.2 between 1987 and 1993 and to 0–1 between 1994 and 2003. Extrapolating the incidence of 6.3 cases/100,000 children between 1980 and 1986 to the time from 1994 to 2003, 124 pediatric TBE cases had been prevented in Styria in the past 10 years. Conclusions: Our data show that the Austrian vaccination program against TBE can lead to the nearly complete disappearance of TBE in children living in areas highly endemic for TBE.

CXCL13 chemokine in pediatric and adult neuroborreliosis

Wutte N, Berghold A, Löffler S, Zenz W, Daghofer E, Krainberger I, Kleinert G, Aberer E. CXCL13 chemokine in pediatric and adult neuroborreliosis. u2028Acta Neurol Scand: 2011: 124: 321–328. u2028© 2011 John Wiley & Sons A/S.