[Measles epidemic in a highly developed country: low mortality, high morbidity and extensive costs]. / Masernepidemie in der Zentralschweiz 2006-2009: Hohe Morbidität und Kosten.

BACKGROUND: Vaccination with 2 doses of > 95% of the population is necessary to eliminate measles. In Switzerland and especially in the central part, vaccine coverage is low (2006: 65%). This led 2006-2009 to a measles epidemic with thousands of cases and high costs. One death was noted in a formerly healthy 12 year old girl. PATIENTS AND METHODS: All measles cases, either hospitalized or reported to the authority, in the canton Lucerne between 2006 and 2009 were included. Course, complications, immunization rates and costs of the hospitalized children were analyzed. RESULTS: A total of 1 041 cases of measles were recorded; 758 (73%) were children < 16 years of age. 56 (6%) of the patients were admitted to hospital; half of them were children (n=26, admission rate 3.4%). Main complications were pneumonia with oxygen requirement (n=19), bacterial infections of the base of the skull (n=2) and acute measles encephalitis (n=3). One child each developed acute appendicitis and diabetes mellitus type 1. No death was noted. Median hospitalisation costs were 18 780 CHF. The surveillance system was incomplete: Every third admitted child was not reported to the authority. CONCLUSION: Due to low vaccine coverage measles still account for epidemics with high morbidity and extensive costs. Instant reporting of all cases is crucial for disease control. Early identification of persons at risk allows timely immunization. Switzerland will remain of central importance to eliminate measles in Europe by 2015.

Epidemiological and ornithological aspects of outbreaks of highly pathogenic avian influenza virus H5N1 of Asian lineage in wild birds in Germany, 2006 and 2007.

In Germany, two distinct episodes of outbreaks of highly pathogenic avian influenza virus of subtype H5N1 (HPAIV H5N1) in wild birds occurred at the beginning of 2006, and in summer 2007. High local densities of wild bird populations apparently sparked clinically detectable outbreaks. However, these remained restricted in (i) number of birds, (ii) species found to be affected, (iii) time, and (iv) location despite the presence of several hundred thousands of susceptible wild birds and further stressors (food shortage, harsh weather conditions and moulting). Northern and southern subpopulations of several migratory anseriform species can be distinguished with respect to their preference for wintering grounds in Germany. This corroborates viral genetic data by Starick et al. (2008) demonstrating the introduction of two geographically restricted virus subpopulations of Qinghai-like lineage (cluster 2.2.A and 2.2.B) into northern and southern Germany, respectively, in 2006. The incursion of virus emerging in 2007, found to be distinct from the clusters detected in 2006 (Starick et al., 2008), may have been associated with moulting movements. Intensive past-outbreak investigations with negative results of live and dead wild birds and of terrestrial scavengers excluded continued circulation of virus on a larger scale. However, persistence of virus in small pockets of local wild bird populations could not be ruled out resiliently. 1.5% of investigated sera originating from cats sampled at the epicentres of the Ruegen 2006-outbreak contained H5-antibodies. Passive monitoring was found to be highly superior to live bird surveillance when aiming at the detection of HPAIV H5N1 in wild birds (P < 0.0001).

Influence of MMR-vaccinations and diseases on atopic sensitization and allergic symptoms in Swiss schoolchildren.

