Comment
earlier investigation done during 2006–07 in which 9% and 46% had heard of HCV, of whom 20% and 37%, respectively, underwent HCV testing.10 A 2010 systematic review of HIV prevention and care services for people who inject drugs estimated that although 78% of people who inject drugs were covered by HIV prevention and care services in India, the number of needles-syringes distributed per person who injects drugs per year was around 34 (22–58) and there were three oral substitution therapy recipients in 100 people who inject drugs;11 estimates for HIV positive people who inject drugs receiving antiretroviral therapy were not available. Moreover, the assessment from Punjab6 showed that people who inject drugs reporting irregular supply of syringes and needles from targeted intervention sites had almost twice the odds of being HCV seroreactive compared with their counterparts. All this evidence underscores the fact that access to prevention, care, and treatment remains a challenge for people who inject drugs. It will be a while before treatment for HCV infection becomes affordable and available through public health programmes. Prevention efforts should therefore consist of awareness about HCV (and hepatitis B), safe injection practices, including an emphasis on clean injection paraphernalia, oral substitution therapy, and sexual risk reduction in people who inject drugs. Global evidence is evolving such that quality coverage with comprehensive harmreduction interventions at a sufficient scale can reduce HCV incidence.12
Avina Sarna, *Samiran Panda Population Council, India Office,Dehli, India (AS); and National Institute of Cholera & Enteric Diseases (ICMR), Kolkata, West Bengal, India 700010 (SP) [email protected] 1 2
3 4
5
6
7
8
9
10
11
12
The Lancet. Only just the beginning of the end of hepatitis C. Lancet 2014; 383: 281. Solomon SS, Mehta SH, Srikirishnan AK, et al. High burden of HCV disease and poor access to HCV services among people who inject drugs in India: A crosssectional study among 14,481 drug users across India. Lancet Infect Dis 2014; published online Dec 3. http://dx.doi.org/10.1016/S1473-3099(14)71054-0. Panda S, Chatterjee A, Sarkar S, et al. Injection drug use in Calcutta: a potential focus for an explosive HIV epidemic. Drug Alcohol Rev 1997; 16: 17–23. Eicher AD, Crofts N, Benjamin S, Deutschmann P, Rodger AJ. A certain fate: spread of HIV among young injecting drug users in Manipur, north-east India. AIDS Care 2000; 12: 497–504. Solomon SS, Srikrishnan AK, Mehta SH, et al. High prevalence of HIV, HIV/ hepatitis C virus coinfection, and risk behaviors among injection drug users in Chennai, India: a cause for concern. J Acquir Immune Defic Syndr 2008; 49: 327–32. Panda S, Roy T, Pahari S, et al. Alarming epidemics of human immunodeficiency virus and hepatitis C virus among injection drug users in the northwestern bordering state of Punjab, India: prevalence and correlates. Int J STD AIDS 2013; 25: 596–606. Platt L, Vickerman P, Collumbien M, et al. Prevalence of HIV, HCV and sexually transmitted infections among injecting drug users in Rawalpindi and Abbottabad, Pakistan: evidence for an emerging injection-related HIV epidemic. Sex Transm Infect 2009; 85 (suppl 2): ii17–22. Taylor LE, Swan T, Mayer KH. HIV coinfection with hepatitis C virus: evolving epidemiology and treatment paradigms. Clin Infect Dis 2012; 55 (suppl 1): S33–42. Paintsil E, Binka M, Patel A, Lindenbach BD, Heimer R. Hepatitis C virus maintains infectivity for weeks after drying on inanimate surfaces at room temperature: implications for risks of transmission. J Infect Dis 2014; 209: 1205–11. Sarna A, Tun W, Bhattacharya A, Lewis D, Singh YS, Apicella L. Assessment of unsafe injection practices and sexual behaviors among male injecting drug users in two urban cities of India using respondent driven sampling. Southeast Asian Journal of Tropical Medicine & Public Health 2012; 43: 652–67. Mathers BM, Degenhardt L, Ali H, et al. HIV prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage. Lancet 2010; 375: 1014–28. Palmateer NE, Taylor A, Goldberg DJ, et al. Rapid decline in HCV incidence among people who inject drugs associated with national scale-up in coverage of a combination of harm reduction interventions. PLoS One 2014; 9: e104515.
