- Email: [email protected]
Call to duty revisited
Correspondence
See Online for appendix
532
UK MenB strains, 1 allowing for the possibility of MenB disease in Bexsero-immunised individuals due to strains not covered by the vaccine (appendix). But how easy is it to distinguish whether an infection is caused by a covered or a non-covered strain? Bexserocomprises three recombinant proteins (fHbp, NHBA, and NadA) and detergent-extracted outer membrane vesicles containing native PorA protein and several minor proteins.2 The recombinant proteins exhibit substantial diversity between meningococcal strains in both sequence and levels of expression, so that protection only occurs if a strain has medium-to-high expression of one or more homologous antigens. Monitoring requires detection of whether antigens have the requisite homology and expression to render an infective strain sensitive to protection by Bexsero. Homology can be determined by sequencing vaccine antigens in DNA extracted from either the live strain or directly from the clinical samples. However, expression levels can only be assessed with assays requiring a live bacterial isolate and are unmeasurable in cases wherein confirmation is solely based on PCR results from clinical samples.3 Since 1998–99, 8567 (47%) of the 18 141 confirmed cases of MenB disease were confirmed by PCR only, without isolation of the liveinfective strain. Why is precise monitoring required? All cases of meningococcal disease in Bexsero-immunised individuals could be classified as vaccine failures but this approach would underestimate the vaccine’s effectiveness. So how will coverage be assessed in the Bexsero era? First, for every suspected case of meningococcal disease in immunised individuals, extensive efforts will be necessary to isolate the causative meningococcal strain and run a full battery of tests for monitoring whether strains were covered or not covered (appendix). These tests will have to include sampling of contacts before
prophylaxis as potential sources of a live isolate of the infecting strain. If confirmation is solely done by PCR, running of gene-specific PCRs/DNA sequencing reactions can determine if the disease-causing strain has antigens homologous to the vaccine antigens and hence is covered (appendix). If there are no matches, a case can be marked as due to a non-covered strain. Conversely, a good match will indicate a so-called true vaccine failure by a covered strain, except that strains with low expression of a homologous fHbp allele should be marked as noncovered strains. Can monitoring be improved? There is potential for estimating expression of target antigen in clinical samples by the indirect approach of analysing promoter sequences in extracted DNA or the direct approach of measuring RNA or peptide concentrations for target antigens. But for now, the separation of lack of coverage from vaccine failure for Bexseroimmunised individuals might have to rely on improving isolation of the live infective strain. CDB, JAM, and RB are in receipt of funding from the Meningitis Research Foundation for a project entitled “Determining the molecular basis of vaccine failure” by Bexsero. RB has conducted clinical trials of capsular group B meningococcal vaccines on behalf of Public Health England funded by Novartis Vaccines and Pfizer but has no pecuniary or other interests with any vaccine manufacturer. CDB and JAM declare no competing interests.
*Christopher D Bayliss, Julie A Morrissey, Ray Borrow [email protected] Department of Genetics, University of Leicester, Leicester LE1 7RH, UK (CDB, JM); Vaccine Evaluation Unit, Public Health England, Manchester, UK (RB) 1
2
3
Frosi G, Biolchi A, Lo Sapio M, et al. Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. Vaccine 2013; 31: 4968–74. Giuliani MM, Adu-Bobie J, Comanducci M, et al. A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci USA 2006; 103: 10834–39. Donnelly J, Medini D, Boccadifuoco G, et al. Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proc Natl Acad Sci USA 2010; 107: 19490–95.