The prevalence of asthma and allergic disease has increased in many countries. It has been proposed that vaccinations may contribute to the development of allergic disease by reducing clinical infections in infancy or through the direct IgE-inducing effects of the vaccines. Evidence for a potential role of immunizations in the development of allergic disease is scarce. Therefore the objective was to study the associations between vaccinations against measles, mumps and rubella (MMR), natural infections of these diseases and atopic sensitization to indoor and outdoor allergens and allergic symptoms in schoolchildren. The cross-sectional study including 1537 8(th) grade school children aged 13-15 years living in 10 communities across Switzerland was organized in the framework of an environmental health surveillance program within the School Health Services (Swiss Surveillance Program of Childhood Asthma and Allergies with respect to Air Pollution and Climate, SCARPOL). Main outcome measures were asthma and sneezing during pollen season assessed by parental questionnaires and atopic sensitization determined by IgE concentrations to various allergens. It was found that parents' reported history of measles or mumps was associated with a stronger immune response than two or more vaccinations against the respective infection (measles: geometric mean IgG titers (GMT) lU/ml (95% Cl) 2.8 (2.0-3.9) vs. 1.2 (1.0-1.4), mumps: GMT PE/ml (95% Cl) 16.3 (13.9-19.1) vs. 8.5 (6.1-11.7). With respect to atopic sensitization similar associations for exposure by natural MMR-infections or MMR-vaccinations were found: measles: OR (95% Cl) 1.02 (0.53-1.96) vs. 1.22 (0.69-2.16), mumps: 0.59 (0.38-0.93) vs. 0.79 (0.49-1.27), rubella: 0.93 (0.61-1.43) vs. 0.95 (0.66-1.37), respectively. Inverse relationships were found between the risk of asthma and a positive disease history or vaccination of measles 0.36 (0.14-0.91) vs. 0.45 (0.21-0.98) or a positive serum titer against measles 0.65 (0.35-1.20). From the present study can be concluded that exposure by MMR-vaccinations or natural MMR-infections in childhood does not increase the risk of sensitization to common allergens as well as to allergic respiratory diseases. MMR-vaccinations or natural MMR-infections are therefore an unlikely factor contributing to the increase in atopic disease in developed countries.

Role of current and childhood exposure to cat and atopic sensitization. European Community Respiratory Health Survey.

BACKGROUND: Clinical and population studies have shown that exposure and sensitization to allergens derived from furred pets, particularly cats, represent an important risk factor of allergic respiratory disease and also a significant risk factor for asthma. OBJECTIVE: In the framework of the multicenter European Community Respiratory Health Survey an analysis of the association of current and childhood exposure to cat with atopic sensitization to cat was conducted. METHODS: This study included cross-sectional data from 35 centers representing 16 countries. Altogether, 18,097 subjects were included, of whom 13,509 (75%) provided a blood sample for the measurement of specific IgE. Exposure data and data for potential confounders were extracted from an interviewer-led questionnaire. RESULTS: The prevalence of sensitization to cat (serum specific IgE >0.35 kU/L) was 9%. Among those who did not report allergic symptoms in the presence of pets or house dust, those who owned cats were significantly more likely to be sensitized to cats than were those who did not (odds ratio [95% confidence interval] 1.57 [1.20-2.06]. Childhood exposure to pets including cats was associated with lower sensitization to cats in adulthood, particularly among those with a positive family history of atopy (odds ratio [95% confidence interval] 0.68 [0.51-0.93]. Positive correlations were found between the community prevalence of cat and the prevalences of sensitization to cat, respiratory symptoms, physician-diagnosed asthma, and current asthma medication. CONCLUSIONS: Current cat ownership represents a significant risk for sensitization to cat if cats are allowed indoors. Our results support the hypothesis that childhood exposure to pets, including cats, might modulate immunologic mechanisms and reduce sensitization to cat in adulthood. The significant correlation found between the community prevalence of cat ownership and community prevalence of specific sensitization to cat represents the first documentation of such a relationship.

The role of antibody concentration and avidity in antiviral protection.

Neutralizing antibodies are necessary and sufficient for protection against infection with vesicular stomatitis virus (VSV). The in vitro neutralization capacities and in vivo protective capacities of a panel of immunoglobulin G monoclonal antibodies to the glycoprotein of VSV were evaluated. In vitro, neutralizing activity correlated with avidity and with neutralization rate constant, a measure of on-rate. However, in vivo, protection was independent of immunoglobulin subclass, avidity, neutralization rate constant, and in vitro neutralizing activity; above a minimal avidity threshold, protection depended simply on a minimum serum concentration. These two biologically defined thresholds of antibody specificity offer hope for the development of adoptive therapy with neutralizing antibodies.

The role of somatic mutation in the generation of the protective humoral immune response against vesicular stomatitis virus.

