Summary Background Existing studies of the quality of tuberculosis care have relied on recall-based patient surveys, questionnaire surveys of knowledge, and prescription or medical record analysis, and the results mostly show the health-care provider's knowledge rather than actual practice. No study has used standardised patients to assess clinical practice. Therefore we aimed to assess quality of care for tuberculosis using such patients. Methods We did a pilot, cross-sectional validation study of a convenience sample of consenting private health-care providers in low-income and middle-income areas of Delhi, India. We recruited standardised patients in apparently good health from the local community to present four cases (two of presumed tuberculosis and one each of confirmed tuberculosis and suspected multidrug-resistant tuberculosis) to a randomly allocated health-care provider. The key objective was to validate the standardised-patient method using three criteria: negligible risk and ability to avoid adverse events for providers and standardised patients, low detection rates of standardised patients by providers, and data accuracy across standardised patients and audio verification of standardised-patient recall. We also used medical vignettes to assess providers' knowledge of presumed tuberculosis. Correct case management was benchmarked using Standards for Tuberculosis Care in India (STCI). Findings Between Feb 2, and March 28, 2014, we recruited and trained 17 standardised patients who had 250 interactions with 100 health-care providers, 29 of whom were qualified in allopathic medicine (ie, they had a Bachelor of Medicine & Surgery [MBBS] degree), 40 of whom practised alternative medicine, and 31 of whom were informal health-care providers with few or no qualifications. The interactions took place between April 1, and April 23, 2014. The proportion of detected standardised patients was low (11 [5%] detected out of 232 interactions among providers who completed the follow-up survey), and standardised patients' recall correlated highly with audio recordings ( r =0·63 [95% CI 0·53–0·79]), with no safety concerns reported. The mean consultation length was 6 min (95% CI 5·5–6·6) with a mean of 6·18 (5·72–6·64) questions or examinations completed, representing 35% (33–38) of essential checklist items. Across all cases, only 52 (21% [16–26]) of 250 were correctly managed. Correct management was higher among MBBS-qualified doctors than other types of health-care provider (adjusted odds ratio 2·41 [95% CI 1·17–4·93]; p=0·0166). Of the 69 providers who completed the vignette, knowledge in the vignettes was more consistent with STCI than their actual clinical practice—eg, 50 (73%) ordered a chest radiograph or sputum test during the vignette compared with seven (10%) during the standardised-patient interaction; OR 0·04 (95% CI 0·02–0·11); p<0·0001. Interpretation Standardised patients can be successfully implemented to assess tuberculosis care. Our data suggest a big gap between private provider knowledge and practice. Additional work is needed to substantiate our pilot data, understand the know-do gap in provider behaviour, and to identify the best approach to measure and improve the quality of tuberculosis care in India. Funding Grand Challenges Canada , the Bill & Melinda Gates Foundation , Knowledge for Change Program , and the World Bank Development Research Group.
Summary The emergence and spread of antimicrobial-resistant bacterial, viral, and fungal pathogens for which diminishing treatment options are available is of major global concern. New viral respiratory tract infections with epidemic potential, such as severe acute respiratory syndrome, swine-origin influenza A H1N1, and Middle East respiratory syndrome coronavirus infection, require development of new antiviral agents. The substantial rise in the global numbers of patients with respiratory tract infections caused by pan-antibiotic-resistant Gram-positive and Gram-negative bacteria, multidrug-resistant Mycobacterium tuberculosis , and multiazole-resistant fungi has focused attention on investments into development of new drugs and treatment regimens. Successful treatment outcomes for patients with respiratory tract infections across all health-care settings will necessitate rapid, precise diagnosis and more effective and pathogen-specific therapies. This Series paper describes the development and use of new antimicrobial agents and immune-based and host-directed therapies for a range of conventional and emerging viral, bacterial, and fungal causes of respiratory tract infections.
Summary Background No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza. Methods We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups). Findings We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51–67] in adults aged 18–65 years). No such trials met inclusion criteria for children aged 2–17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69–91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8–17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60–93). Interpretation Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality. Funding Alfred P Sloan Foundation.
To link to full-text access for this article, visit this link:
Byline: Claudio Guedes Salgado, Josafa Goncalves Barreto, Moises
Batista da Silva, Marco Andrey Cipriani Frade, John Stewart Spencer
(a) Laboratorio de Dermato-Imunologia, Instituto de Ciencias
Biologicas, Universidade Federal do Para, Marituba, Para, Brazil
(b) Universidade Federal do Para, Campus Castanhal, Para, Brazil
(c) Departamento de Dermatologia, Faculdade de Medicina da
Universidade de Sao Paulo em Ribeirao Preto, Sao Paulo, Brazil
(d) Department of Microbiology, Immunology and Pathology, Colorado
State University, Fort Collins, CO, USA
Summary Background Diagnosis of meningococcal disease relies on recognition of clinical signs and symptoms that are notoriously non-specific, variable, and often absent in the early stages of the disease. Loop-mediated isothermal amplification (LAMP) has previously been shown to be fast and effective for the molecular detection of meningococcal DNA in clinical specimens. We aimed to assess the diagnostic accuracy of meningococcal LAMP as a near-patient test in the emergency department. Methods For this observational cohort study of diagnostic accuracy, children aged 0–13 years presenting to the emergency department of the Royal Belfast Hospital for Sick Children (Belfast, UK) with suspected meningococcal disease were eligible for inclusion. Patients underwent a standard meningococcal pack of investigations testing for meningococcal disease. Respiratory (nasopharyngeal swab) and blood specimens were collected from patients and tested with near-patient meningococcal LAMP and the results were compared with those obtained by reference laboratory tests (culture and PCR of blood and cerebrospinal fluid). Findings Between Nov 1, 2009, and Jan 31, 2012, 161 eligible children presenting at the hospital underwent the meningococcal pack of investigations and were tested for meningococcal disease, of whom 148 consented and were enrolled in the study. Combined testing of respiratory and blood specimens with use of LAMP was accurate (sensitivity 89% [95% CI 72–96], specificity 100% [97–100], positive predictive value 100% [85–100]; negative predictive value 98% [93–99]) and diagnostically useful (positive likelihood ratio 213 [95% CI 13–infinity] and negative likelihood ratio 0·11 [0·04–0·32]). The median time required for near-patient testing from sample to result was 1 h 26 min (IQR 1 h 20 min–1 h 32 min). Interpretation Meningococcal LAMP is straightforward enough for use in any hospital with basic laboratory facilities, and near-patient testing with this method is both feasible and effective. By contrast with existing UK National Institute of Health and Care Excellence guidelines, we showed that molecular testing of non-invasive respiratory specimens from children is diagnostically accurate and clinically useful. Funding Health and Social Care Research and Development, Public Health Agency, Northern Ireland.
