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and colleagues1 and Moore and colleagues2 are essential for decisions about next steps. In summarising more than 50 years of research in The Biology of Pneumococcus9 from 1938, Benjamin White wrote in awe of this “altogether amazing cell”, but commented that “man has not been content to allow Pneumococcus to destroy human life in an unrestrained way”. In fact, he noted that “the epidemiologist has attempted to track the mode of dissemination…in the hope of breaking the vicious cycle of transmission from man to man”. White would surely rejoice at the reduction in pneumococcal disease in the 21st century. He would probably not be surprised that the pneumococcus continues to fascinate and provide opportunities for further restraint.

Copyright © Griffin et al. Open Access article distributed under the terms of CC BY. 1

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*Marie R Griffin, Carlos G Grijalva Department of Health Policy, Vanderbilt University Medical Center, Villlage at Vanderbilt, Nashville, Tennessee 37232, USA marie.griffi[email protected] CGG has served as consultant for GSK and Pfizer and declares grant funding from the US Centers for Disease Control and Prevention and the US Agency for Healthcare Research and Quality, outside of the submitted work. MRG declares grant funding from the US Centers for Disease Control and Prevention, outside of the submitted work.

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Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MPE, Miller E. Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. Lancet Infect Dis 2015; published online March 20. http://dx.doi.org/10.1016/S1473-3099(15)70044-7. Moore MR, Link-Gelles R, Schaffner W, et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, populationbased surveillance. Lancet Infect Dis 2015; 15: 301–09. Wroe PC, Lee GM, Finkelstein JA, et al. Pneumococcal carriage and antibiotic resistance in young children before 13-valent conjugate vaccine. Pediatr Infect Dis J 2012; 31: 249–54. Loughlin AM, Hsu K, Silverio AL, Marchant CD, Pelton SI. Direct and indirect effects of PCV13 on nasopharyngeal carriage of PCV13 unique pneumococcal serotypes in Massachusetts’ children. Pediatr Infect Dis J 2014; 33: 504–10. van Hoek AJ, Sheppard CL, Andrews NJ, et al. Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England. Vaccine 2014; 32: 4349–55. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010; 201: 32–41. Flasche S, Edmunds WJ, Miller E, Goldblatt D, Robertson C, Choi YH. The impact of specific and non-specific immunity on the ecology of Streptococcus pneumoniae and the implications for vaccination. Proc Biol Sci 2013; 280: 20131939. Nurhonen M, Auranen K. Optimal serotype compositions for Pneumococcal conjugate vaccination under serotype replacement. PLoS Comput Biol 2014; 10: e1003477. White B, Robinson ES, Barnes LA. The biology of pneumococcus. The bacteriological, biochemical, and immunological characters and activities of Diplococcus pneumoniae. New York: The Commonwealth fund, 1938.

Cristina Pedrazzini/Science Photo Library

Autopsies and better data on causes of death in Africa

Published Online March 10, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70096-4 See Articles page 544

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Active tuberculosis, particularly when extrapulmonary or disseminated, can be extremely difficult to diagnose before death and is often missed, including as a cause of death. Therefore, autopsy studies can be especially informative. In their classic 1960 study, Petersdorf and Beeson1 identified tuberculosis as the most common cause of fever of unknown origin; most cases were extrapulmonary, and although most were diagnosed both before and after death, one case was only identified after death. In the same decade, autopsy played a crucial part in defining cryptic disseminated tuberculosis as a variant of reactivated tuberculosis that occurred particularly in elderly Scottish women and that was difficult to diagnose.2 More recently, autopsy studies have helped delineate the spectrum of HIV-associated disease in Africa and have shown that active tuberculosis in all its forms is a common cause of adult death.3,4 The global burden of tuberculosis remains immense. In 2014, WHO reported that as many as 3 million people with active tuberculosis remained undiagnosed

and thus untreated, 1·5 million people died from tuberculosis in 2014, and the situation with multidrug resistant tuberculosis is worsening.5 These estimates remain imprecise because of ongoing challenges with diagnosis, inadequate case reporting, and the poor state of vital statistics and death registration in most lowincome and middle-income countries. More accurate estimates of the burden of tuberculosis and the number of deaths from tuberculosis are crucial for appropriate resource allocation to improve case detection, reduce tuberculosis transmission, and achieve global tuberculosis control. The results of the meticulous autopsy study in Zambia by Matthew Bates and colleagues6 published in The Lancet Infectious Diseases are thus timely and important. Bates and colleagues highlight the substantial burden of active tuberculosis in adult patients (≥16 years) who died on adult general medical wards at a tertiary care centre in Lusaka. Overall, over 80% of patients had underlying HIV infection. Active tuberculosis was present in nearly www.thelancet.com/infection Vol 15 May 2015