During most clinically relevant infections with cytopathic viruses, neutralizing antibodies are generated early, i.e., within the first week of infection. As early as 4 days after immunization of mice with vesicular stomatitis virus (VSV), a cytopathic virus closely related to rabies virus, hybridomas could be isolated that secreted virus-neutralizing IgGs. Such antibodies were devoid of somatic mutations, showed high binding avidities (approximately 10(9) M-1), and used V gene fragments predominantly belonging to the VHQ52 and VK19-28 families. In contrast, most secondary and hyperimmune response IgGs isolated 12 and 150 days after infection used several additional V gene combinations. These, which used the VHQ52/VK19-28 combination of early IgGs, were point mutated but showed only marginally enhanced binding avidities. Since all VHQ52/ VK19-28-positive IgGs bound to one subsite within the major antigenic site of VSV-G irrespective of the presence or absence of somatic point mutations, fine specificity diversification of secondary and hyperimmune responses was achieved by newly appearing V gene combinations.

Mapping of the dominant neutralizing antigenic site of a virus using infected cells.

Panels of neutralizing monoclonal antibodies (MAbs) and antisera to vesicular stomatitis virus of the serotype Indiana (VSV-IND) were generated in mice and rats. They were used in competition studies to map epitopes on the viral glycoprotein that are involved in virus neutralization. Since neutralizing antibodies bind to the viral glycoproteins on the surface of intact viruses and of infected cells, infected cells were used for measuring the binding of competing antibodies by cytofluorometric analysis. A single immunodominant neutralizing epitope was recognised by 90% (58) of the MAbs including all of strong neutralizing capacity. 10% (6) of the neutralizing MAbs that all exhibited low neutralizing titers recognised spatially closely related epitopes. This approach offers a convenient method to determine antibody interaction with complex conformational epitopes of membrane proteins.

Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity.

Affinity maturation of IgG antibodies in adaptive immune responses is a well-accepted mechanism to improve effector functions of IgG within 2 weeks to several months of antigen encounter. This concept has been defined mainly for IgG responses against chemically defined haptens. We have evaluated this concept in a viral system and analyzed neutralizing IgG antibody responses against vesicular stomatitis virus (a close relative of rabies virus) with a panel of monoclonal antibodies obtained early (day 6 or 12) and late (day 150) after hyperimmunization. These neutralizing IgG antibodies recognize a single major antigenic site with high affinities (Ka of 10(8)-10(10) liter.mol-1) and with rapid on-rates already on day 6 of a primary response and with no evidence for further antigen dose- and time-dependent overall improvement of affinity. This type of IgG response is probably representative for viruses or bacterial toxins which are crucially controlled by neutralizing antibodies.

Analysis of the kinetics of antiviral memory T help in vivo: characterization of short-lived cross-reactive T help.

To evaluate the kinetics of functional effector and memory T help in vivo the effect of priming with one serotype of vesicular stomatitis virus-Indiana (VSV-IND) on the antibody response to a serologically distinct heterologous second serotype (VSV-New Jersey: VSV-NJ) was studied. Mice primed with VSV-IND 4 or 8 days before being given a second infection of VSV-NJ developed an earlier and enhanced IgG response to neutralizing determinants of the second VSV serotype. However, this enhanced response was not detected in mice primed 15 or more days prior to a second infection. After 15 days, mice challenged with the heterologous VSV-NJ mounted a strictly normal primary response without evidence of suppression. It was shown by in vivo time-kinetics experiments that efficient VSV cross-reactive T help, capable of enhancing the IgG response is short lived and cyclosporin A resistant. Adoptive transfer experiments demonstrated in the absence of experimental evidence for suppression that this short-lived capacity to enhance neutralizing IgG antibody responses is mediated by T cells. These findings have implications for understanding antiviral protection and immunological memory against related but serologically distinct viruses.

[Palliative biliodigestive anastomosis in non-resectable cancer of the head of the pancreas--with or without preventive gastroenterostomy?]. / Palliative biliodigestive Anastomose bei nicht resektablem Pankreaskopfkarzinom--mit oder ohne prophylaktische Gastroenterostomie?

