Antimicrobial resistance in bacterial wound, skin, soft tissue and surgical site infections in Central, Eastern, Southern and Western Africa: A systematic review and meta-analysis.

Antimicrobial resistance (AMR) is a major global threat and AMR-attributable mortality is particularly high in Central, Eastern, Southern and Western Africa. The burden of clinically infected wounds, skin and soft tissue infections (SSTI) and surgical site infections (SSI) in these regions is substantial. This systematic review reports the extent of AMR from sampling of these infections in Africa, to guide treatment. It also highlights gaps in microbiological diagnostic capacity. PubMed, MEDLINE and Embase were searched for studies reporting the prevalence of Staphylococcus aureus, Eschericheria coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii in clinically infected wounds, SSTI and SSI in Central, Eastern, Southern or Western Africa, and studies reporting AMR from such clinical isolates. Estimates for proportions were pooled in meta-analyses, to estimate the isolation prevalence of each bacterial species and the proportion of resistance observed to each antibiotic class. The search (15th August 2022) identified 601 articles: 59 studies met our inclusion criteria. S. aureus was isolated in 29% (95% confidence interval [CI] 25% to 34%) of samples, E. coli in 14% (CI 11% to 18%), K. pneumoniae in 11% (CI 8% to 13%), P. aeruginosa in 14% (CI 11% to 18%) and A. baumannii in 8% (CI 5% to 12%). AMR was high across all five species. S. aureus was resistant to methicillin (MRSA) in >40% of isolates. E. coli and K. pneumoniae were both resistant to amoxicillin-clavulanic acid in ≥80% of isolates and resistant to aminoglycosides in 51% and 38% of isolates respectively. P. aeruginosa and A. baumannii were both resistant to anti-pseudomonal carbapenems (imipenem or meropenem) in ≥20% of isolates. This systematic review found that a large proportion of the organisms isolated from infected wounds, SSTI and SSI in Africa displayed resistance patterns of World Health Organisation (WHO) priority pathogens for critical or urgent antimicrobial development.

Effects of COVID-19 on Maternal and Neonatal Outcomes and Access to Antenatal and Postnatal Care, Malawi.

We used national facility-level data from all government hospitals in Malawi to examine the effects of the second and third COVID-19 waves on maternal and neonatal outcomes and access to care during September 6, 2020-October 31, 2021. The COVID-19 pandemic affected maternal and neonatal health not only through direct infections but also through disruption of the health system, which could have wider indirect effects on critical maternal and neonatal outcomes. In an interrupted time series analysis, we noted a cumulative 15.4% relative increase (63 more deaths) in maternal deaths than anticipated across the 2 COVID-19 waves. We observed a 41% decrease in postnatal care visits at the onset of the second COVID-19 wave and 0.2% by the third wave, cumulative to 36,809 fewer visits than anticipated. Our findings demonstrate the need for strengthening health systems, particularly in resource-constrained settings, to prepare for future pandemic threats.

Early Warning Surveillance for SARS-CoV-2 Omicron Variants, United Kingdom, November 2021-September 2022.

Since June 2020, the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study has conducted routine PCR testing in UK healthcare workers and sequenced PCR-positive samples. SIREN detected increases in infections and reinfections and delected Omicron subvariant waves emergence contemporaneous with national surveillance. SIREN's sentinel surveillance methods can be used for variant surveillance.

Comparison of maternal and neonatal outcomes of COVID-19 before and after SARS-CoV-2 omicron emergence in maternity facilities in Malawi (MATSurvey): data from a national maternal surveillance platform.

