Characterization of low-density granulocytes in COVID-19.

Severe COVID-19 is characterized by extensive pulmonary complications, to which host immune responses are believed to play a role. As the major arm of innate immunity, neutrophils are one of the first cells recruited to the site of infection where their excessive activation can contribute to lung pathology. Low-density granulocytes (LDGs) are circulating neutrophils, whose numbers increase in some autoimmune diseases and cancer, but are poorly characterized in acute viral infections. Using flow cytometry, we detected a significant increase of LDGs in the blood of acute COVID-19 patients, compared to healthy controls. Based on their surface marker expression, COVID-19-related LDGs exhibit four different populations, which display distinctive stages of granulocytic development and most likely reflect emergency myelopoiesis. Moreover, COVID-19 LDGs show a link with an elevated recruitment and activation of neutrophils. Functional assays demonstrated the immunosuppressive capacities of these cells, which might contribute to impaired lymphocyte responses during acute disease. Taken together, our data confirms a significant granulocyte activation during COVID-19 and suggests that granulocytes of lower density play a role in disease progression.

International travel increases risk of urinary tract infection caused by extended-spectrum beta-lactamase-producing Enterobacterales-three-arm case-control study.

BACKGROUND: Extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE) have worldwide become increasingly prevalent as pathogens causing urinary tract infections (UTIs), posing challenges in their treatment. Of particular concern are travellers to low- and middle-income countries (LMICs), a substantial proportion of whom become colonized by ESBL-PE, with UTIs as the most common clinical manifestation. Seeking tools for preventing ESBL-PE UTI, we explored factors associated with (i) any UTI (versus control), (ii) ESBL-PE UTI (versus control) and (iii) ESBL-PE versus non-ESBL-PE UTI. METHODS: During 2015-20, we recruited patients with recent ESBL-PE or non-ESBL-PE UTIs, and controls with no UTI to fill in questionnaires covering potential (ESBL-PE-)UTI risk factors. RESULTS: Of our 430 participants, 130 had ESBL-PE UTI and 187 non-ESBL-PE UTI; 113 were controls. Our three comparisons showed several risk factors as exemplified for any UTI versus controls by female sex, lower education, age, diabetes, antibiotic use, diarrhoea; for ESBL-PE UTI versus controls by travel to LMICs, antibiotic use, swimming; and ESBL-PE versus non-ESBL-PE UTI by male sex, higher education, LMIC travel (participant/household member), pets and antibiotic use. Weekly fish meals appeared protective against both UTI and ESBL-PE UTI. CONCLUSIONS: Of the numerous factors predisposing to UTI and/or ESBL-PE UTI, our study highlights antibiotic use and LMIC travel. Household members' LMIC travel appears to pose a risk of ESBL-PE UTI, pointing to household transmission of travel-acquired uropathogens. As predisposing factors to multidrug-resistant UTI, international travel and antibiotic use constitute practical targets for prevention efforts.

Safety and immunogenicity of ETVAX®, an oral inactivated vaccine against enterotoxigenic Escherichia coli diarrhoea: a double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa.

BACKGROUND: No licensed human vaccines are available against enterotoxigenic Escherichia coli (ETEC), a major diarrhoeal pathogen affecting children in low- and middle-income countries and foreign travellers alike. ETVAX®, a multivalent oral whole-cell vaccine containing four inactivated ETEC strains and the heat-labile enterotoxin B subunit (LTB), has proved promising in Phase 1 and Phase 1/ 2 studies. METHODS: We conducted a Phase 2b double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa. This report presents study design and safety and immunogenicity data. Volunteers aged 18-65 years were randomized 1:1 to receive ETVAX® or placebo. They visited Benin for 12 days, provided stool and blood samples and completed adverse event (AE) forms. IgA and IgG antibodies to LTB and O78 lipopolysaccharide (LPS) were measured by electrochemiluminescence. RESULTS: The AEs did not differ significantly between vaccine (n = 374) and placebo (n = 375) recipients. Of the solicited AEs, loose stools/diarrhoea (26.7/25.9%) and stomach ache (23.0/20.0%) were reported most commonly. Of all possibly/probably vaccine-related AEs, the most frequent were gastrointestinal symptoms (54.0/48.8%) and nervous system disorders (20.3/25.1%). Serious AEs were recorded for 4.3/5.6%, all unlikely to be vaccine related. Amongst the ETVAX® recipients, LTB-specific IgA antibodies increased 22-fold. For the 370/372 vaccine/placebo recipients, the frequency of ≥2-fold increases against LTB was 81/2.4%, and against O78 LPS 69/2.7%. The majority of ETVAX® recipients (93%) responded to either LTB or O78. CONCLUSIONS: This Phase 2b trial is the largest on ETVAX® undertaken amongst travellers to date. ETVAX® showed an excellent safety profile and proved strongly immunogenic, which encourages the further development of this vaccine.

International travel and travelers' diarrhea - Increased risk of urinary tract infection.