Summary Background Artemisinin resistance in Plasmodium falciparum lengthens parasite clearance half-life during artemisinin monotherapy or artemisinin-based combination therapy. Absence of in-vitro and ex-vivo correlates of artemisinin resistance hinders study of this phenotype. We aimed to assess whether an in-vitro ring-stage survival assay (RSA) can identify culture-adapted P falciparum isolates from patients with slow-clearing or fast-clearing infections, to investigate the stage-dependent susceptibility of parasites to dihydroartemisinin in the in-vitro RSA, and to assess whether an ex-vivo RSA can identify artemisinin-resistant P falciparum infections. Methods We culture-adapted parasites from patients with long and short parasite clearance half-lives from a study done in Pursat, Cambodia, in 2010 (registered with ClinicalTrials.gov , number NCT00341003 ) and used novel in-vitro survival assays to explore the stage-dependent susceptibility of slow-clearing and fast-clearing parasites to dihydroartemisinin. In 2012, we implemented the RSA in prospective parasite clearance studies in Pursat, Preah Vihear, and Ratanakiri, Cambodia ( NCT01736319 ), to measure the ex-vivo responses of parasites from patients with malaria. Continuous variables were compared with the Mann-Whitney U test. Correlations were analysed with the Spearman correlation test. Findings In-vitro survival rates of culture-adapted parasites from 13 slow-clearing and 13 fast-clearing infections differed significantly when assays were done on 0–3 h ring-stage parasites (10·88% vs 0·23%; p=0·007). Ex-vivo survival rates significantly correlated with in-vivo parasite clearance half-lives (n=30, r =0·74, 95% CI 0·50–0·87; p<0·0001). Interpretation The in-vitro RSA of 0–3 h ring-stage parasites provides a platform for the molecular characterisation of artemisinin resistance. The ex-vivo RSA can be easily implemented where surveillance for artemisinin resistance is needed. Funding Institut Pasteur du Cambodge and the Intramural Research Program, NIAID, NIH.
To link to full-text access for this article, visit this link:
Byline: Luke Hunt, Victoria Knott
(a) Liverpool School of Tropical Medicine, Liverpool, UK
Summary Background Chikungunya is an emerging arthropod-borne disease that has spread from tropical endemic areas to more temperate climates of the USA and Europe. However, no specific treatment or preventive measure is yet available. We aimed to investigate the immunogenicity and safety of a live recombinant measles-virus-based chikungunya vaccine. Methods We did a randomised, double-blind, placebo-controlled, active-comparator, phase 1, dose-escalation study at one centre in Vienna, Austria. Healthy men and women aged 18–45 years with no comorbidities were randomly assigned, by computer-generated block randomisation (block size of 14), to receive either one of three escalating doses of the measles-virus-based candidate vaccine (low dose [1·5 × 104 median tissue culture infection doses (TCID50 ) per 0·05 mL], medium dose [7·5 × 104 TCID50 per 0·25 mL], or high dose [3·0 × 105 TCID50 per 1·0 mL]), or the active comparator—Priorix. Participants were additionally block-randomised to receive a booster injection on either day 28 or day 90 after the first vaccination. Participants and study investigators were masked to group allocation. The primary endpoint was the presence of neutralising anti-chikungunya antibodies on day 28, as assessed by 50% plaque reduction neutralisation test. Analysis was by intention to treat and per protocol. This trial is registered with EudraCT, number 2013-001084-23. Findings Between Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) of the measles-virus-based candidate vaccine, or Priorix (n=6), of whom 36 participants (86%; n=9, n=12, n=10, n=5, respectively) were included in the per-protocol population. The candidate vaccine raised neutralising antibodies in all dose cohorts after one immunisation, with seroconversion rates of 44% (n=4) in the low-dose group, 92% (n=11) in the medium-dose group, and 90% (n=10) in the high-dose group. The immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded. Interpretation The live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of anti-vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings. Funding Themis Bioscience GmBH.
Summary Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen in the debilitated host. S maltophilia is not an inherently virulent pathogen, but its ability to colonise respiratory-tract epithelial cells and surfaces of medical devices makes it a ready coloniser of hospitalised patients. S maltophilia can cause blood-stream infections and pneumonia with considerable morbidity in immunosuppressed patients. Management of infection is hampered by high-level intrinsic resistance to many antibiotic classes and the increasing occurrence of acquired resistance to the first-line drug co-trimoxazole. Prevention of acquisition and infection depends upon the application of modern infection-control practices, with emphasis on the control of antibiotic use and environmental reservoirs.