Effective control measures limited measles outbreak after extensive nosocomial exposures in January-February 2008 in Gothenburg, Sweden.

In January-February 2008, one imported case of measles initiated a series of exposures with around 380 nosocomial secondary contacts. Susceptible individuals were traced early and control measures were initiated that managed to limit the consequences considerably. Only four secondary cases were identified by the end of March. This minor outbreak illustrates the importance and efficiency of early control measures as well as the fact that the risk of measles outbreaks still exists in a country that has high measles, mumps, rubella vaccination coverage among children.

Differential expression of tissue-specific adhesion molecules on human circulating antibody-forming cells after systemic, enteric, and nasal immunizations. A molecular basis for the compartmentalization of effector B cell responses.

Expression of the adhesion molecules CD44, L-selectin (CD62L), and integrin alpha 4 beta 7 by antibody-secreting cells (ASC) was examined in human volunteers after oral, rectal, intranasal, or systemic immunization with cholera toxin B subunit. Almost all blood ASC, irrespective of immunization route, isotype (IgG and IgA), and immunogen, expressed CD44. On the other hand, marked differences were observed between systemically and intestinally induced ASC with respect to expression of integrin alpha 4 beta 7 and L-selectin, adhesion molecules conferring tissue specificity for mucosal tissues and peripheral lymph nodes, respectively. Thus, most ASC induced at systemic sites expressed L-selectin, whereas only a smaller proportion of ASC expressed alpha 4 beta 7. In contrast, virtually all IgA- and even IgG-ASC detected after peroral and rectal immunizations expressed alpha 4 beta 7, with only a minor fraction of these cells expressing L-selectin. Circulating ASC induced by intranasal immunization displayed a more promiscuous pattern of adhesion molecules, with a large majority of ASC coexpressing L-selectin and alpha 4 beta 7. These results demonstrate that circulating ASC induced by mucosal and systemic immunization express different sets of adhesion molecules. Furthermore, these findings provide for the first time evidence for differential expression of adhesion molecules on circulating ASC originating from different mucosal sites. Collectively, these results may explain the anatomical division of mucosal and systemic immune responses in humans as well as the compartmentalization of mucosal immune responses initiated in the upper vs. the lower aerodigestive tract.

[Infection a dreaded central venous catheter-related complication. A reminder of the significance of good aseptics is justified]. / Infektion en fruktad komplikation till användning av central venkateter. Motiverat att påminna om vikten av god aseptik.

The use of central venous catheters has increased markedly. Large numbers of patients are therefore at risk for catheter-related infections. This paper reviews the literature on prevention of intravascular catheter-related complications. Microbes colonising the catheter hubs and the skin around the insertion site are the source of most of these infections. By simple routines it is possible to reduce the risk for microbial spread from these sites to the bloodstream.

[Control of methicillin resistant staphylococci at the Sahlgrenska hospital. Successful control program against MRSA outbreak]. / Bekämpningen av meticillinresistenta stafylokocker på Sahlgrenska. Framgångsrikt kontrollprogram har hävt MRSA-utbrottet.

In 1998-1999 a strain of methicillin resistant Staphylococcus aureus (MRSA) infected 147 patients in 40 out of 160 ward units at Sahlgrenska University Hospital, Gothenburg. The strain originated from a patient who had been treated in a hospital in Cyprus. In order to control this outbreak a plan of action was decided upon and carried out, including extensive information to the hospital staff, screening for carriers, and establishing a hospital infection control committee. Furthermore, a policy for screening all patients readmitted to the hospital was established in November 1999. This screening could be discontinued on July 1, 2001.

Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein.