In 226 patients with malignant obstructive jaundice over a 10-year period (1975-1984) 92 presented with an unresectable carcinoma of the head of the pancreas and were treated with a palliative bilioenteric diversion: in 52 cases alone, in 20 cases with a therapeutic gastroenterostomy because of early duodenal obstruction, and in 20 cases with a simultaneous prophylactic gastroenterostomy. The latter did not increase perioperative morbidity (25% vs. 50% in bilioenteric diversion alone), mortality (5% vs. 19%) nor length of hospital stay (19.9 vs. 20.6 days). Later on patients with a prophylactic gastroenterostomy showed a decreased incidence of chronic vomiting (15% vs. 42%). No secondary gastroenterostomy was performed in this group, vs. 14% (6 patients) in cases with bilioenteric diversion alone (mortality 33%). We recommend the simultaneous prophylactic gastroenterostomy which does not increase morbidity, mortality and length of hospital stay and helps avoiding a risky secondary gastroenterostomy.

An acquired immune suppression in mice caused by infection with lymphocytic choriomeningitis virus.

A murine model of virally induced acquired immunodeficiency was analyzed in mice. The effect of systemic infection with various isolates of lymphocytic choriomeningitis virus (LCMV) on the capacity of mice to mount a T cell-independent IgM and a T cell-dependent IgG neutralizing antibody response against a subsequent infection with vesicular stomatitis virus (VSV) was analyzed. DBA/2 mice infected with the LCMV-WE isolate were impaired in their IgM and IgG responses to VSV. Immune suppression was not caused by interferons inhibiting proper VSV antigen expression, since responses to inactivated VSV were also suppressed. The higher the dose of the LCMV and the lower the dose of the challenging VSV infection the more drastic was the apparent lack of immune responsiveness and the longer it lasted. Kinetics of induction of suppression of the T cell-independent IgM responses closely followed that of a normal cytotoxic T cell response to LCMV-WE, starting on day 6 and reaching maximal levels by day 8 to 10. The T cell-dependent IgG response to VSV was suppressed with a kinetics that was shifted by about 6 days when compared with suppression of IgM responses, i.e. LCMV infection on the same day or before (but not after) VSV infection led to suppression of IgG responses that are usually first detected by day 6-7 after initiation of the VSV infection. Severity and duration of immunosuppressiveness depended upon the LCMV isolate and the mouse strain used: LCMV-WE and LCMV-Docile were most, whereas LCMV-Armstrong was in general least immunosuppressive. Antibody responses to VSV-NJ seemed to be more subject to LCMV-induced immune suppression than VSV-IND-specific responses. Mouse strains differed considerably with respect to extent of suppression, dependent upon both major histocompatibility genes (MHC) and non-MHC genes. DBA and Swiss type mice were generally more susceptible than C57BL and CBA mice, and H-2q and H-2k seemed to be more susceptible than H-2b or H-2d mice. Mice infected with LCMV-WE showed signs of acquired immunodeficiency diseases since they were more susceptible to superinfection with VSV and developed paralytic disease and tended to die from VSV infection. Since LCMV is basically a noncytopathic virus, this murine model of virally induced immune suppression may serve to analyze immune pathogenesis of virus-induced acquired immunodeficiency.

A cause of right ventricular dysfunction after cardiac operations.

We examined the impact of mediastinal healing on right ventricular performance in three groups of five piglets by performing gated blood pool scans in two planes to determine right ventricular ejection fraction. Animals in Group I then had sternotomy and excision of anterior pericardium. Group II animals had a similar operation plus insertion of a silicone rubber sheet as a pericardial substitute. Group III animals (controls) had no operation. Each group was followed up for 60 days, after which gated blood pool scans were repeated in a manner identical to the initial study. Experimental animals in Groups I and II were then put to death and autopsied. Adhesion formation between the right ventricle and sternum was graded on a 0 to 3 scale. Group I animals showed a significant average decline in right ventricular ejection fraction of 19.2% (p less than 0.02). Group II animals demonstrated an average decrease in ejection fraction, although not significant, of 12.2%. Groups I and II combined showed a significant average loss in ejection fraction of 15.7% (p less than 0.01). Severity of adhesions between the right ventricle and sternum correlated well with loss of right ventricular ejection fraction (p less than 0.01). Group III controls demonstrated no significant change in ejection fraction. Mediastinal healing and fibrous attachment of the right ventricle to the sternum may play a significant role in loss of right ventricular ejection fraction after cardiac operations. Variability in loss of right ventricular ejection fraction is related to intensity of the mediastinal healing process.