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Infection in cancer and transplantation
DEFENCE AGAINST INFECTION
Infection in cancer and transplantation
Key points
Vanya A Gant
C
Antibiotic resistance is now challenging cancer outcomes
C
Resistance to antifungal agents is now emerging
C
Antibiotic infusion rather than bolus therapy is advantageous
C
Fluoroquinolone prophylaxis carries unacceptable consequences
Abstract Treatment options and the promise of cure for malignancy have increased in the last few years and will continue to do so as we ‘personalize’ more treatment modalities. Although innovations such as checkpoint inhibitors and chimaeric antigen receptor T cell therapy hold much promise, almost all therapy in 2017 remains exceedingly toxic and indiscriminate, killing rapidly dividing (tumour) cells as well as some or all other bystander immune cells. These advances with increasingly aggressive chemotherapy have only been made possible by the prevention and treatment of opportunistic, life-threatening infections. We are now challenged by the inexorable rise of antimicrobial resistance, the appearance of antifungal resistance and the longer term consequences of immunosuppression beyond cancer cure. The latter relates to being tumour-free but immunosuppressed because of graft-versus-host disease and its treatment, unpredictable poor graft function or the longer term damage from chemotherapeutic agents, which can destroy T cell immunological memory for months if not years. Until and unless we match increasingly effective but immune-destructive therapy with anti-infective therapy, an increasing proportion of patients will perish not of their tumour, but of their infections.
too much when dealing with a feverish patient with malignancy. Recalcitrant fever in a neutropenic patient might, for example, represent tuberculosis in evolution.
Resistance to antibacterials Resistance, especially in Gram-negative organisms, continues to accelerate globally. A single example for one organism is shown in Figure 2. Bacteraemic infection in the neutropenic phase is the norm rather than the exception, and if left unchecked by neutrophils and/or effective antibiotics will be rapidly lethal. We have become too complacent regarding the value of our antibiotics. These now cannot be predictably expected to protect neutropenic patients for weeks without overwhelming infection. The UK is the first country to have reacted to such complacency.1 This ‘safety net’ has almost disappeared in some countries through antibiotic profligacy and its link to resistance. Grampositive organisms remain less of a threat: neutropenia might even offer some protection against the mortality and morbidity these organisms drive when bacteraemia ensues. Accordingly, 20% of patients in some countries are already colonized with extended-spectrum b-lactamase (ESBL)-producing Gram-negative organisms; this figure rises to 33% in Asia. These patients have a 13-fold higher risk of ESBL bacteraemia and significantly worse 28-day mortality. Italian figures show ‘hotspots’ for Klebsiella pneumoniae, with an eye-watering 46% mortality compared with 15% in patients not colonized with such organisms.2 This relates to ineffective empirical antibiotic use at the onset of neutropenic sepsis.3 Empirical piperacillinetazobactam was until recently considered by most to be the agent of choice in neutropenic sepsis. This is now not always the case e to which must be added the emergence of carbapenem resistance to a wide range of Gramnegative organisms. Centres with a high prevalence of piperacillinetazobactam resistance had until recently used empirical meropenem as a backstop first-line choice for neutropenic sepsis. This ‘last bastion’ of protection is now beginning to fail through acquired resistance, prompting the need for more than one class of empirical agent until the identity of the organism is known. This can have a dramatic impact in terms of mortality for example e 23% as opposed to 10% when appropriate treatment is given from the start. More recent evidence suggests that not all multidrug-resistant organisms (MDROs) drive additional mortality beyond this e one study showed an equivalent mortality for MDRO carriage, apart from MDR Pseudomonas aeruginosa, which carries a dismal prognosis.
Keywords Antibiotic infusion; antibiotic resistance; antifungal resistance; diagnostics; immunocompromise; MRCP; neutropenic fever; sepsis
Introduction Patients with malignancy continue to be broadly described as ‘immunosuppressed’, a term about as useful as ‘fever’ or ‘breathlessness’. Healthy immunity to bacteria, viruses and fungi relies on numerous and varied pathways: innate, acquired, T cell, phagocytic, humoral or mostly a combination of these. Accordingly, some primary assumptions e such as whether absent or deficient phagocytes (neutropenia, acute myeloid leukaemia) or damaged cell-mediated immunity (lymphoma, transplantation) is responsible for susceptibility e still offer a reasonable risk classification of likely opportunistic pathogenic types. What is increasingly clear is that the more intensive the chemotherapy, the larger the risk from opportunistic infection (Figure 1). These assumptions are increasingly blurred as many treatments impact on more than one immune pathway, some for up to 2 years after ‘cure’. Therefore, it is most unwise to ‘assume’
Vanya A Gant PhD FRCP FRCPath is Microbiologist and Clinical Director at UCLH NHS Foundation Trust, London, UK. Competing interests: VG has contributed to Advisory Boards organized by Merck, Sharp and Dohme, Gilead, Basilea, and has received support for attendance at International meetings.