We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhea containing killed recombinant E. coli bacteria expressing increased levels of ETEC colonization factors (CFs) and a recombinant protein (LCTBA), i.e. a hybrid between the binding subunits of E. coli heat labile toxin (LTB) and cholera toxin (CTB). We describe a randomized, comparator controlled, double-blind phase I trial in 60 adult Swedish volunteers of a prototype of this vaccine. The safety and immunogenicity of the prototype vaccine, containing LCTBA and an E. coli strain overexpressing the colonization factor CFA/I, was compared to a previously developed oral ETEC vaccine, consisting of CTB and inactivated wild type ETEC bacteria expressing CFA/I (reference vaccine). Groups of volunteers were given two oral doses of either the prototype or the reference vaccine; the prototype vaccine was administered at the same or a fourfold higher dosage than the reference vaccine. The prototype vaccine was found to be safe and equally well-tolerated as the reference vaccine at either dosage tested. The prototype vaccine induced mucosal IgA (fecal secretory IgA and intestine-derived IgA antibody secreting cell) responses to both LTB and CFA/I, as well as serum IgA and IgG antibody responses to LTB. Immunization with LCTBA resulted in about twofold higher mucosal and systemic IgA responses against LTB than a comparable dose of CTB. The higher dose of the prototype vaccine induced significantly higher fecal and systemic IgA responses to LTB and fecal IgA responses to CFA/I than the reference vaccine. These results demonstrate that CF over-expression and inclusion of the LCTBA hybrid protein in an oral inactivated ETEC vaccine does not change the safety profile when compared to a previous generation of such a vaccine and that the prototype vaccine induces significant dose dependent mucosal immune responses against CFA/I and LTB.

Phlebitis induced by parenteral treatment with flucloxacillin and cloxacillin: a double-blind study.

Two studies were performed on a total of 54 patients with staphylococcal infections. Study I compares with phlebitogenic properties of flucloxacillin after intravenous infusions when either saline or sterile water was used as a solvent. No difference was observed between the two solvents, and the frequency of phlebitis for the total material without respect to solvents was 5% after 1 day of treatment and 13% after 2 days. Study II was a double-blind comparison of phlebitis caused by intravenous infusions of either flucloxacillin or cloxacillin. The frequencies of phlebitis were found to be 18 and 13%, respectively. After 2 days of treatment the frequency of phlebitis increased dramatically for both drugs. All infusions were given through a plastic cannula of 5-cm length and 1.2-mm diameter.

Enterotoxin-producing bacteria isolated from Swedish travellers with diarrhoea.

The isolation rate of bacterial enteropathogens of different species, particularly enterotoxin-producing Gram-negative bacteria, was determined in stool specimens from Swedish travellers with diarrhoea. Overall, bacterial enteropathogens were identified in 101 (47%) of the 217 travellers on their return home. The most common isolates were enterotoxin-producing bacteria (20%), Salmonellae (18%) and Campylobacter (8%), whereas Shigellae (3%) and Yersinia (0.5%) were rarely identified. Mixed infections were only found in 8 (4%) of the stool specimens. Enterotoxigenic bacteria of Escherichia coli (ETEC), Klebsiella, Morganella, Citrobacter, Pseudomonas and EF-group 10 species were identified. ETEC accounted for 37/43 (86%) enterotoxin-producing strains, and among them 54% produced heat-stable enterotoxin (ST) alone, 16% heat-labile enterotoxin (LT) alone and 30% both LT and ST. Four of the enterotoxin-producing non-E. coli strains produced ST and 2 produced LT alone. The isolation rate of enterotoxin-producing bacteria was somewhat higher in travellers visiting Africa, Asia and Latin America (24%) than in those travelling to Southern Europe (14%). Salmonellae, on the other hand, were identified in stools significantly more often after travel to Southern Europe (26%) than to various subtropical and tropical areas (12.5%).

[Prevention and treatment of traveler's diarrhea]. / Profylax och behandling vid turistdiarré.

Travelers' diarrhea (TD) affects 20-50 per cent of individuals going to developing countries in Asia, Africa, or Latin America. The etiology varies but is dominated by enterotoxigenic E. coli, found in 30-50 per cent. TD is usually a mild disease, self-limiting in 3-4 days, but 10 per cent of those afflicted have symptoms for one week or more. Prophylaxis of TD involves dietary restrictions and, in selected medical risk groups, antimicrobial drugs. The most important treatment of TD is oral rehydration and loperamide in mild to moderate, non-invasive illness. Antibiotics for self-treatment shall be restricted for medical risk groups and individuals travelling far from medical service.