Call to duty revisited As longserving surgeons in the Veterans Health Administration (VHA) system, we found the Editorial1 about the VHA both disturbing and misleading. In view of the fact that the UK does not have a specific agency devoted to veterans, this critique of the VHA is unwarranted and non-specific. The Editorial is another gratuitous example of piling on criticism in response to news of admittedly egregious administrative wrongdoing in the misreporting of waiting times for access to primary care in the VHA health-care system. A massive increase in demand for primary care and mental health care is associated with an increase from 4·5 million veterans to about 9 million veterans between 2001 and 2013 flooding the system.2 Without appropriate administrative foresight and preparation, the system became overwhelmed in various (but not all) centres throughout the USA. We admit that the scarcity of planning and poor reporting were inexcusable. However, one needs only to run a search of the UK National Health Service (NHS) to note similar unflattering press criticisms. Despite difficulties, we believe the VHA is still a model of health-care delivery. The VHA provides lifelong coverage for veterans, while promoting health rather than treatment of ill health, which is more profitable. The VHA primary care system aims to integrate seamlessly into its expert specialty services. Advanced electronic medical records ease patient care, collect outcomes to enable the monitoring and improvement of surgical and medical practice, and provide a clinical database for research. The VHA led the decentralisation of patient care to outpatient clinics and patients’ homes. The VHA has pioneered telemedicine and secure internet messaging between patients and health-care providers. The list of VHA innovations goes on, and these innovations have been recognised in www.thelancet.com Vol 387 February 6, 2016
Correspondence
www.thelancet.com Vol 387 February 6, 2016
is widespread, and perhaps needed, for all publicly supported agencies in democratic societies; but reason must prevail. Although not perfect, we believe the VHA is probably the best health-care model for people who have borne the burden of battle. Health-care professionals help those who are called to arms in the tradition of excellence they deserve; the quality of these services needs recognition and respect. We are employees of the Department of Veterans Affairs. The opinions expressed are those of the authors and not those of the US Government or the Department of Veterans Affairs.
*Earl Gaar, Jon White, Ralph G DePalma [email protected] Department of Veterans Affairs, Robley Rex Veteran Affairs Medical Center, University of Louisville School of Medicine, Louisville, KY, USA (EG); Department of Veterans Affairs, Washington DC Veterans Affairs Medical Center, Washington, DC, USA (JW); Department of Surgery, George Washington University, Washington, DC, USA (JW); Veteran Affairs Office of Research and Development, Department of Veterans Affairs, Washington, DC, USA (RGD); and Department of Surgery, Uniformed University of the Health Sciences, Bethesda, MD, USA (RGD) 1 2
3
The Lancet. Veterans’ health care: a call of duty. Lancet 2015; 386: 1014. United States Department of Veterans Affairs. National Center for Veteran Analysis and Statistics. 2015. http://www.va.gov/vetdata (accessed Nov 1, 2015). Longman P. Best care anywhere: why VA health care is better than yours. San Francisco, CA: Berrett-Koehler Publishers, 2012.
Bacterial neonatal sepsis and antibiotic resistance in low-income countries Tackling neonatal sepsis and antibiotic resistance is extremely challenging in low-income countries where neonatal mortality is high and antibiotic resistance is growing.1,2 Essential data on the burden of severe bacterial infections in neonates and bacterial causes are scarce in low-income countries, and the role of antibiotic resistance remains unclear. Relevant surveillance systems are needed to improve understanding of these issues and to guide local, regional,
and international public health policies. Importantly, surveillance of infections should include rigorous population-level measures within the community because a large proportion of people in low-income countries might not consult in-health facilities. Additionally, effective surveillance must account for the timely diagnosis of severe bacterial infections, which can be challenging in low-income country settings and particularly for neonates as infections can quickly become fatal. Along with scarce access to health facilities, early detection of severe bacterial infections is further delayed by inadequate family knowledge of clinical signs suggestive of neonatal infections and training of health-care workers. Lastly, accurate bacterial diagnosis and resistance profiles need health-care workers to be trained to take samples from infants and need skilled staff with access to appropriate laboratory equipment, which are generally only available in hospitals in low-income countries.3 Additionally, optimisation of treatment against severe bacterial infections should be a priority in lowincome countries to reduce mortality and manage antibiotic resistance. Unfortunately, it is not currently possible to update local antibiotic guidelines and change patient antibiotic regimens in many countries because there is no diagnostic capacity (eg, resistance profiles). Development of innovative point-of-care instruments for use in low-income countries might provide a solution. New antibiotics would help to restrict the emergence of resistance and to treat severe bacterial infections, but their use needs to be monitored to avoid the development of new resistance mechanisms.4 Lastly, a better understanding of the driving forces of bacterial sepsis and transmission, particularly the role of mother-to-child transmission, is needed to help fight neonatal sepsis and antibiotic resistance. 5 Insights are needed into the factors that affect pathogenicity and
