Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

α2-Macroglobulin can crosslink multiple plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) molecules and may facilitate adhesion of parasitized erythrocytes

Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, involves clonal variants of the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) and soluble serum factors. While rosetting is a well-known phenotypic marker of parasites associated with severe malaria, the reason for this association remains unclear, as do the molecular details of the interaction between the infected erythrocyte (IE) and the adhering erythrocytes. Here, we identify for the first time a single serum factor, the abundant serum protease inhibitor α2-macroglobulin (α2M), which is both required and sufficient for rosetting mediated by the PfEMP1 protein HB3VAR06 and some other rosette-mediating PfEMP1 proteins. We map the α2M binding site to the C terminal end of HB3VAR06, and demonstrate that α2M can bind at least four HB3VAR06 proteins, plausibly augmenting their combined avidity for host receptors. IgM has previously been identified as a rosette-facilitating soluble factor that acts in a similar way, but it cannot induce rosetting on its own. This is in contrast to α2M and probably due to the more limited cross-linking potential of IgM. Nevertheless, we show that IgM works synergistically with α2M and markedly lowers the concentration of α2M required for rosetting. Finally, HB3VAR06+ IEs share the capacity to bind α2M with subsets of genotypically distinct P. falciparum isolates forming rosettes in vitro and of patient parasite isolates ex vivo. Together, our results are evidence that P. falciparum parasites exploit α2M (and IgM) to expand the repertoire of host receptors available for PfEMP1-mediated IE adhesion, such as the erythrocyte carbohydrate moieties that lead to formation of rosettes. It is likely that this mechanism also affects IE adhesion to receptors on vascular endothelium. The study opens opportunities for broad-ranging immunological interventions targeting the α2M--(and IgM-) binding domains of PfEMP1, which would be independent of the host receptor specificity of clinically important PfEMP1 antigens

Influence of α2-macroglobulin, anti-parasite IgM and ABO blood group on rosetting in <i>Plasmodium falciparum</i> clinical isolates and their associations with disease severity in a Ghanaian population

PURPOSE: The severity of Plasmodium falciparum infections is associated with the ability of the infected red blood cells to cytoadhere to host vascular endothelial surfaces and to uninfected RBCs. Host blood group antigens and two serum proteins α(2)-macroglobulin (α(2)M) and IgM have been implicated in rosette formation in laboratory-adapted P. falciparum. However, there is only limited information about these phenotypes in clinical isolates. METHODS: This was a hospital-based study involving children under 12 years-of-age reporting to the Hohoe Municipal Hospital with different clinical presentations of malaria. Parasite isolates were grown and rosette capabilities and characteristics were investigated by fluorescence microscopy. α(2)M and IgM were detected by ELISA. RESULTS: Rosette formation was observed in 46.8% (75/160) of the parasite isolates from all the blood groups tested. Rosettes were more prevalent (55%) among isolates from patients with severe malaria compared to isolates from patients with uncomplicated malaria (45%). Rosette prevalence was highest (30%) among patients with blood group O (30%) and B (29%), while the mean rosette frequency was higher in isolates from patients with blood group A (28.7). Rosette formation correlated negatively with age (r = −0.09, P= 0.008). Participants with severe malaria had a lower IgM concentration (3.683±3.553) than those with uncomplicated malaria (5.256±4.294) and the difference was significant (P= 0.0228). The mean concentrations of anti-parasite IgM measured among the clinical isolates which formed rosettes was lower (4.2 ±3.930 mg/mL), than that in the non rosetting clinical isolates (4.604 ±4.159 mg/mL) but the difference was not significant (P=0.2733). There was no significant difference in plasma α(2)M concentration between rosetting and non rosetting isolates (P=0.442). CONCLUSION: P. falciparum parasite rosette formation was affected by blood group type and plasma concentration of IgM. A lower IgM concentration was associated with severe malaria whilst a higher α(2)M concentration was associated with uncomplicated malaria

The role of chronic norovirus infection in the enteropathy associated with common variable immunodeficiency

OBJECTIVES: A severe enteropathy of unknown etiology can be associated with common variable immuno deficiency (CVID).METHODS: Stool and archived small intestinal mucosal biopsies from patients with CVID enteropathy were analyzed by PCR for the presence of Norovirus RNA. The PCR products were sequenced to determine the relationship of viral isolates. Stool samples from 10 patients with CVID but no enteropathy served as controls.RESULTS: All eight patients in our CVID cohort with enteropathy showed persistent fecal excretion of Norovirus. Analysis of archived duodenal biopsies revealed a strong association between the presence of Norovirus and villous atrophy over a period of up to 8 years. Analysis of the viral isolates from each patient revealed distinct strains of genogroup II. 4. Sequence analysis from consecutive biopsy specimens of one patient demonstrated persistence of the same viral strain over a 6-year period. CVID patients without enteropathy showed no evidence of Norovirus carriage. Viral clearance occurred spontaneously in one patient and followed oral Ribavirin therapy in two further patients, and resulted in complete symptomatic and histological recovery. However, Ribavirin treatment in two further patients was unsuccessful.CONCLUSIONS: Norovirus is an important pathogen for patients with CVID and a cause of CVID enteropathy, as viral clearance, symptom resolution, and histological recovery coincide. Ribavirin requires further evaluation as a potential therapy

Binding of native and MA-activated α₂M to HB3VAR06.

