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Summary: Two SARS-CoV-2 nosocomial outbreaks occurred on the haematology ward of our hospital. Patients on the ward were at high risk for severe infection because of their immunocompromised status. Whole Genome Sequencing proved transmission of a particular SARS-CoV-2 variant in each outbreak. The first outbreak (20 patients/31 healthcare workers (HCW)) occurred in November 2020 and was caused by a variant belonging to lineage B.1.221. At that time, there were still uncertainties on mode of transmission of SARS-CoV-2, and vaccines nor therapy were available. Despite HCW wearing II-R masks in all patient contacts and FFP-2 masks during aerosol generating procedures (AGP), the outbreak continued. Therefore, extra measures were introduced. Firstly, regular PCR-screening of asymptomatic patients and HCW; positive patients were isolated and positive HCW were excluded from work as a rule and they were only allowed to resume their work if a follow-up PCR CT-value was ≥30 and were asymptomatic or having only mild symptoms. Secondly, the use of FFP-2 masks was expanded to some long-lasting, close-contact, non-AGPs. After implementing these measures, the incidence of new cases declined gradually. Thirty-seven percent of patients died due to COVID-19.The second outbreak (10 patients/2 HCW) was caused by the highly transmissible omicron BA.1 variant and occurred in February 2022, where transmission occurred on shared rooms despite the extra infection control measures. It was controlled much faster, and the clinical impact was low as the majority of patients was vaccinated; no patients died and symptoms were relatively mild in both patients and HCW.

Introduction: Higher antibody levels, in particular antibodies directed against the receptor-binding domain (RBD) of the spike protein, protect against re-infection with SARS-CoV-2. Quantitative antibody response data provide insight into population immunity and are essential for decision-making on booster-vaccination strategies. We aimed to identify predictors for higher antibody responses such as gender, age, experienced COVID-19-compatible symptoms, disease severity and exposure to pre-determined risk factors associated with SARS-CoV-2 seropositivity. Materials and methods: Quantitative anti-S-RBD responses were analysed in seropositive vaccine-naive individuals (n = 1,857) from a study population of 10,001 adults, including healthcare workers (n = 211) and individuals with a known date of a positive PCR (n = 214). Regression models tested associations between age, gender, the period of symptoms, disease severity, pre-identified exposure factors associated with SARS-CoV-2 seropositivity, and anti-S-RBD responses. Results: Symptoms of more severe disease (fever and/or dyspnoea: OR 2.42 [95%CI 1.76–3.34], and hospital admission: OR 11.41 [95%CI 4.66–27.97]), and a longer interval between COVID-19-compatible symptoms and serum collection (OR 3.17 [95%CI 1.32–7.63]) were predictive for anti-S-RBD levels ≥300 U/mL. Working in healthcare was inversely associated with anti-S-RBD levels ≥300 U/mL (OR 0.51 [95%CI 0.31–0.82]). None of the pre-identified exposure factors associated with SARS-CoV-2 seropositivity could be identified as predictive of higher anti-S-RBD responses. Conclusion: No exposure factors were identified as predictors of higher neutralising antibody responses. Nevertheless, higher neutralising antibody levels in individuals with more severe symptoms suggest better immunological protection against SARS-CoV-2 re-infection. In seroprevalence studies, that mainly include asymptomatic or mildly infected individuals, the determination of quantitative antibody responses may help in the interpretation of population immunity.