Mauro Fermariello/Science Photo Library
many published, peer-reviewed studies. Both the VHA and the NHS face unique public relations problems. In the USA, however, 151 VHA hospitals operate in the same geographical area served by 5000 non-VHA hospitals. Both the VHA and the NHS are directed by and answer to political administrative organisations responsible for overseeing the service, which might not be as responsive as private sector organisations. The VHA should respond with honesty and integrity to congressional oversight. The increase in veteran enrollees and demand for more primary and emergent care led to access problems in the VHA system. The well publicised mistakes at the Phoenix Veteran Affairs Medical Center in 2014 have been published. Prompt responses allowed veterans who lived 40 miles away from a VHA facility, needed specialty services that were not available, or had to wait more than 30 days for any appointment to access the Veterans Choice programme of private care. VHA health services research is now carefully assessing efficiency and quality outcomes of this alternative care option. Anecdotal reports suggest that some patients who used the Veterans Choice programme returned to the VHA because waiting times in the private sector are often longer than those in the VHA. Despite the deluge of criticisms, a large, loyal group of patients prefer to receive health care from the VHA. Most healthcare systems outside of the VHA are not equipped to handle the unique health-care needs of veterans, who have two to three times the number of comorbidities as non-veteran patients in the private sector. Comparisons of VHA and private sector health care have been highly complimentary of VHA care.3 The VHA Surgical Quality Improvement Program has been adopted by the American College of Surgeons as a national model. Continued vilification of the VHA is as demoralising to its committed professionals as it would be to those working in the NHS. Public critique
533
See Online for appendix
532
UK MenB strains, 1 allowing for the possibility of MenB disease in Bexsero-immunised individuals due to strains not covered by the vaccine (appendix). But how easy is it to distinguish whether an infection is caused by a covered or a non-covered strain? Bexserocomprises three recombinant proteins (fHbp, NHBA, and NadA) and detergent-extracted outer membrane vesicles containing native PorA protein and several minor proteins.2 The recombinant proteins exhibit substantial diversity between meningococcal strains in both sequence and levels of expression, so that protection only occurs if a strain has medium-to-high expression of one or more homologous antigens. Monitoring requires detection of whether antigens have the requisite homology and expression to render an infective strain sensitive to protection by Bexsero. Homology can be determined by sequencing vaccine antigens in DNA extracted from either the live strain or directly from the clinical samples. However, expression levels can only be assessed with assays requiring a live bacterial isolate and are unmeasurable in cases wherein confirmation is solely based on PCR results from clinical samples.3 Since 1998–99, 8567 (47%) of the 18 141 confirmed cases of MenB disease were confirmed by PCR only, without isolation of the liveinfective strain. Why is precise monitoring required? All cases of meningococcal disease in Bexsero-immunised individuals could be classified as vaccine failures but this approach would underestimate the vaccine’s effectiveness. So how will coverage be assessed in the Bexsero era? First, for every suspected case of meningococcal disease in immunised individuals, extensive efforts will be necessary to isolate the causative meningococcal strain and run a full battery of tests for monitoring whether strains were covered or not covered (appendix). These tests will have to include sampling of contacts before
prophylaxis as potential sources of a live isolate of the infecting strain. If confirmation is solely done by PCR, running of gene-specific PCRs/DNA sequencing reactions can determine if the disease-causing strain has antigens homologous to the vaccine antigens and hence is covered (appendix). If there are no matches, a case can be marked as due to a non-covered strain. Conversely, a good match will indicate a so-called true vaccine failure by a covered strain, except that strains with low expression of a homologous fHbp allele should be marked as noncovered strains. Can monitoring be improved? There is potential for estimating expression of target antigen in clinical samples by the indirect approach of analysing promoter sequences in extracted DNA or the direct approach of measuring RNA or peptide concentrations for target antigens. But for now, the separation of lack of coverage from vaccine failure for Bexseroimmunised individuals might have to rely on improving isolation of the live infective strain. CDB, JAM, and RB are in receipt of funding from the Meningitis Research Foundation for a project entitled “Determining the molecular basis of vaccine failure” by Bexsero. RB has conducted clinical trials of capsular group B meningococcal vaccines on behalf of Public Health England funded by Novartis Vaccines and Pfizer but has no pecuniary or other interests with any vaccine manufacturer. CDB and JAM declare no competing interests.