Sepsis in children: some good news, some confusing news In critically ill children in Australia and New Zealand, the incidence of invasive infections, sepsis, and septic shock has increased in the past decade while mortality has decreased. This simple message, reported in The Lancet Infectious Diseases by Luregn Schlapbach and colleagues,1 provides some reassurance that, despite the heavy burden of severe infections in children, clinical outcomes are improving. However, it also shows the complexity of understanding data in a subject as murky as sepsis. For instance, both in Schlapbach and colleagues’ study and in a similar report from the USA,2 most of the increase in incidence of severe infections was attributable to www.thelancet.com/infection Vol 15 January 2015
neonatal disease. Neonatal and paediatric sepsis are in many respects different diseases; therefore, conflating them into a single analysis makes interpretation challenging. Another example is the categorisation of patients into three supposedly non-overlapping groups: invasive infection, sepsis, and septic shock. Many readers will find it hard to understand how, for example, a patient with necrotising fasciitis who is sick enough to be in a paediatric intensive care unit would not be regarded as having sepsis. Such difficulties, which have long bedevilled studies of sepsis, do not detract from the importance of the overall conclusions of the study. But they do serve
Published Online December 1, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71044-8 See Articles page 46
5
Comment
Ria Novosti/Science Photo Library
as a reminder that although the term sepsis is a valuable clinical descriptor of a condition that almost every doctor will encounter, the catch-all nature of the term often conceals more than it reveals. Determining the true incidence of sepsis and its underlying causes is important, not just to quantify the burden of disease and to ensure that adequate resources are provided to deal with it, but also because it informs priorities for clinical research. However, the use of registry data can have unexpected pitfalls.3 Factors such as ascertainment artefact, subtle changes in definitions, better and earlier diagnosis, and even reimbursement considerations can falsely seem to increase incidence in a population.4 Kaukonen and colleagues have published an analysis of trends in the incidence and mortality associated with sepsis in adults in Australia and New Zealand that carefully avoided these dangers.5 They showed that, as for the data for children, incidence was rising but mortality was falling. But they also reported significant differences in outcome depending on age and presence of comorbidities. The overall crude hospital mortality in patients with comorbidities was 33% compared with just 5% in patients younger than 44 years of age without other underlying complications. These data have important implications. Imagine planning a phase 3 trial of a new intervention for sepsis in which the primary endpoint was hospital mortality. The calculation of the number of patients to enrol would be based on the anticipated effect size of the intervention and the mortality rate in the placebo group. If the study population contained a subgroup with a much lower than expected mortality, the calculations would be wrong (mortality in the placebo group would be lower) and a true effect of the intervention might be missed (a type 2 error). This possibility has concerned many people studying sepsis. Furthermore, by using broad enrolment criteria, investigators might have included a very mixed
population, only some of whom might be responsive to the intervention, thereby lowering the signal-to-noise ratio to a point where potentially valuable treatments have not been identified. This possibility is the reason why accurate information about the incidence and severity of sepsis, be it in children or adults, is so important. It is also why researchers should be careful in describing exactly which patients they are talking about and in interpreting data. Although sepsis is instantly recognisable (although sadly, not always as instantly as it should be), many investigators are increasingly uneasy about using it as the basis of clinical trials.6,7 Schlapbach and colleagues have provided valuable data showing that sepsis in children remains a significant challenge, and discarding the term sepsis would not be wise. But paradoxically, meeting that challenge might mean that researchers no longer use sepsis as the starting point for clinical research in this difficult and frustrating field. Jonathan Cohen Brighton & Sussex Medical School, University of Sussex, Falmer, BN1 9PH, UK [email protected] I declare no competing interests. 1
2 3
4
5
6 7
Schlapbach LJ, Straney L, Alexander J, et al, for the ANZICS Paediatric Study Group. Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study. Lancet Infect Dis 2014; published online Dec 1. http://dx.doi.org/10.1016/S1473-3099(14)71003-5. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis. Pediatr Crit Care Med 2013; 7: 686–93. Iwashyna TJ, Angus DC. Declining case fatality rates for severe sepsis. Good data bring good news with ambiguous implications. JAMA 2014; 311: 1295–97. Feinstein AR, Sosin DA, Wells CK. The Will Rogers phenomenon: stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985; 312: 1604–08. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 13: 1308–16. Cohen J, Opal S, Calandra T. Sepsis studies need new direction. Lancet Infect Dis 2012; 7: 503–05. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet 2013; 381: 774–75.