Abstract Background Variant of concern (VOC) SARS-CoV-2 alpha variant (B.1.1.7) was the dominant strain in the Netherlands between March 2021–June 2021. We describe three primary school outbreaks due to the alpha variant using whole genome sequencing with evidence of large-scale transmission among children, teachers and their household contacts. Method All outbreaks described were investigated by the South Limburg Public Health Service, the Netherlands. A case was defined as an individual with a real-time polymerase chain reaction test or antigen test positive for SARS-CoV-2. Whole genome sequencing was performed on random samples from at least one child and one teacher of each affected class. Results Peak attack rates in classes were 53%, 33% and 39%, respectively. Specific genotypes were identified for each school across a majority of affected classes. Attack rates were high among staff members, likely to promote staff-to-children transmission. Cases in some classes were limited to children, indicating child-to-child transmission. At 39%, the secondary attack rate (SAR) in household contacts of infected children was remarkably high, similar to SAR in household contacts of staff members (42%). SAR of household contacts of asymptomatic children was only 9%. Conclusion Our findings suggest increased transmissibility of the alpha variant in children compared to preceding non-VOC variants, consistent with a substantial rise in the incidence of cases observed in primary schools and children aged 5–12 since the alpha variant became dominant in March 2021. Lack of mandatory masking, insufficient ventilation and lack of physical distancing also probably contributed to the school outbreaks. The rise of the delta variant (B.1.617.2) since July 2021 which is estimated to be 55% more transmissible than the alpha variant, provides additional urgency to adequate infection prevention in school settings.

Abstract Background Individuals with intellectual and developmental disabilities (IDD) living in congregated settings have increased risk of COVID-19 infection and mortality. Little is known about variant B.1.1.519 with spike mutation T478K, dominant in Mexico. We describe a linked SARS-CoV-2 B.1.1.519 outbreak in three IDD facilities in the Netherlands. Methods Following notification of the index, subsequent cases were identified through serial PCR group testing. Positive specimens were submitted for whole-genome-sequencing. Clinical information was gathered through interviews with staff members of the three facilities. Results Attack rate (AR) in clients of the index facility was 92% (23/25), total AR in clients 45% (33/73) and in staff members 24% (8/34). 55% (18/33) of client cases were asymptomatic, versus 25% (2/8) of staff members. Five client cases (15%) were hospitalized, two died (6%). Sequencing yielded the same specific B.1.1.519 genotype in all three facilities. No significant difference in median viral load was established comparing the B.1.1.519 variant with other circulating variants. The index of the linked outbreak reported no travel history or link to suspected or confirmed cases suggesting regional surveillance. Observed peak regional prevalence of B.1.1.519 during the outbreak supports this. Conclusion AR, morbidity and mortality prior to control measures taking effect were high, probably related to the specific characteristics of the IDD setting and its clients. We assessed no evidence for intrinsic contributing properties of variant B.1.1.519. Our study argues for enhanced infection prevention protocols in the IDD setting, and prioritization of this group for vaccination against COVID-19.

Summary: In 2019–2020, two subsequent outbreaks caused by phenotypically identical ESBL-producing Enterobacter cloacae and multi-drug-resistant (MDR) Pseudomonas putida were detected in respectively 15 and 9 patients of the haematology-oncology department. Both bacterial species were resistant to piperacillin-tazobactam, used empirically in (neutropenic) sepsis in our hospital, and ciprofloxacin, used prophylactically in selective digestive decontamination for haematology patients. The E. cloacae outbreak was identified in clinical cultures of blood and urine. Despite intensified infection control measures, new cases were found in weekly point-prevalence screening cultures. Environmental samples of sinks and shower drains appeared positive in 18.1%. To diminish the environmental contamination burden, all siphons of sinks were replaced, and disinfection of sinks and shower drains was intensified using chlorine and soda on a daily basis. Replacement of shower drains was not possible. The outbreak of P. putida remained limited to rectal cultures only, and disappeared spontaneously without interventions. During both outbreaks, multiple strains of the incriminated bacterium were found simultaneously (demonstrated by Amplified-Fragment Length Polymorphism and/or Whole-Genome Multi-locus Sequencing Typing) in patients as well as the environment. It was experimentally shown that a biofilm on the toilet edge may act as a source for nosocomial transmission of Gram-negative bacteria. In conclusion, the drainage system of the hospital is an important reservoir of MDR bacteria, threatening the admitted patients. In existing hospitals, biofilms in the drainage systems cannot be removed. Therefore, it is important that in (re)building plans for hospitals a plan for prevention of nosocomial transmission from environment to patients is incorporated.