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two-thirds of patients, with most having substantial comorbidity that probably contributed to death. Nearly 20% of patients had multidrug-resistant tuberculosis. Health-seeking behaviour seemed compromised because the median time from admission to death was 7 days, suggesting that most patients who died were very sick when they arrived at the wards and there was insufficient time for diagnostic investigations and therapeutic interventions. A quarter of the patients with active tuberculosis were only diagnosed at autopsy and were not on antituberculosis treatment. The attending physicians judged tuberculosis to be the cause of death in just 60% of those with active tuberculosis found at autopsy. From a service perspective, Bates and colleagues concluded that increased clinical awareness of active tuberculosis is needed in the general medical inpatient services, backed up by more proactive screening for tuberculosis and multidrug resistant tuberculosis. Since most patients who died with undiagnosed tuberculosis had presented very late to the hospital, the effect this would have on reducing tuberculosis mortality would probably be small unless substantial efforts are made to support better health-seeking behaviour, coupled with strategies to improve the health-care cascade with earlier identification of active tuberculosis at the primary care level. Patients who end up in a tertiary centre are not representative of the patterns of morbidity and mortality in the general population, and without data on the rates of multidrug-resistant tuberculosis across Zambia, whether tuberculosis screening in all general medical services should routinely include drug resistance testing or not is unclear. Adding this test would have substantial cost and resource implications and highlights the need for population-level surveillance data in addition to autopsy data to put into context many of the study’s key findings. From a system perspective, the findings of the study by Bates and colleagues6 further challenges the assumption that causes of death are being accurately recorded and reported in hospitals.7 Health systems worldwide depend on reliable information about causes of mortality to be able to effectively respond to changing epidemiological circumstances and appropriately allocate resources. Unfortunately, the poor state of health information systems, particularly mortality statistics, is widely documented.8 The gold standard for cause-of-death reporting is to have the www.thelancet.com/infection Vol 15 May 2015

cause certified by a medical practitioner using the rules and procedures of the International Classification of Diseases (ICD), which is available in its tenth revision.9 Unfortunately, clinicians might not have the time, incentives, diagnostic facilities, or training to correctly certify causes of death, and they seldom appreciate that these diagnoses guide national health priorities.10 In this regard, information on how thoroughly this university teaching hospital routinely reports and codes inpatient deaths, and whether the additional autopsy data were fed back and included to improve the accuracy of hospital death reports, would have been useful. Ultimately, one study alone has limited ability to improve patient outcome and contribute to better appreciation of the burden of tuberculosis disease and deaths in Zambia. Rather than recommending further autopsy studies to ascertain the validity of these findings, we argue that the best investment in the short-to-medium term would be to develop strategies to improve the accuracy, recording, and reporting of all causes of death. Autopsies provide the most accurate data about cause of death, but are prohibitively expensive and impossible to scale up to cover a whole country.11 Improved training of selected physicians using ICD-compliant death certification guidelines to review medical records in a sample of hospitals is more practical and affordable, and can cover more facilities.7 Funding is likely to be available, because the World Bank with WHO have recently produced a plan to scale up investment in global civil registration and vital statistics to help address the deficit in this crucial but neglected area.12 This comprehensive autopsy study could be the catalyst to unlock funds to improve Zambia’s health information system, with particular reference to cause-of-death reporting. That would be an unexpected but extremely important outcome, with benefits above and beyond tuberculosis control for general health planning and policy development. Rasika Rampatige, *Charles F Gilks School of Public Health, The University of Queensland, Brisbane, QLD 4006, Australia [email protected] We declare no competing interests. 1 2

Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine 1961; 40: 1–30. Proudfoot AT, Akhtar AJ, Douglas AC, Horne NW. Miliary tuberculosis in adults. BMJ 1969; 2: 273–76.