MEDICINE 45:10
605
Ó 2017 Published by Elsevier Ltd.
DEFENCE AGAINST INFECTION
Very few new effective antibiotics active against MDROs are currently available other than ceftolozaneetazobactam and ceftazidimeeavibactam (indication under investigation). These drugs offer considerable advantages against many ESBL-producing organisms, but they nevertheless may fail in many situations where plasmidemediated resistance is responsible. Although it is active against P. aeruginosa, whose resistance mechanisms include upregulated efflux or ampC derepression, there is no activity against strains containing plasmid-mediated metallobetalactamase (MBL) producers. P. aeruginosa strains in this category are likely to be susceptible only to colistin. Ceftolozaneetazobactam is currently active against perhaps 50% of otherwise pan-b-lactam-resistant organisms, rising to perhaps 80% if ESBL and MBL producers are excluded. Similarly, while ceftazidimeeavibactam would also seem to offer activity beyond the previous generation of b-lactams, a small Spanish study has shown dire mortality rates in haematological malignancy, with a significant change in crude mortality. As a result, various escalation/de-escalation algorithms to limit resistance have been designed and tested to show whether early antibiotic discontinuation in neutropenia can safely be
Balance of power between ablative chemotherapeutics and immunity
The ‘sweet spot’ Survival ‘Immune power’
‘Therapy power’
Figure 1
Mitigating this without new anti-Gram-negative agents currently requires tuning empirical therapy for febrile neutropenia with ‘personalized’ regimens suggested by prior MDRO screening. Such screening before the predictable neutropenic phases of treatment should now be considered mandatory.
Global dissemination of OXA-48-like-producing Klebsiella pneumoniae
30
25 21
14 13
23
24
12 10 9 11 15
26 27 28
8
22
29
3
2 31
4
1 19 16 5
18 17
34 35
20
40
36 6
41 38
32 37
39
42 33 7 43
Endemic spread of OXA-48-like producers Sporadic spread of OXA-48-like producers OXA-48-like recorded Not recorded Reproduced with permission from Lee CR, Lee JH, Park KS, et al. Global dissemination of OXA-48-like-producing Klebsiella pneumoniae epidemiology, genetic context, treatment options, and detection methods strains. Front Microbiol 2016; 7: 895. Figure 2
MEDICINE 45:10
606
Ó 2017 Published by Elsevier Ltd.
DEFENCE AGAINST INFECTION
Fluoroquinolone ‘prophylaxis’
carried out. ‘Early’ discontinuation seems effective, with equivalent outcomes, although a considerable ‘relapse’ rate in terms of fever seems to be the norm. It is too early to assess how effective the next generation of promising but as yet unlicensed and unproven antibiotics, such as plazomycin and cefiderocol, might be.
Fluoroquinolone prophylaxis was widely adopted to provide benefit for the reduction of septic episodes in patients predicted to be neutropenic. Early evidence suggested efficacy, with downstream issues (resistance, Clostridium difficile infection) not reported. Unsurprisingly, the more quinolones are used, the more resistance emerges. It has been demonstrated recently that cessation of quinolone prophylaxis reduced quinolone resistance from 73% to 8%, and that the prevalence of ESBL also decreased from 42% to 10%, leading to reduced use of meropenem. This finding of associated, increased resistance to different antibiotic classes was predictable, as quinolones are mutagenic for the bacteria themselves and drive resistance to other antibiotic classes. Many if not most centres have now correctly abandoned this strategy.
Antibiotic infusion therapy There is renewed interest in getting more out of fewer antibiotics. New data based on theoretical calculations support the equivalence or superiority of infusional regimens over more classical intermittent ones. This would seem particularly important for P. aeruginosa, a pathogen commonly found in these patient groups. Available data suggest that continuous infusion statistically significantly reduces hospital mortality and might improve clinical cure. This intervention was beneficial for patients with either unknown or with Gram-negative organisms, There are therefore both antibiotic stewardship and efficacy drivers to instituting a change in the usual intermittent administration practice to one where many antibiotics are administered as infusions.