We investigated the effect of international travel on the gut resistome of 122 healthy travelers from the Netherlands by using a targeted metagenomic approach. Our results confirm high acquisition rates of the extended-spectrum β-lactamase encoding gene blaCTX-M, documenting a rise in prevalence from 9.0% before travel to 33.6% after travel (p

We determined the prevalence and characteristics of extended-spectrum β-lactamase (ESBL) genes of Enterobacteriaceae in retail chicken meat and humans in the Netherlands. Raw meat samples were obtained, and simultaneous cross-sectional surveys of fecal carriage were performed in 4 hospitals in the same area. Human blood cultures from these hospitals that contained ESBL genes were included. A high prevalence of ESBL genes was found in chicken meat (79.8%). Genetic analysis showed that the predominant ESBL genes in chicken meat and human rectal swab specimens were identical. These genes were also frequently found in human blood culture isolates. Typing results of Escherichia coli strains showed a high degree of similarity with strains from meat and humans. These findings suggest that the abundant presence of ESBL genes in the food chain may have a profound effect on future treatment options for a wide range of infections caused by gram-negative bacteria.

A new methicillin-resistant Staphylococcus aureus (MRSA) clone related to pig and cattle farming was detected in the Netherlands. We investigated the extent of S. aureus presence in meat and found 36 S. aureus strains in 79 samples. Two strains were MRSA; 1 was multilocus sequence type 398, the clone related to farming.

Abstract Background It is controversial to what degree α+-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium. Methods In Tanzania, in children aged 6-60 months and height-for-age z-score < -1.5 SD (n = 612), rates of fevers due to malaria and other causes were compared between those with heterozygous or homozygotes α+-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child. Results The overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α+-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α+-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes. Conclusions In this population, the association between α+-thalassaemia and malaria depends on age. Our data suggest that protection by α+-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity.

Abstract Background Deficiencies in vitamins and mineral elements are important causes of morbidity in developing countries, possibly because they lead to defective immune responses to infection. The aim of the study was to assess the effects of mineral element deficiencies on early innate cytokine responses to Plasmodium falciparum malaria. Methods Peripheral blood mononuclear cells from 304 Tanzanian children aged 6-72 months were stimulated with P. falciparum-parasitized erythrocytes obtained from in vitro cultures. Results The results showed a significant increase by 74% in geometric mean of TNF production in malaria-infected individuals with zinc deficiency (11% to 240%; 95% CI). Iron deficiency anaemia was associated with increased TNF production in infected individuals and overall with increased IL-10 production, while magnesium deficiency induced increased production of IL-10 by 46% (13% to 144%) in uninfected donors. All donors showed a response towards IL-1β production, drawing special attention for its possible protective role in early innate immune responses to malaria. Conclusions In view of these results, the findings show plasticity in cytokine profiles of mononuclear cells reacting to malaria infection under conditions of different micronutrient deficiencies. These findings lay the foundations for future inclusion of a combination of precisely selected set of micronutrients rather than single nutrients as part of malaria vaccine intervention programmes in endemic countries.