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Lucas SB, Hounnou A, Peacock C, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993; 7: 1569–79. Rana FS, Hawken MP, Mwachari C, et al. Autopsy study of HIV-1-positive and HIV-1-negative adult medical patients in Nairobi, Kenya. J Acquir Immune Defic Synd 2000; 24: 23–29. WHO. Global tuberculosis report 2014. Geneva: World Health Organization, 2014. Bates M, Mudenda V, Shibemba A, et al. Burden of tuberculosis at post mortem in inpatients at a tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study. Lancet Infect Dis 2015; published online March 10. http://dx.doi.org/10.1016/S1473-3099(15)70058-7. Rampatige R, Mikkelsen L, Hernandez B, Riley I, Lopez AD. Systematic review of statistics on causes of deaths in hospitals: strengthening the evidence for policy-makers. Bull World Health Organ 2014; 92: 807–16.

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Mahapatra P, Shibuya K, Lopez AD, et al. Monitoring vital events, civil registration systems and vital statistics: successes and missed opportunities. Lancet 2007; 370: 1653–63. WHO. International Classification of Diseases. 10th revision. Geneva: World Health Organization, 2007. Shojania KG, Burton EC, McDonald KM, Goldman L. Changes in rates of autopsy-detected diagnostic errors over time: a systematic review. JAMA 2003; 289: 2849–56. Rampatige R, Mikkelsen L, Hernandez B, Riley I, Lopez AD. Hospital cause-of-death statistics: what should we make of them? Bull World Health Organ 2014; 92: 3-3A. World Bank, WHO. Global civil registration and vital statistics: scaling up investment plan 2015–2024. Washington: World Bank Group, 2014.

A.B. Dowsett/Science Photo Library

Illuminating meningococcal diagnosis with LAMP

Published Online February 27, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70066-6 See Articles page 552

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Traditional PCR-based assays have enabled reasonably rapid detection of pathogens in clinical specimens with better sensitivity than culture-based microbiology.1 Unfortunately, actual use of PCR is limited by the requirements for laboratory personnel expertise, sophisticated laboratory equipment, and the high cost of commercial PCR reagents, which make the use of this technique rare outside urban medical centres in highincome countries.2 Therefore, many PCR-based tests are only available at reference laboratories. The time needed for shipping, processing, and communicating results adds substantial delay to the time when the clinician can act on the findings. Clinicians therefore have to rely on empirical treatment and often pursue a multitude of diagnostics that—had a definitive test result been returned promptly—would have been unnecessary. In The Lancet Infectious Diseases, Thomas Bourke and colleagues present a well-conducted, prospective clinical cohort study validating the use of loop-mediated isothermal amplification (LAMP) for the detection of meningococcal disease in children.3 LAMP is a nucleic acid amplification method that is isothermic—ie, the sample and assay reagents are able to rapidly duplicate the DNA of the target at a fairly constant temperature.4 This approach allows for less laboratory infrastructure requirements—specifically, an expensive thermal cycler for PCR is not needed. LAMP results can be detected by visual turbidity or fluorescence, which makes this method a practical near-patient assay.4 The authors showed that meningococcal LAMP had a sensitivity of 89% and negative predictive value of 98% when tested on respiratory and blood specimens, with 100% specificity and 100% positive predictive value, when tested in real-world near-patient settings.3

Additionally, the test was useful on cerebrospinal fluid samples from patients in whom antibiotic therapy had already been started, which is a common situation in which culture and Gram stain are of limited use.5 The performance of LAMP PCR was roughly equivalent to that of traditional PCR and was much better than culture. Perhaps one of the most interesting findings was that the median time to results was around 90 min. Delay in effective treatment of meningitis or sepsis of any cause is highly detrimental and often leads to poor outcomes. A rapid test such as LAMP for meningococcal disease could greatly improve diagnostic capability, especially in cases in which empirical antibiotic treatment has been started. The use of LAMP has been investigated in several situations, many of which are aimed at assessing the use of the method in resource-limited settings.6,7 The technical requirements for LAMP are much less onerous than are those of traditional PCR7 and, as shown in Bourke and colleagues’ report, LAMP for meningococcal disease is rapid and accurate. The relative simplicity of LAMP makes the test an attractive option. In middleincome and high-income countries, laboratory labour is a substantial component of an assay cost. Therefore, LAMP could be an ideal test for the detection of meningococcal disease in many settings. However, three challenges exist for commercialisation. First, the implementation of new conjugate meningococcal vaccines in Europe (serotype B) and in Africa (serotype A) could greatly diminish the need for meningococcal diagnostics as the disease prevalence decreases. Second, the meningococcal LAMP is a singleplex test, yet we live in a multiplex world in which www.thelancet.com/infection Vol 15 May 2015

Autopsies and better data on causes of death in Africa.

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