Evaluation of different immunization schedules for oral cholera B subunit-whole cell vaccine in Swedish volunteers.

Different immunization schedules for oral B subunit-whole cell (B-WC) cholera vaccine were evaluated in Swedish volunteers to obtain information for recommendations of vaccine use in non-endemic areas. Two peroral doses of B-WC vaccine were as effective as three doses in inducing IgA and IgG antitoxin as well as vibriocidal antibody responses in serum. Administration of two vaccine doses either at 7, 14 or 28-42 day intervals resulted in comparable antitoxin responses in serum, whereas a 3-day immunization interval resulted in significantly lower titre increases. Vibriocidal antibody responses were comparable after the different time intervals tested (3-42 days). The B-WC vaccine can be effectively administered together with a cheap, commercially available sodium bicarbonate powder dissolved in water to protect the vaccine from gastric acid.

Immunological memory after immunization with oral cholera B subunit--whole-cell vaccine in Swedish volunteers.

The capacity of peroral immunization with either two or three doses of B subunit-whole cell (B-WC) cholera vaccine to induce immunological memory was examined in Swedish volunteers by testing the immune responses to a single dose of B-WC vaccine given 10 months after the initial immunization. Antibody responses in serum and antibody-secreting cell (ASC) responses in peripheral blood were studied, since these responses seem to reflect the gut mucosal IgA immune responses after oral immunization with B-WC vaccine. Previously immunized volunteers responded to a single dose of B-WC vaccine more frequently and with higher levels of IgA and IgG antitoxin antibodies as well as vibriocidal antibodies in serum than did previously unvaccinated controls. The IgA-ASC responses to cholera toxin B subunit were also higher in primed volunteers than in controls. Two doses of B-WC vaccine were as effective as three doses in inducing immunological memory for cholera immunity. A new B-WC cholera vaccine based on recombinant B subunit had the same capacity as the first generation of B-WC vaccine to induce immunological memory for cholera antitoxin immunity.

Saliva, breast milk, and serum antibody responses as indirect measures of intestinal immunity after oral cholera vaccination or natural disease.

The possibility that antibody responses in serum, saliva, or breast milk samples to oral vaccines or enteric infections may reflect the intestinal immune response was evaluated in Bangladeshi volunteers orally immunized with a cholera B subunit-whole-cell vaccine (B + WCV) and in patients convalescing from enterotoxin-induced diarrheal disease. Two peroral doses of B + WCV induced antitoxin and antibacterial antibody responses in the intestinal fluids of 76 and 92%, respectively, of the volunteers and in serum samples in 90 and 69% of those tested. These responses were comparable to those obtained after cholera or enterotoxigenic Escherichia coli disease. Whereas immunoglobulin A (IgA) antitoxin titer increases in saliva (44%) and breast milk (29%) specimens after vaccination were less frequent than in intestinal fluid (76%), antitoxin responses in saliva and breast milk occurred in 80 to 90% of the patients after disease. Also, antilipopolysaccharide (anti-LPS) titer increases in extraintestinal body fluids were found more frequently after disease than after vaccination. A comparison of the frequency and magnitude of antibody response in different body fluids with those in intestinal lavage fluid revealed no extraintestinal antibody that directly reflected the intestinal immunity. However, comparison of vibriocidal and IgG antitoxin antibodies in serum specimens with antitoxin and anti-LPS IgA responses in intestinal fluids after the vaccination of volunteers showed a sensitivity of 70 to 90% and a predictive accuracy of about 80% for the serum analyses reflecting the intestinal immune responses. Furthermore, antitoxin and anti-LPS antibody responses in saliva and breast milk samples seemed to be useful proxy indicators of a gut mucosal response of these antibodies after enterotoxin-induced diarrheal disease showing sensitivity vales of 70 to 90% and predictive accuracy vales of 70 to 100%.