BACKGROUND: Outcomes of omicron-associated COVID-19 in pregnancy have not been reported from low-resource settings, and data from sub-Saharan Africa before the emergence of omicron are scarce. Using a national maternal surveillance platform (MATSurvey), we aimed to compare maternal and neonatal outcomes of COVID-19 in Malawi during the omicron wave to the preceding waves of beta and delta. METHODS: All pregnant and recently pregnant patients, up to 42 days following delivery, admitted to 33 health-care facilities throughout Malawi with symptomatic, test-proven COVID-19 during the second (beta [B.1.351]: January to April, 2021), third (delta [B.1.617.2]: June to October, 2021), and fourth (omicron [B.1.1.529]: December 2021 to March, 2022) waves were included, with no age restrictions. Demographic and clinical features, maternal outcomes of interest (severe maternal outcome [a composite of maternal near-miss events and maternal deaths] and maternal death), and neonatal outcomes of interest (stillbirth and death during maternal stay in the health-care facility of enrolment) were compared between the fourth wave and the second and third waves using Fisher's exact test. Adjusted odds ratios (ORs) for maternal outcomes were estimated using mixed-effects logistic regression. FINDINGS: Between Jan 1, 2021, and March 31, 2022, 437 patients admitted to 28 health-care facilities conducting MATSurvey had symptoms of COVID-19. SARS-CoV-2 infection was confirmed in 261 patients; of whom 76 (29%) had a severe maternal outcome and 45 (17%) died. These two outcomes were less common during the fourth wave (omicron dominance) than the second wave (adjusted OR of severe maternal outcome: 3·96 [95% CI 1·22-12·83], p=0·022; adjusted OR of maternal death: 5·65 [1·54-20·69], p=0·0090) and the third wave (adjusted OR: 3·18 [1·03-9·80], p=0·044; adjusted OR: 3·52 [0·98-12·60], p=0·053). Shortness of breath was the only symptom associated with poor maternal outcomes of interest (p<0·0001), and was less frequently reported in the fourth wave (23%) than in the second wave (51%; p=0·0007) or third wave (50%; p=0·0004). The demographic characteristics and medical histories of patients were similar across the three waves. During the second and third waves, 12 (13%) of 92 singleton neonates were stillborn or died during maternal stay in the health-care facility of enrolment, compared with 0 of the 25 born in the fourth wave (p=0·067 vs preceding waves combined). INTERPRETATION: Maternal and neonatal outcomes from COVID-19 were less severe during the fourth wave of the SARS-CoV-2 pandemic in Malawi, during omicron dominance, than during the preceding beta and delta waves. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, and the National Institute for Health and Care Research. TRANSLATION: For the Chichewa translation of the abstract see Supplementary Materials section.

Antibody correlates of protection from SARS-CoV-2 reinfection prior to vaccination: A nested case-control within the SIREN study.

OBJECTIVES: To investigate serological differences between SARS-CoV-2 reinfection cases and contemporary controls, to identify antibody correlates of protection against reinfection. METHODS: We performed a case-control study, comparing reinfection cases with singly infected individuals pre-vaccination, matched by gender, age, region and timing of first infection. Serum samples were tested for anti-SARS-CoV-2 spike (anti-S), anti-SARS-CoV-2 nucleocapsid (anti-N), live virus microneutralisation (LV-N) and pseudovirus microneutralisation (PV-N). Results were analysed using fixed effect linear regression and fitted into conditional logistic regression models. RESULTS: We identified 23 cases and 92 controls. First infections occurred before November 2020; reinfections occurred before February 2021, pre-vaccination. Anti-S levels, LV-N and PV-N titres were significantly lower among cases; no difference was found for anti-N levels. Increasing anti-S levels were associated with reduced risk of reinfection (OR 0·63, CI 0·47-0·85), but no association for anti-N levels (OR 0·88, CI 0·73-1·05). Titres >40 were correlated with protection against reinfection for LV-N Wuhan (OR 0·02, CI 0·001-0·31) and LV-N Alpha (OR 0·07, CI 0·009-0·62). For PV-N, titres >100 were associated with protection against Wuhan (OR 0·14, CI 0·03-0·64) and Alpha (0·06, CI 0·008-0·40). CONCLUSIONS: Before vaccination, protection against SARS-CoV-2 reinfection was directly correlated with anti-S levels, PV-N and LV-N titres, but not with anti-N levels. Detectable LV-N titres were sufficient for protection, whilst PV-N titres >100 were required for a protective effect. TRIAL REGISTRATION NUMBER: ISRCTN11041050.

Burden of SARS-CoV-2 infection in healthcare workers during second wave in England and impact of vaccines: prospective multicentre cohort study (SIREN) and mathematical model.