Recognition and definition of sepsis A new international consensus classification for sepsis (Sepsis-3) prompts the use of simpler clinical algorithms for early detection of sepsis. When combined with national efforts to raise the profile of the importance of early sepsis recognition as well as a protocolized approach to its treatment it is likely to beneficially impact mortality.5
Resistance to antifungal agents Although azole resistance, either induced or constitutive, in Candida spp. is well known, these organisms are usually fairly easily dealt with. Mould-active azoles were a significant advance, affording often oral treatment for both treatment and prophylaxis in conditions previously associated with a high mortality (heartelung transplants, acute myeloid leukaemia, bone marrow transplant with graft-versus-host disease). It was only a matter of time before azole-resistant Aspergillus isolates emerged among patients taking these drugs. Azole resistance is commonly caused by one of several mutations in the Cyp51A gene, which encodes the target enzyme of antifungal azoles. The so-called ‘tandem repeat’ mutation in Aspergillus fumigatus was then reported from the Netherlands, probably related to industrial quantities of azoles used for the control of crop and flower-spoiling fungi. This and other mutations have now been found in many other countries, and there is a genuine possibility that spores containing these resistance markers might disseminate worldwide literally on the winds. There continues to be sporadic, geographical variation in the prevalence of resistance, however e with individual countries reporting markedly different rates from different centres, from almost none to perhaps as high as 25%. There is also the added threat of resistant strains being ‘selected’ to thrive in vivo in immunocompromised hosts carrying relevant tissue concentrations of antifungal drugs.4 A new oral antifungal agent, isavuconazonium sulphate (a prodrug, converted to isavuconazole), is now licensed in the UK for the treatment of invasive mould infections. Its interest lies in its readily absorbed formulation, its favourable pharmacokinetic/pharmacodynamic characteristics, its more predictable activity against the often resistant Mucorales and its lower potential for drug interactions compared with other azole drugs, especially voriconazole. Licensing trials have demonstrated equivalence; whether it is more effective than previous generations of azoles, and in what situations, remains to be established, although to date its safety/toxicity profile seems very favourable.
MEDICINE 45:10
Diagnostics Newer, faster and more accurate diagnostics for recognition of sepsis, the organisms responsible for it and rapid resistance determination have been promised for well over a decade. No high-performance test has emerged. Available platforms claim to detect and speciate microorganisms within several hours, but how good they are, and how useful they might be, needs more independent work. The initial promise of clinically useful, accessible, rapid, easily performed and rapid biomarker assays has yet to be delivered. Paradoxically, this has prompted renewed interest in whether the procalcitonin test might deliver a rule-out test for bacterial infection, allowing for all-important antibiotic de-escalation. A KEY REFERENCES 1 Tackling drug-resistant infection globally: final report and recommendations. The review on antimicrobial resistance chaired by Jim O’Neill. Accessible at: https://amrreview.org/sites/default/files/ 160525_Final%20paper_with%20cover.pdf. 2 Alevizakos M, Gaitanidis A, Andreatos N, Arunachalam K, Flokas ME, Mylonakis E. Colonisation with extended-spectrum b-lactamase-producing Enterobacteriaceae and risk for infection among patients with solid or haematological malignancy: a systematic review and meta-analysis. Int J Antimicrob Agents 2016; 48: 647e54. 3 Heidenreich D, Kreil S, Nolte F, Hofmann WK, Miethke T, Klein SA. Multidrug-resistant organisms in allogeneic hematopoietic cell transplantation. Eur J Haematol 2017; 98: 485e92. 4 Vermeulen E, Lagrou K, Verweij PE. Azole resistance in Aspergillus fumigatus: a growing public health concern. Curr Opin Infect Dis 2013; 26: 493e500. 5 Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). J Am Med Assoc 2016; 315: 801e10.
607
Ó 2017 Published by Elsevier Ltd.
Infection in cancer and transplantation
Key points
Vanya A Gant
C
Antibiotic resistance is now challenging cancer outcomes
C
Resistance to antifungal agents is now emerging
C
Antibiotic infusion rather than bolus therapy is advantageous
C
Fluoroquinolone prophylaxis carries unacceptable consequences
Abstract Treatment options and the promise of cure for malignancy have increased in the last few years and will continue to do so as we ‘personalize’ more treatment modalities. Although innovations such as checkpoint inhibitors and chimaeric antigen receptor T cell therapy hold much promise, almost all therapy in 2017 remains exceedingly toxic and indiscriminate, killing rapidly dividing (tumour) cells as well as some or all other bystander immune cells. These advances with increasingly aggressive chemotherapy have only been made possible by the prevention and treatment of opportunistic, life-threatening infections. We are now challenged by the inexorable rise of antimicrobial resistance, the appearance of antifungal resistance and the longer term consequences of immunosuppression beyond cancer cure. The latter relates to being tumour-free but immunosuppressed because of graft-versus-host disease and its treatment, unpredictable poor graft function or the longer term damage from chemotherapeutic agents, which can destroy T cell immunological memory for months if not years. Until and unless we match increasingly effective but immune-destructive therapy with anti-infective therapy, an increasing proportion of patients will perish not of their tumour, but of their infections.
too much when dealing with a feverish patient with malignancy. Recalcitrant fever in a neutropenic patient might, for example, represent tuberculosis in evolution.