*Christopher D Bayliss, Julie A Morrissey, Ray Borrow [email protected] Department of Genetics, University of Leicester, Leicester LE1 7RH, UK (CDB, JM); Vaccine Evaluation Unit, Public Health England, Manchester, UK (RB) 1
2
3
Frosi G, Biolchi A, Lo Sapio M, et al. Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. Vaccine 2013; 31: 4968–74. Giuliani MM, Adu-Bobie J, Comanducci M, et al. A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci USA 2006; 103: 10834–39. Donnelly J, Medini D, Boccadifuoco G, et al. Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proc Natl Acad Sci USA 2010; 107: 19490–95.
Call to duty revisited As longserving surgeons in the Veterans Health Administration (VHA) system, we found the Editorial1 about the VHA both disturbing and misleading. In view of the fact that the UK does not have a specific agency devoted to veterans, this critique of the VHA is unwarranted and non-specific. The Editorial is another gratuitous example of piling on criticism in response to news of admittedly egregious administrative wrongdoing in the misreporting of waiting times for access to primary care in the VHA health-care system. A massive increase in demand for primary care and mental health care is associated with an increase from 4·5 million veterans to about 9 million veterans between 2001 and 2013 flooding the system.2 Without appropriate administrative foresight and preparation, the system became overwhelmed in various (but not all) centres throughout the USA. We admit that the scarcity of planning and poor reporting were inexcusable. However, one needs only to run a search of the UK National Health Service (NHS) to note similar unflattering press criticisms. Despite difficulties, we believe the VHA is still a model of health-care delivery. The VHA provides lifelong coverage for veterans, while promoting health rather than treatment of ill health, which is more profitable. The VHA primary care system aims to integrate seamlessly into its expert specialty services. Advanced electronic medical records ease patient care, collect outcomes to enable the monitoring and improvement of surgical and medical practice, and provide a clinical database for research. The VHA led the decentralisation of patient care to outpatient clinics and patients’ homes. The VHA has pioneered telemedicine and secure internet messaging between patients and health-care providers. The list of VHA innovations goes on, and these innovations have been recognised in www.thelancet.com Vol 387 February 6, 2016
Correspondence
www.thelancet.com Vol 387 February 6, 2016
is widespread, and perhaps needed, for all publicly supported agencies in democratic societies; but reason must prevail. Although not perfect, we believe the VHA is probably the best health-care model for people who have borne the burden of battle. Health-care professionals help those who are called to arms in the tradition of excellence they deserve; the quality of these services needs recognition and respect. We are employees of the Department of Veterans Affairs. The opinions expressed are those of the authors and not those of the US Government or the Department of Veterans Affairs.