<p>(A) Titration of binding of native α₂M (black circles) and α₂M-MA (white circles) to recombinant full-length HB3VAR06 measured by ELISA. Means and SD are indicated. (B) Titration of binding of native α₂M (black circles) and α₂M-MA (white circles) to HB3VAR06⁺ IEs measured by flow cytometry. Means and SD are indicated. (C) Activation of α₂M measured by SDS gel electrophoresis of soluble and immobilized α₂M in the presence of mPEG: soluble α₂M alone (lane 1), soluble α₂M and MA (lane 2), soluble α₂M and FV6 (lane 3), bead-immobilized α₂M-FV6 complexes alone (lane 4), and bead-immobilized α₂M-FV6 complexes and MA (lane 5). While native α₂M was detectable in all lanes, activated α₂M having a higher molecular weight than native α₂M due to incorporation of mPEG was only detected in the presence of MA (lanes 2 and 5).</p

Identification of α₂M as the soluble serum factor binding HB3VAR06.

<p>(A) 2D gel electrophoresis of serum components pulled down with recombinant full-length HB3VAR06 (FV6; left) or PFD1235w-DBLβ3_D5 (right). Spots subsequently identified as α₂M and IgM in the left panel are boxed. Molecular weight (kDa) markers are shown along the left margins. (B) Binding of α₂M to recombinant full-length HB3VAR06 (FV6; left) and IT4VAR04 (FV2; right), measured by ELISA. Means and SD are indicated. (C) Binding of α₂M to HB3VAR06⁺ IEs (left) and IT4VAR04⁺ IEs (right), measured by flow cytometry. Control sample labeling (no α₂M added) is indicated by gray shading. (D) Fluorescence micrographs of DAPI-labeled HB3VAR06⁺ IEs in the presence (top) and absence (bottom) of fluorescein isothiocyanate-labeled α₂M at low (scale bar: 20 μm; left) and high (scale bar: 5 μm; right) magnification are shown.</p

α₂M binding in parasites not expressing HB3VAR06.

<p>(A) Binding of α₂M to erythrocytes infected by eight genotypically and/or phenotypically different parasite lines, measured by flow cytometry. Control sample labeling (secondary antibody only) is indicated by gray shading. (B) Rosetting frequencies of erythrocytes infected by six genotypically or phenotypically different parasite lines at increasing concentrations of α₂M but without serum, measured by flow cytometry. Means and SD relative to rosetting in the presence of serum are indicated. (C) <i>Ex vivo</i> binding of α₂M (left) and IgM (right) to erythrocytes infected by a <i>P</i>. <i>falciparum</i> patient isolate (P25). (D) Correlation of <i>ex vivo</i> binding of α₂M and IgM to erythrocytes infected by <i>P</i>. <i>falciparum</i> parasites from 12 patients with uncomplicated malaria. Isolate P25 shown in panel C is indicated by an arrow.</p

Capacity of α₂M to induce resetting.

<p>(A) Size-exclusion chromatography of α₂M alone (black), recombinant full-length HB3VAR06 alone (FV6; green), or the two together at α₂M:FV6 molar ratios of 1:1 (brown), 1:3 (blue), 1:5 (pink), and 1:7 (red), measured by size-exclusion chromatography. The prominent shoulder of unbound FV6 at 1:7 is indicated by a red arrow. (B) Size-exclusion chromatography of α₂M-MA alone (black), recombinant full-length HB3VAR06 alone (FV6; green), or the two together at α₂M-MA:FV6 molar ratios of 1:1 (brown) and 1:2 (blue), measured by size-exclusion chromatography. The prominent shoulder of unbound FV6 at 1:2 is indicated by a blue arrow. (C) Rosetting of HB3VAR06⁺ IEs in Albumax medium at different concentrations of α₂M (black circles), α₂M-MA (○), and α₂M in the presence of fixed concentration (3 mg/mL) IgM (black point-up triangles) or IgA (black point-down triangles). Means and SDs relative to rosetting in serum-containing medium are indicated. (D) Ability of α₂M to restore the capacity of IgM-depleted serum to support rosetting of HB3VAR06⁺ IEs. Means and SD are indicated.</p

Identification and characterization of the α₂M-binding domain in HB3VAR06.

<p>(A) Schematic representation of the domain structure of HB3VAR06. Domain nomenclature as described by Rask <i>et al</i>. [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005022#ppat.1005022.ref037" target="_blank">37</a>], as well as the first and last amino acid in each domain are indicated. (B) Binding of α₂M to recombinant HB3VAR06 single-, double-, and triple-domain constructs (labeled as in panel A) as well as to full-length HB3VAR06 (FV6) measured by ELISA. Means and SD are indicated. (C) Inhibition of α₂M binding to HB3VAR06⁺ IEs by anti-sera raised against the N-terminal head structure (D1–D3), DBLξ2 (D8), and full-length HB3VAR06 (FV6), respectively, measured by flow cytometry. Means and SD relative to binding without anti-serum are indicated. (D) Simultaneous labeling of HB3VAR06⁺ IEs by α₂M and IgM (left), measured by flow cytometry. A control experiment with all detecting antibodies present but without α₂M and IgM is shown to the right. (E) Inhibition of IgM binding to HB3VAR06⁺ IEs by increasing concentrations of α₂M, measured by flow cytometry. Means and SD relative to binding in the absence of α₂M are indicated. (F) Inhibition of α₂M binding to HB3VAR06⁺ IEs by increasing concentrations of IgM, measured by flow cytometry. Means and SD relative to binding in the absence of IgM are indicated.</p