BACKGROUND: Urinary tract infections (UTIs) rank among the most common infections encountered in health care, with an annual incidence of 12% for women. Despite the vast numbers of international travels (over 1.5 billion annually), no prospective studies have had primary focus on UTIs during travel. METHODS: We recruited in 2008-17 international travelers who all filled out pre- and post-travel questionnaires. Incidence rates of UTI were calculated separately for both sexes. Multivariable analyses were conducted to identify risk factors for UTI during travel. RESULTS: In total 15/517 (2,9%) travelers acquired UTI during travel, yielding an annual incidence of 62% for female and 18% for male travelers. Travelers' diarrhea (TD) was identified as a factor predisposing to UTI (OR 9.2, 95% CI 1.5-+∞, p = 0.011); all UTI cases were recorded by travelers with TD. CONCLUSIONS: To our knowledge, this is the first prospective study with a primary focus on UTI during travel. Our data reveal that among travelers the incidence of UTI far exceeds that reported for the general population. TD was identified as a major risk factor for the infection. Our results suggest TD prevention as a means of also preventing UTI during travel.

Scent dogs in detection of COVID-19: triple-blinded randomised trial and operational real-life screening in airport setting.

OBJECTIVE: To estimate scent dogs' diagnostic accuracy in identification of people infected with SARS-CoV-2 in comparison with reverse transcriptase polymerase chain reaction (RT-PCR). We conducted a randomised triple-blinded validation trial, and a real-life study at the Helsinki-Vantaa International Airport, Finland. METHODS: Four dogs were trained to detect COVID-19 using skin swabs from individuals tested for SARS-CoV-2 by RT-PCR. Our controlled triple-blinded validation study comprised four identical sets of 420 parallel samples (from 114 individuals tested positive and 306 negative by RT-PCR), randomly presented to each dog over seven trial sessions. In a real-life setting the dogs screened skin swabs from 303 incoming passengers all concomitantly examined by nasal swab SARS-CoV-2 RT-PCR. Our main outcomes were variables of diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value) for scent dog identification in comparison with RT-PCR. RESULTS: Our validation experiments had an overall accuracy of 92% (95% CI 90% to 93%), a sensitivity of 92% (95% CI 89% to 94%) and a specificity of 91% (95% CI 89% to 93%) compared with RT-PCR. For our dogs, trained using the wild-type virus, performance was less accurate for the alpha variant (89% for confirmed wild-type vs 36% for alpha variant, OR 14.0, 95% CI 4.5 to 43.4). In the real-life setting, scent detection and RT-PCR matched 98.7% of the negative swabs. Scant airport prevalence (0.47%) did not allow sensitivity testing; our only SARS-CoV-2 positive swab was not identified (alpha variant). However, ad hoc analysis including predefined positive spike samples showed a total accuracy of 98% (95% CI 97% to 99%). CONCLUSIONS: This large randomised controlled triple-blinded validation study with a precalculated sample size conducted at an international airport showed that trained scent dogs screen airport passenger samples with high accuracy. One of our findings highlights the importance of continuous retraining as new variants emerge. Using scent dogs may present a valuable approach for high-throughput, rapid screening of large numbers of people.

SARS-CoV-2 infections among healthcare workers at Helsinki University Hospital, Finland, spring 2020: Serosurvey, symptoms and risk factors.

BACKGROUND: Exposure, risks and immunity of healthcare workers (HCWs), a vital resource during the SARS-CoV-2 pandemic, warrant special attention. METHODS: HCWs at Helsinki University Hospital, Finland, filled in questionnaires and provided serum samples for SARS-CoV-2-specific antibody screening by Euroimmun IgG assay in March-April 2020. Positive/equivocal findings were confirmed by Abbott and microneutralization tests. Positivity by two of the three assays or RT-PCR indicated a Covid-19 case (CoV+). RESULTS: The rate of CoV(+) was 3.3% (36/1095) and seropositivity 3.0% (33/1095). CoV(+) was associated with contact with a known Covid-19 case, and working on a Covid-19-dedicated ward or one with cases among staff. The rate in the Covid-19-dedicated ICU was negligible. Smoking and age <55 years were associated with decreased risk. CoV(+) was strongly associated with ageusia, anosmia, myalgia, fatigue, fever, and chest pressure. Seropositivity was recorded for 89.3% of those with prior documented RT-PCR-positivity and 2.4% of those RT-PCR-negative. The rate of previously unidentified cases was 0.7% (8/1067) and asymptomatic ones 0% (0/36). CONCLUSION: Undiagnosed and asymptomatic cases among HCWs proved rare. An increased risk was associated with Covid-19-dedicated wards. Particularly high rates were seen for wards with liberal HCW-HCW contacts, highlighting the importance of social distancing also among HCWs.

Kinetics of Neutralizing Antibodies of COVID-19 Patients Tested Using Clinical D614G, B.1.1.7, and B 1.351 Isolates in Microneutralization Assays.

Increasing evidence suggests that some newly emerged SARS-CoV-2 variants of concern (VoCs) resist neutralization by antibodies elicited by the early-pandemic wild-type virus. We applied neutralization tests to paired recoveree sera (n = 38) using clinical isolates representing the first wave (D614G), VoC1, and VoC2 lineages (B.1.1.7 and B 1.351). Neutralizing antibodies inhibited contemporary and VoC1 lineages, whereas inhibition of VoC2 was reduced 8-fold, with 50% of sera failing to show neutralization. These results provide evidence for the increased potential of VoC2 to reinfect previously SARS-CoV-infected individuals. The kinetics of NAbs in different patients showed similar decline against all variants, with generally low initial anti-B.1.351 responses becoming undetectable, but with anti-B.1.1.7 NAbs remaining detectable (>20) for months after acute infection.