*Earl Gaar, Jon White, Ralph G DePalma [email protected] Department of Veterans Affairs, Robley Rex Veteran Affairs Medical Center, University of Louisville School of Medicine, Louisville, KY, USA (EG); Department of Veterans Affairs, Washington DC Veterans Affairs Medical Center, Washington, DC, USA (JW); Department of Surgery, George Washington University, Washington, DC, USA (JW); Veteran Affairs Office of Research and Development, Department of Veterans Affairs, Washington, DC, USA (RGD); and Department of Surgery, Uniformed University of the Health Sciences, Bethesda, MD, USA (RGD) 1 2
3
The Lancet. Veterans’ health care: a call of duty. Lancet 2015; 386: 1014. United States Department of Veterans Affairs. National Center for Veteran Analysis and Statistics. 2015. http://www.va.gov/vetdata (accessed Nov 1, 2015). Longman P. Best care anywhere: why VA health care is better than yours. San Francisco, CA: Berrett-Koehler Publishers, 2012.
Bacterial neonatal sepsis and antibiotic resistance in low-income countries Tackling neonatal sepsis and antibiotic resistance is extremely challenging in low-income countries where neonatal mortality is high and antibiotic resistance is growing.1,2 Essential data on the burden of severe bacterial infections in neonates and bacterial causes are scarce in low-income countries, and the role of antibiotic resistance remains unclear. Relevant surveillance systems are needed to improve understanding of these issues and to guide local, regional,
and international public health policies. Importantly, surveillance of infections should include rigorous population-level measures within the community because a large proportion of people in low-income countries might not consult in-health facilities. Additionally, effective surveillance must account for the timely diagnosis of severe bacterial infections, which can be challenging in low-income country settings and particularly for neonates as infections can quickly become fatal. Along with scarce access to health facilities, early detection of severe bacterial infections is further delayed by inadequate family knowledge of clinical signs suggestive of neonatal infections and training of health-care workers. Lastly, accurate bacterial diagnosis and resistance profiles need health-care workers to be trained to take samples from infants and need skilled staff with access to appropriate laboratory equipment, which are generally only available in hospitals in low-income countries.3 Additionally, optimisation of treatment against severe bacterial infections should be a priority in lowincome countries to reduce mortality and manage antibiotic resistance. Unfortunately, it is not currently possible to update local antibiotic guidelines and change patient antibiotic regimens in many countries because there is no diagnostic capacity (eg, resistance profiles). Development of innovative point-of-care instruments for use in low-income countries might provide a solution. New antibiotics would help to restrict the emergence of resistance and to treat severe bacterial infections, but their use needs to be monitored to avoid the development of new resistance mechanisms.4 Lastly, a better understanding of the driving forces of bacterial sepsis and transmission, particularly the role of mother-to-child transmission, is needed to help fight neonatal sepsis and antibiotic resistance. 5 Insights are needed into the factors that affect pathogenicity and
Mauro Fermariello/Science Photo Library
many published, peer-reviewed studies. Both the VHA and the NHS face unique public relations problems. In the USA, however, 151 VHA hospitals operate in the same geographical area served by 5000 non-VHA hospitals. Both the VHA and the NHS are directed by and answer to political administrative organisations responsible for overseeing the service, which might not be as responsive as private sector organisations. The VHA should respond with honesty and integrity to congressional oversight. The increase in veteran enrollees and demand for more primary and emergent care led to access problems in the VHA system. The well publicised mistakes at the Phoenix Veteran Affairs Medical Center in 2014 have been published. Prompt responses allowed veterans who lived 40 miles away from a VHA facility, needed specialty services that were not available, or had to wait more than 30 days for any appointment to access the Veterans Choice programme of private care. VHA health services research is now carefully assessing efficiency and quality outcomes of this alternative care option. Anecdotal reports suggest that some patients who used the Veterans Choice programme returned to the VHA because waiting times in the private sector are often longer than those in the VHA. Despite the deluge of criticisms, a large, loyal group of patients prefer to receive health care from the VHA. Most healthcare systems outside of the VHA are not equipped to handle the unique health-care needs of veterans, who have two to three times the number of comorbidities as non-veteran patients in the private sector. Comparisons of VHA and private sector health care have been highly complimentary of VHA care.3 The VHA Surgical Quality Improvement Program has been adopted by the American College of Surgeons as a national model. Continued vilification of the VHA is as demoralising to its committed professionals as it would be to those working in the NHS. Public critique
533