Immune responses in ileostomy fluid and serum after oral cholera vaccination of patients colectomized because of ulcerative colitis.

The capacity of an oral inactivated B-subunit-whole-cell cholera vaccine to induce immune responses in patients colectomized due to ulcerative colitis was studied. Two doses of vaccine induced significant mucosal immunoglobulin A (IgA) antibody responses in ileostomy fluid against cholera toxin in 14 of 15 (93%) patients and against whole vibrios in 9 of 15 (60%) cases. The serological responses were lower (but not significantly) than those observed in healthy Swedish volunteers. Increased IgA antitoxin levels were found in ileostomy fluid as late as 2 years after vaccination.

Dose-dependent circulating immunoglobulin A antibody-secreting cell and serum antibody responses in Swedish volunteers to an oral inactivated enterotoxigenic Escherichia coli vaccine.

The immunogenicity of different preparations of an oral inactivated enterotoxigenic Escherichia coli (ETEC) vaccine was evaluated in Swedish volunteers previously unexposed to ETEC infection. The vaccine preparations consisted of recombinant cholera toxin B subunit (CTB) and various amounts of formalin-killed whole bacteria expressing the most prevalent colonization factor antigens (CFAs). Significant immunoglobulin A (IgA) antibody-secreting cell (ASC) responses against CTB and the various CFA components were seen in a majority of volunteers after two doses of ETEC vaccine independent of the vaccine lot given. The IgA ASC responses against CTB were significantly higher after the second than after the first immunization, whereas the CFA-specific IgA ASC responses were almost comparable after the first and second doses of ETEC vaccine. Two immunizations with one-third of a full dose of CFA-ETEC bacteria induced lower frequencies of IgA ASC responses against all the different CFAs than two full vaccine doses, i.e., 63 versus 80% for CFA/I, 56 versus 70% for CS1, 31 versus 65% for CS2, and 56 versus 75% for CS4. The proportion of vaccinees responding with rises in the titer of serum IgA antibody against the various CFA antigens was also lower after immunization with the reduced dose of CFA-ETEC bacteria. These findings suggest that measurements of circulating IgA ASCs can be used not only for qualitative but also for quantitative assessments of the immunogenicity of individual fimbrial antigens in various preparations of ETEC vaccine.

Kinetics of local and systemic immune responses to an oral cholera vaccine given alone or together with acetylcysteine.

The possibility that a mucolytic drug, i.e., acetylcysteine, given orally may enhance the gut mucosal or systemic immune response to an oral B-subunit-whole-cell (B-WC) cholera vaccine was evaluated for 40 adult Swedish volunteers, and the kinetics of the immune responses were monitored for responding volunteers. Two doses of vaccine induced similar frequencies of immunoglobulin A (IgA) and IgG antitoxin responses (80 to 90%) and vibriocidal titer increases (60 to 65%) in serum irrespective of whether the vaccine was given alone or together with 2 g of acetylcysteine. In feces the frequencies of IgA antitoxin (67%) and antibacterial (33 to 40%) antibody responses were also comparable in the two immunization groups. Six months after vaccination, IgA and IgG antitoxin as well as vibriocidal antibody titer increases in serum could still be detected in approximately 80% of initially responding vaccinees. Significantly elevated fecal antitoxin and antibacterial IgA antibody levels were found in, respectively, 50 and 43% of those volunteers who initially had responded to the vaccine. Determination of IgA antibodies in feces does not seem to offer any advantages compared to determination in serum for assessment of immune responses after immunization with inactivated cholera vaccine.

Safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli vaccine.