Reflections on travel-associated infections in Europe Published Online December 2, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71055-2 See Articles page 55
6
In The Lancet Infectious Diseases, Patricia Schlagenhauf and colleagues1 analyse travel-associated morbidity in 32 136 travellers presenting to European sites of the GeoSentinel Network with a post-travel illness over the period 2008–12. Knowledge about illness in travellers contributes to the understanding of disease
epidemiology in our interconnected world. In addition to their own ill health, travellers serve as sentinels of infectious diseases; moreover, they can also transmit and disseminate infections.2–4 Travellers have shown these important roles in emerging infections such as SARS (severe acute respiratory syndrome), dengue www.thelancet.com/infection Vol 15 January 2015
earlier investigation done during 2006–07 in which 9% and 46% had heard of HCV, of whom 20% and 37%, respectively, underwent HCV testing.10 A 2010 systematic review of HIV prevention and care services for people who inject drugs estimated that although 78% of people who inject drugs were covered by HIV prevention and care services in India, the number of needles-syringes distributed per person who injects drugs per year was around 34 (22–58) and there were three oral substitution therapy recipients in 100 people who inject drugs;11 estimates for HIV positive people who inject drugs receiving antiretroviral therapy were not available. Moreover, the assessment from Punjab6 showed that people who inject drugs reporting irregular supply of syringes and needles from targeted intervention sites had almost twice the odds of being HCV seroreactive compared with their counterparts. All this evidence underscores the fact that access to prevention, care, and treatment remains a challenge for people who inject drugs. It will be a while before treatment for HCV infection becomes affordable and available through public health programmes. Prevention efforts should therefore consist of awareness about HCV (and hepatitis B), safe injection practices, including an emphasis on clean injection paraphernalia, oral substitution therapy, and sexual risk reduction in people who inject drugs. Global evidence is evolving such that quality coverage with comprehensive harmreduction interventions at a sufficient scale can reduce HCV incidence.12
Avina Sarna, *Samiran Panda Population Council, India Office,Dehli, India (AS); and National Institute of Cholera & Enteric Diseases (ICMR), Kolkata, West Bengal, India 700010 (SP) [email protected] 1 2
3 4
5
6
7
8
9
10
11
12
The Lancet. Only just the beginning of the end of hepatitis C. Lancet 2014; 383: 281. Solomon SS, Mehta SH, Srikirishnan AK, et al. High burden of HCV disease and poor access to HCV services among people who inject drugs in India: A crosssectional study among 14,481 drug users across India. Lancet Infect Dis 2014; published online Dec 3. http://dx.doi.org/10.1016/S1473-3099(14)71054-0. Panda S, Chatterjee A, Sarkar S, et al. Injection drug use in Calcutta: a potential focus for an explosive HIV epidemic. Drug Alcohol Rev 1997; 16: 17–23. Eicher AD, Crofts N, Benjamin S, Deutschmann P, Rodger AJ. A certain fate: spread of HIV among young injecting drug users in Manipur, north-east India. AIDS Care 2000; 12: 497–504. Solomon SS, Srikrishnan AK, Mehta SH, et al. High prevalence of HIV, HIV/ hepatitis C virus coinfection, and risk behaviors among injection drug users in Chennai, India: a cause for concern. J Acquir Immune Defic Syndr 2008; 49: 327–32. Panda S, Roy T, Pahari S, et al. Alarming epidemics of human immunodeficiency virus and hepatitis C virus among injection drug users in the northwestern bordering state of Punjab, India: prevalence and correlates. Int J STD AIDS 2013; 25: 596–606. Platt L, Vickerman P, Collumbien M, et al. Prevalence of HIV, HCV and sexually transmitted infections among injecting drug users in Rawalpindi and Abbottabad, Pakistan: evidence for an emerging injection-related HIV epidemic. Sex Transm Infect 2009; 85 (suppl 2): ii17–22. Taylor LE, Swan T, Mayer KH. HIV coinfection with hepatitis C virus: evolving epidemiology and treatment paradigms. Clin Infect Dis 2012; 55 (suppl 1): S33–42. Paintsil E, Binka M, Patel A, Lindenbach BD, Heimer R. Hepatitis C virus maintains infectivity for weeks after drying on inanimate surfaces at room temperature: implications for risks of transmission. J Infect Dis 2014; 209: 1205–11. Sarna A, Tun W, Bhattacharya A, Lewis D, Singh YS, Apicella L. Assessment of unsafe injection practices and sexual behaviors among male injecting drug users in two urban cities of India using respondent driven sampling. Southeast Asian Journal of Tropical Medicine & Public Health 2012; 43: 652–67. Mathers BM, Degenhardt L, Ali H, et al. HIV prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage. Lancet 2010; 375: 1014–28. Palmateer NE, Taylor A, Goldberg DJ, et al. Rapid decline in HCV incidence among people who inject drugs associated with national scale-up in coverage of a combination of harm reduction interventions. PLoS One 2014; 9: e104515.