Resistance to antibacterials Resistance, especially in Gram-negative organisms, continues to accelerate globally. A single example for one organism is shown in Figure 2. Bacteraemic infection in the neutropenic phase is the norm rather than the exception, and if left unchecked by neutrophils and/or effective antibiotics will be rapidly lethal. We have become too complacent regarding the value of our antibiotics. These now cannot be predictably expected to protect neutropenic patients for weeks without overwhelming infection. The UK is the first country to have reacted to such complacency.1 This ‘safety net’ has almost disappeared in some countries through antibiotic profligacy and its link to resistance. Grampositive organisms remain less of a threat: neutropenia might even offer some protection against the mortality and morbidity these organisms drive when bacteraemia ensues. Accordingly, 20% of patients in some countries are already colonized with extended-spectrum b-lactamase (ESBL)-producing Gram-negative organisms; this figure rises to 33% in Asia. These patients have a 13-fold higher risk of ESBL bacteraemia and significantly worse 28-day mortality. Italian figures show ‘hotspots’ for Klebsiella pneumoniae, with an eye-watering 46% mortality compared with 15% in patients not colonized with such organisms.2 This relates to ineffective empirical antibiotic use at the onset of neutropenic sepsis.3 Empirical piperacillinetazobactam was until recently considered by most to be the agent of choice in neutropenic sepsis. This is now not always the case e to which must be added the emergence of carbapenem resistance to a wide range of Gramnegative organisms. Centres with a high prevalence of piperacillinetazobactam resistance had until recently used empirical meropenem as a backstop first-line choice for neutropenic sepsis. This ‘last bastion’ of protection is now beginning to fail through acquired resistance, prompting the need for more than one class of empirical agent until the identity of the organism is known. This can have a dramatic impact in terms of mortality for example e 23% as opposed to 10% when appropriate treatment is given from the start. More recent evidence suggests that not all multidrug-resistant organisms (MDROs) drive additional mortality beyond this e one study showed an equivalent mortality for MDRO carriage, apart from MDR Pseudomonas aeruginosa, which carries a dismal prognosis.
Keywords Antibiotic infusion; antibiotic resistance; antifungal resistance; diagnostics; immunocompromise; MRCP; neutropenic fever; sepsis
Introduction Patients with malignancy continue to be broadly described as ‘immunosuppressed’, a term about as useful as ‘fever’ or ‘breathlessness’. Healthy immunity to bacteria, viruses and fungi relies on numerous and varied pathways: innate, acquired, T cell, phagocytic, humoral or mostly a combination of these. Accordingly, some primary assumptions e such as whether absent or deficient phagocytes (neutropenia, acute myeloid leukaemia) or damaged cell-mediated immunity (lymphoma, transplantation) is responsible for susceptibility e still offer a reasonable risk classification of likely opportunistic pathogenic types. What is increasingly clear is that the more intensive the chemotherapy, the larger the risk from opportunistic infection (Figure 1). These assumptions are increasingly blurred as many treatments impact on more than one immune pathway, some for up to 2 years after ‘cure’. Therefore, it is most unwise to ‘assume’
Vanya A Gant PhD FRCP FRCPath is Microbiologist and Clinical Director at UCLH NHS Foundation Trust, London, UK. Competing interests: VG has contributed to Advisory Boards organized by Merck, Sharp and Dohme, Gilead, Basilea, and has received support for attendance at International meetings.
MEDICINE 45:10
605
Ó 2017 Published by Elsevier Ltd.