The safety and immunogenicity of two different lots, 001 and 003, of an oral inactivated enterotoxigenic Escherichia coli (ETEC) vaccine consisting of a mixture of formalin-killed whole bacteria expressing the most prevalent colonisation factor antigens, i.e. CFA/I, CFA/II and CFA/IV and recombinantly produced cholera B subunit (rCTB) have been evaluated in Swedish volunteers. Neither of the two vaccine preparations, containing different CFA/II-expressing strains but otherwise identical, gave rise to any significant side-effects. Mucosal immune responses, as reflected in antibody-secreting cell (ASC) responses in peripheral blood, were studied after two doses of vaccine and did not differ significantly for the two vaccine lots. Vaccination induced high levels of CTB-specific IgA ASCs in 100% of the volunteers, and significant IgA ASC responses (9- to 36-fold) were noted in 84% of them against CFA/I, in 87% against CFA/II subcomponents CS1-CS3 and in 91% against CFA/IV subfactors CS4 and/or CS5. The frequencies and magnitudes of CFA IgA ASC responses were similar when giving the vaccine with a 1 or 2 week interval. Results from serological analyses showed that the local IgA responses against CFAs are only infrequently associated with serum antibody titre rises.

Intestinal immune responses to an inactivated oral enterotoxigenic Escherichia coli vaccine and associated immunoglobulin A responses in blood.

An inactivated oral enterotoxigenic Escherichia coli (ETEC) vaccine against ETEC diarrhea was given to 25 adult Swedish volunteers. The vaccine consisted of formalin-killed E. coli bacteria expressing the most common colonization factor antigens (CFAs), i.e., CFA/I, -II, and -IV, and recombinantly produced cholera B subunit (CTB). Immunoglobulin A (IgA) antibody responses in intestinal lavage fluid to CTB and CFAs were determined and compared with corresponding responses in stool extracts and serum as well as with IgA antibody-secreting cell (ASC) responses in peripheral blood. Two doses of vaccine induced significant IgA responses to the different CFAs in lavage fluid in 61 to 87% of the vaccinees and in stool in 38 to 81% of them. The most frequent responses were seen against CFA/I. The magnitudes of the antibody responses against CTB and CFA/I in stool correlated significantly (CTB, P < 0.01; CFA/I, P < 0. 05) with those in intestinal lavage. Intestinal lavage responses against CFAs were best reflected by the ASC responses, with the sensitivity of the ASC assay being 80 to 85%, followed by stool (sensitivity of 50 to 88%) and serum antibody (sensitivity of 7 to 65%) analyses. CTB-specific immune responses were seen in >90% of the vaccinees in all assays.

Intestinal and systemic immune responses in humans after oral immunization with a bivalent B subunit-O1/O139 whole cell cholera vaccine.

There is a need for an effective vaccine that can protect against cholera caused by either Vibrio cholerae O1 or by the new pandemic serotype O139 Bengal. An oral bivalent B subunit-O1/O139 whole cell (B-O1/O139 WC) cholera vaccine has been prepared by adding formalin-killed O139 vibrios to the recently licensed oral recombinant B-O1 WC vaccine. When tested in Swedish volunteers, this B-O1/O139 WC vaccine was found to be safe and immunogenic. Two vaccine doses given 2 weeks apart induced statistically significant, P < 0.05, mucosal IgA antibody responses in intestinal lavage fluid against cholera toxin in all of nine vaccinees and against both O1 and O139 vibrios in seven of nine cases. The intestinal responses were associated with similar high frequencies of intestine-derived antibody-secreting cell responses in peripheral blood to the different antigens. A third dose of vaccine given after 5-6 weeks did not result in any further increased response. All of 12 vaccinees responded with significant IgA and IgG antitoxin responses in serum associated with significant vibriocidal antibody titre rises against O1 vibrios in 10 cases (83%) and against O139 vibrios in eight vaccinees (67%). The frequencies and magnitudes of the serological responses to the B subunit and O1 WC components were similar to those induced by the B-O1 WC vaccine. Thus, the O139 component of the vaccine induced intestinal and systemic antibacterial immune responses in the majority of the vaccinees, and its addition to the vaccine did not interfere with the immunogenicity of the B subunit or O1 WC components.