Sepsis in children: some good news, some confusing news In critically ill children in Australia and New Zealand, the incidence of invasive infections, sepsis, and septic shock has increased in the past decade while mortality has decreased. This simple message, reported in The Lancet Infectious Diseases by Luregn Schlapbach and colleagues,1 provides some reassurance that, despite the heavy burden of severe infections in children, clinical outcomes are improving. However, it also shows the complexity of understanding data in a subject as murky as sepsis. For instance, both in Schlapbach and colleagues’ study and in a similar report from the USA,2 most of the increase in incidence of severe infections was attributable to www.thelancet.com/infection Vol 15 January 2015
neonatal disease. Neonatal and paediatric sepsis are in many respects different diseases; therefore, conflating them into a single analysis makes interpretation challenging. Another example is the categorisation of patients into three supposedly non-overlapping groups: invasive infection, sepsis, and septic shock. Many readers will find it hard to understand how, for example, a patient with necrotising fasciitis who is sick enough to be in a paediatric intensive care unit would not be regarded as having sepsis. Such difficulties, which have long bedevilled studies of sepsis, do not detract from the importance of the overall conclusions of the study. But they do serve
Published Online December 1, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71044-8 See Articles page 46
5
Comment
Ria Novosti/Science Photo Library
as a reminder that although the term sepsis is a valuable clinical descriptor of a condition that almost every doctor will encounter, the catch-all nature of the term often conceals more than it reveals. Determining the true incidence of sepsis and its underlying causes is important, not just to quantify the burden of disease and to ensure that adequate resources are provided to deal with it, but also because it informs priorities for clinical research. However, the use of registry data can have unexpected pitfalls.3 Factors such as ascertainment artefact, subtle changes in definitions, better and earlier diagnosis, and even reimbursement considerations can falsely seem to increase incidence in a population.4 Kaukonen and colleagues have published an analysis of trends in the incidence and mortality associated with sepsis in adults in Australia and New Zealand that carefully avoided these dangers.5 They showed that, as for the data for children, incidence was rising but mortality was falling. But they also reported significant differences in outcome depending on age and presence of comorbidities. The overall crude hospital mortality in patients with comorbidities was 33% compared with just 5% in patients younger than 44 years of age without other underlying complications. These data have important implications. Imagine planning a phase 3 trial of a new intervention for sepsis in which the primary endpoint was hospital mortality. The calculation of the number of patients to enrol would be based on the anticipated effect size of the intervention and the mortality rate in the placebo group. If the study population contained a subgroup with a much lower than expected mortality, the calculations would be wrong (mortality in the placebo group would be lower) and a true effect of the intervention might be missed (a type 2 error). This possibility has concerned many people studying sepsis. Furthermore, by using broad enrolment criteria, investigators might have included a very mixed
population, only some of whom might be responsive to the intervention, thereby lowering the signal-to-noise ratio to a point where potentially valuable treatments have not been identified. This possibility is the reason why accurate information about the incidence and severity of sepsis, be it in children or adults, is so important. It is also why researchers should be careful in describing exactly which patients they are talking about and in interpreting data. Although sepsis is instantly recognisable (although sadly, not always as instantly as it should be), many investigators are increasingly uneasy about using it as the basis of clinical trials.6,7 Schlapbach and colleagues have provided valuable data showing that sepsis in children remains a significant challenge, and discarding the term sepsis would not be wise. But paradoxically, meeting that challenge might mean that researchers no longer use sepsis as the starting point for clinical research in this difficult and frustrating field. Jonathan Cohen Brighton & Sussex Medical School, University of Sussex, Falmer, BN1 9PH, UK [email protected] I declare no competing interests. 1
2 3
4
5
6 7
Schlapbach LJ, Straney L, Alexander J, et al, for the ANZICS Paediatric Study Group. Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study. Lancet Infect Dis 2014; published online Dec 1. http://dx.doi.org/10.1016/S1473-3099(14)71003-5. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis. Pediatr Crit Care Med 2013; 7: 686–93. Iwashyna TJ, Angus DC. Declining case fatality rates for severe sepsis. Good data bring good news with ambiguous implications. JAMA 2014; 311: 1295–97. Feinstein AR, Sosin DA, Wells CK. The Will Rogers phenomenon: stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985; 312: 1604–08. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 13: 1308–16. Cohen J, Opal S, Calandra T. Sepsis studies need new direction. Lancet Infect Dis 2012; 7: 503–05. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet 2013; 381: 774–75.
Reflections on travel-associated infections in Europe Published Online December 2, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71055-2 See Articles page 55
6
In The Lancet Infectious Diseases, Patricia Schlagenhauf and colleagues1 analyse travel-associated morbidity in 32 136 travellers presenting to European sites of the GeoSentinel Network with a post-travel illness over the period 2008–12. Knowledge about illness in travellers contributes to the understanding of disease
epidemiology in our interconnected world. In addition to their own ill health, travellers serve as sentinels of infectious diseases; moreover, they can also transmit and disseminate infections.2–4 Travellers have shown these important roles in emerging infections such as SARS (severe acute respiratory syndrome), dengue www.thelancet.com/infection Vol 15 January 2015