Introduction: There is a need for detailed data on early antibody responses against SARS-CoV-2 as this may contribute to the prediction of the clinical course of COVID-19 and the optimization of convalescent plasma treatment. This study aims to gain insight into developing antibodies to SARS-CoV-2 in health care workers (HCWs) infected in the first wave of the SARS-CoV-2 pandemic in the Netherlands. Materials and methods: In this retrospective analysis, sera from PCR-confirmed COVID-19 positive HCWs are included at the time of the initial PCR (T = 0, n = 95) and at least 21 days after the initial serum (T ≥ 21, n = 133). This study assesses correlations between qualitative total Ig, IgM, IgA, IgG, and quantitative anti-S-RBD antibody responses and participant characteristics. Results: Higher Ct values were associated with higher antibody positivity rates for total Ig (OR 1.261 (95% CI 1.095–1.452)), IgM (OR 1.373 (95% CI 1.125–1.675)), and IgA (OR 1.222 (95% CI 1.013–1.475)). Gender was predictive of IgM and IgA antibody positivity rates at T = 0 (OR 0.018 (95% CI 0.001–0.268)) and (OR 0.070 (95% CI 0.008–0.646)). At T ≥ 21, a substantial proportion of HCWs developed IgM (103/133; 77.4%) and total Ig (128/133; 96.2%) antibodies. IgA and IgG seroconversions were observed in only 51.1% (67/131) and 55.7% (73/131) of HCWs. Anti-S-RBD responses were higher when the interval between onset of symptoms and sampling was longer. Conclusion: The findings of this study give insight into early antibody responses and may have implications for the selection of convalescent plasma donors and the further development of monoclonal antibody treatment.

Abstract Objectives Maintenance treatment with macrolide antibiotics has shown to be effective in reducing exacerbations in COPD patients. A major concern with prolonged treatment with antibiotics is the development of bacterial resistance. In this study we determined the effect of azithromycin on the development and acquisition of resistance to macrolides in the nasopharyngeal flora in COPD patients. Methods This study was part of the COLUMBUS trial, a randomised, double-blind, placebo-controlled trial to measure the effect of maintenance treatment with azithromycin in 92 COPD patients on the exacerbation rates during a 12-month period. In order to determine resistance to macrolides, we used a targeted metagenomic approach to measure the presence and relative abundance of specific macrolide resistance genes ermB, ermF and mefA in throat samples collected at different time-points during this 12-month period. Results There was no increased risk for acquisition of macrolide resistance genes in the azithromycin group compared to the placebo group in COPD patients. However, loss of the macrolide resistance gene ermB was increased overtime in the placebo treated group compared to the azithromycin group (n = 5 for the placebo group versus n = 0 for the azithromycin group at 12 months; p = 0.012). The change in relative abundance of the three macrolide-resistance genes showed that all but one (ermF) increased during treatment with azithromycin. Conclusions The acquisition rate of macrolide resistance genes in COPD patients treated with azithromycin maintenance therapy was limited, but the relative abundance of macrolide resistance genes increased significantly over time compared to placebo. This study was part of the COLUMBUS trial ( Clinicaltrials.gov , NCT00985244 ).

Abstract Background Most infections are spread through social networks (detrimental effect). However, social networks may also lower infection acquisition (beneficial effect). This study aimed to examine associations between social network parameters and prevalence of self-reported upper and lower respiratory, gastrointestinal and urinary tract infections in a population aged 40–75. Methods In this population-based cross-sectional cohort study (N = 3004, mean age 60.0 ± 8.2 years, 49% women), infections within the past two months were assessed by self-administered questionnaires. Social network parameters were assessed using a name generator questionnaire. To examine the associated beneficial and detrimental network parameters, univariable and multivariable logistic regression was used. Results Participants reported an average of 10 people (alters) with whom they had 231 contacts per half year. Prevalences were 31.1% for upper respiratory, 11.5% for lower respiratory, 12.5% for gastrointestinal, and 5.7% for urinary tract infections. Larger network size, and a higher percentage of alters that were friends or acquaintances were associated with higher odds of upper respiratory, lower respiratory and/or gastrointestinal infections (detrimental). A higher total number of contacts, higher percentages of alters of the same age, and higher percentages of family members/acquaintances were associated with lower odds of upper respiratory, lower respiratory and/or gastrointestinal infections (beneficial). Conclusion We identified both detrimental and beneficial associations of social network parameters with the prevalence of infections. Our findings can be used to complement mathematical models on infection spread, as well as to optimize current infectious disease control.

Abstract Background An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies. Methods Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum-parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status. Results The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-γ response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-γ production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status. Conclusions The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status.