OBJECTIVE: To describe the incidence of, risk factors for, and impact of vaccines on primary SARS-CoV-2 infection during the second wave of the covid-19 pandemic in susceptible hospital healthcare workers in England. DESIGN: Multicentre prospective cohort study. SETTING: National Health Service secondary care health organisations (trusts) in England between 1 September 2020 and 30 April 2021. PARTICIPANTS: Clinical, support, and administrative staff enrolled in the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study with no evidence of previous infection. Vaccination status was obtained from national covid-19 vaccination registries and self-reported. MAIN OUTCOME MEASURE: SARS-CoV-2 infection confirmed by polymerase chain reaction. Mixed effects logistic regression was conducted to determine demographic and occupational risk factors for infection, and an individual based mathematical model was used to predict how large the burden could have been if vaccines had not been available from 8 December 2020 . RESULTS: During England's second wave, 12.9% (2353/18 284) of susceptible SIREN participants became infected with SARS-CoV-2. Infections peaked in late December 2020 and decreased from January 2021, concurrent with the cohort's rapid vaccination coverage and a national lockdown. In multivariable analysis, factors increasing the likelihood of infection in the second wave were being under 25 years old (20.3% (132/651); adjusted odds ratio 1.35, 95% confidence interval 1.07 to 1.69), living in a large household (15.8% (282/1781); 1.54, 1.23 to 1.94, for participants from households of five or more people), having frequent exposure to patients with covid-19 (19.2% (723/3762); 1.79, 1.56 to 2.06, for participants with exposure every shift), working in an emergency department or inpatient ward setting (20.8% (386/1855); 1.76, 1.45 to 2.14), and being a healthcare assistant (18.1% (267/1479); 1.43, 1.16 to 1.77). Time to first vaccination emerged as being strongly associated with infection (P<0.001), with each additional day multiplying a participant's adjusted odds ratio by 1.02. Mathematical model simulations indicated that an additional 9.9% of all patient facing hospital healthcare workers would have been infected were it not for the rapid vaccination coverage. CONCLUSIONS: The rapid covid-19 vaccine rollout from December 2020 averted infection in a large proportion of hospital healthcare workers in England: without vaccines, second wave infections could have been 69% higher. With booster vaccinations being needed for adequate protection from the omicron variant, and perhaps the need for further boosters for future variants, ensuring equitable delivery to healthcare workers is essential. The findings also highlight occupational risk factors that persisted in healthcare workers despite vaccine rollout; a greater understanding of the transmission dynamics responsible for these is needed to help to optimise the infection prevention and control policies that protect healthcare workers from infection and therefore to support staffing levels and maintain healthcare provision. TRIAL REGISTRATION: ISRCTN registry ISRCTN11041050.

Anthelmintics for people with neurocysticercosis.

BACKGROUND: Neurocysticercosis is a parasitic infection of the central nervous system by the larval stage of the pork tapeworm and is a common cause of seizures and epilepsy in endemic areas. Anthelmintics (albendazole or praziquantel) may be given alongside supportive treatment (antiepileptics/analgesia) with the aim of killing these larvae (cysticerci), with or without corticosteroid treatment. However, there are potential adverse effects of these drugs, and the cysticerci may eventually die without directed anthelminthic treatment. OBJECTIVES: To assess the effects of anthelmintics on people with neurocysticercosis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, the WHO ICTRP, and ClinicalTrials.gov, up to 21 October 2020. SELECTION CRITERIA: Randomized controlled trials comparing anthelmintics and supportive treatment (+/- corticosteroids) with supportive treatment alone (+/- corticosteroids) for people with neurocysticercosis. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the title and abstract of all articles identified by the search. We obtained full-text articles to confirm the eligibility of all studies that passed screening. One review author extracted data, which a second review author checked. Two review authors assessed the risk of bias of each trial and performed GRADE assessments. In cases of disagreement at consensus discussion stage between review authors, we consulted a third review author. We calculated risk ratios (RR) for dichotomous variables, with 95% confidence intervals (CIs) for pooled data from studies with similar interventions and outcomes. MAIN RESULTS: We included 16 studies in the review. Only two studies investigated praziquantel and did not report data in a format that could contribute to meta-analysis. Most results in this review are therefore applicable to albendazole versus placebo or no anthelmintic. The aggregate analysis across all participants with neurocysticercosis did not demonstrate a difference between groups in seizure recurrence, but heterogeneity was marked (RR 0.94, 95% CI 0.78 to 1.14; 10 trials, 1054 participants; I2 = 67%; low-certainty evidence). When stratified by participants with a single cyst or multiple cysts, pooled analysis suggests that albendazole probably improves seizure recurrence for participants with a single cyst (RR 0.61, 95% CI 0.4 to 0.91; 5 trials, 396 participants; moderate-certainty evidence). All studies contributing to this analysis recruited participants with non-viable, intraparenchymal cysts only, and most participants were children. We are uncertain whether or not albendazole reduces seizure recurrence in participants with multiple cysts, as the certainty of the evidence is very low, although the direction of effect is towards albendazole causing harm (RR 2.05, 95% CI 1.28 to 3.31; 2 trials, 321 participants; very low-certainty evidence). This analysis included a large study containing a highly heterogeneous population that received an assessment of unclear risk for multiple 'Risk of bias' domains. Regarding radiological outcomes, albendazole probably slightly improves the complete radiological clearance of lesions (RR 1.22, 95% CI 1.07 to 1.39; 13 trials, 1324 participants; moderate-certainty evidence) and the evolution of cysts (RR 1.27, 95% CI 1.10 to 1.47; 6 trials, 434 participants; moderate-certainty evidence). More adverse events appeared to be observed in participants treated with either albendazole or praziquantel compared to those receiving placebo or no anthelmintic. The most commonly reported side effects were headache, abdominal pain, and nausea/vomiting. AUTHORS' CONCLUSIONS: For participants with a single cyst, there was less seizure recurrence in the albendazole group compared to the placebo/no anthelmintic group. The studies contributing to this evidence only recruited participants with a non-viable intraparenchymal cyst. We are uncertain whether albendazole reduces seizure recurrence for participants with multiple cysts. We also found that albendazole probably increases radiological clearance and evolution of lesions. There were very few studies reporting praziquantel outcomes, and these findings apply to albendazole only.

SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN).

BACKGROUND: Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. METHODS: A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. FINDINGS: From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13-0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. INTERPRETATION: A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. FUNDING: Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

Dynamics of sputum conversion during effective tuberculosis treatment: A systematic review and meta-analysis.

BACKGROUND: Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment. METHODS AND FINDINGS: For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation. CONCLUSIONS: This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment. TRIAL REGISTRATION: Systematic review registration: PROSPERO 85226.

Interferon gamma replacement as salvage therapy in chronic pulmonary aspergillosis: effects on frequency of acute exacerbation and all-cause hospital admission.

Chronic pulmonary aspergillosis (CPA) is often poorly responsive to antifungal treatment; secondary infections increase morbidity/mortality, particularly in progressive cases. Interferon gamma (IFNγ) has been implicated in not only Aspergillus control but also bacterial clearance. Clinical notes of patients with CPA treated with IFNγ (2011-2018) were retrospectively hand-searched. In patients treated for >12 months (n=20), the frequency of acute exacerbation reduced from 3.1 to 1.4 episodes/year (p=0.006) in the 12 months after treatment initiation compared with the 12 months before. A significant reduction in the frequency of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). These findings support further prospective studies.

Determination of true patient origin through motorcycle mapping: design and implementation of a community-defined geographic infrastructure surveillance tool in rural Sierra Leone.

BACKGROUND: Village-level geographic infrastructure data are often insufficient in low-resource settings, despite accurate patient origin determination being essential for surveillance and outbreak management. We detail a novel and seemingly reliable method for the determination of true patient origin with proof of concept in rural Sierra Leone. METHODS: Potential villages (n=2263), identified within a 7800 km2 hospital catchment area from satellite imagery, were accessed by motorcycle and surveyed in person, capturing village name and community-defined section/chiefdom/district. RESULTS: A survey established 1740 inhabited villages and a village of origin determination tool (gazetteer) was produced. Recording the district/chiefdom/section/village at hospital registration allowed Global Positioning System patient origin determination in 2277/2344 (97.1%) attendances. CONCLUSIONS: Our proof of concept reports a substantial and sustained record of true patient origin in a low-resource setting.

Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.

Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A variant that alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in FcγRIIA affinity would affect inflammation in an IgA-dominated organ. We found a profound induction of anti-commensal IgG and a concomitant increase in activating FcγR signaling in the colonic mucosa of UC patients. Commensal-IgG immune complexes engaged gut-resident FcγR-expressing macrophages, inducing NLRP3- and reactive-oxygen-species-dependent production of interleukin-1ß (IL-1ß) and neutrophil-recruiting chemokines. These responses were modulated by the FCGR2A genotype. In vivo manipulation of macrophage FcγR signal strength in a mouse model of UC determined the magnitude of intestinal inflammation and IL-1ß-dependent type 17 immunity. The identification of an important contribution of IgG-FcγR-dependent inflammation to UC has therapeutic implications.