DEFENCE AGAINST INFECTION
Very few new effective antibiotics active against MDROs are currently available other than ceftolozaneetazobactam and ceftazidimeeavibactam (indication under investigation). These drugs offer considerable advantages against many ESBL-producing organisms, but they nevertheless may fail in many situations where plasmidemediated resistance is responsible. Although it is active against P. aeruginosa, whose resistance mechanisms include upregulated efflux or ampC derepression, there is no activity against strains containing plasmid-mediated metallobetalactamase (MBL) producers. P. aeruginosa strains in this category are likely to be susceptible only to colistin. Ceftolozaneetazobactam is currently active against perhaps 50% of otherwise pan-b-lactam-resistant organisms, rising to perhaps 80% if ESBL and MBL producers are excluded. Similarly, while ceftazidimeeavibactam would also seem to offer activity beyond the previous generation of b-lactams, a small Spanish study has shown dire mortality rates in haematological malignancy, with a significant change in crude mortality. As a result, various escalation/de-escalation algorithms to limit resistance have been designed and tested to show whether early antibiotic discontinuation in neutropenia can safely be
Balance of power between ablative chemotherapeutics and immunity
The ‘sweet spot’ Survival ‘Immune power’
‘Therapy power’
Figure 1
Mitigating this without new anti-Gram-negative agents currently requires tuning empirical therapy for febrile neutropenia with ‘personalized’ regimens suggested by prior MDRO screening. Such screening before the predictable neutropenic phases of treatment should now be considered mandatory.
Global dissemination of OXA-48-like-producing Klebsiella pneumoniae
30
25 21
14 13
23
24
12 10 9 11 15
26 27 28
8
22
29
3
2 31
4
1 19 16 5
18 17
34 35
20
40
36 6
41 38
32 37
39
42 33 7 43
Endemic spread of OXA-48-like producers Sporadic spread of OXA-48-like producers OXA-48-like recorded Not recorded Reproduced with permission from Lee CR, Lee JH, Park KS, et al. Global dissemination of OXA-48-like-producing Klebsiella pneumoniae epidemiology, genetic context, treatment options, and detection methods strains. Front Microbiol 2016; 7: 895. Figure 2
MEDICINE 45:10
606
Ó 2017 Published by Elsevier Ltd.
DEFENCE AGAINST INFECTION
Fluoroquinolone ‘prophylaxis’
carried out. ‘Early’ discontinuation seems effective, with equivalent outcomes, although a considerable ‘relapse’ rate in terms of fever seems to be the norm. It is too early to assess how effective the next generation of promising but as yet unlicensed and unproven antibiotics, such as plazomycin and cefiderocol, might be.
Fluoroquinolone prophylaxis was widely adopted to provide benefit for the reduction of septic episodes in patients predicted to be neutropenic. Early evidence suggested efficacy, with downstream issues (resistance, Clostridium difficile infection) not reported. Unsurprisingly, the more quinolones are used, the more resistance emerges. It has been demonstrated recently that cessation of quinolone prophylaxis reduced quinolone resistance from 73% to 8%, and that the prevalence of ESBL also decreased from 42% to 10%, leading to reduced use of meropenem. This finding of associated, increased resistance to different antibiotic classes was predictable, as quinolones are mutagenic for the bacteria themselves and drive resistance to other antibiotic classes. Many if not most centres have now correctly abandoned this strategy.
Antibiotic infusion therapy There is renewed interest in getting more out of fewer antibiotics. New data based on theoretical calculations support the equivalence or superiority of infusional regimens over more classical intermittent ones. This would seem particularly important for P. aeruginosa, a pathogen commonly found in these patient groups. Available data suggest that continuous infusion statistically significantly reduces hospital mortality and might improve clinical cure. This intervention was beneficial for patients with either unknown or with Gram-negative organisms, There are therefore both antibiotic stewardship and efficacy drivers to instituting a change in the usual intermittent administration practice to one where many antibiotics are administered as infusions.
Recognition and definition of sepsis A new international consensus classification for sepsis (Sepsis-3) prompts the use of simpler clinical algorithms for early detection of sepsis. When combined with national efforts to raise the profile of the importance of early sepsis recognition as well as a protocolized approach to its treatment it is likely to beneficially impact mortality.5
Resistance to antifungal agents Although azole resistance, either induced or constitutive, in Candida spp. is well known, these organisms are usually fairly easily dealt with. Mould-active azoles were a significant advance, affording often oral treatment for both treatment and prophylaxis in conditions previously associated with a high mortality (heartelung transplants, acute myeloid leukaemia, bone marrow transplant with graft-versus-host disease). It was only a matter of time before azole-resistant Aspergillus isolates emerged among patients taking these drugs. Azole resistance is commonly caused by one of several mutations in the Cyp51A gene, which encodes the target enzyme of antifungal azoles. The so-called ‘tandem repeat’ mutation in Aspergillus fumigatus was then reported from the Netherlands, probably related to industrial quantities of azoles used for the control of crop and flower-spoiling fungi. This and other mutations have now been found in many other countries, and there is a genuine possibility that spores containing these resistance markers might disseminate worldwide literally on the winds. There continues to be sporadic, geographical variation in the prevalence of resistance, however e with individual countries reporting markedly different rates from different centres, from almost none to perhaps as high as 25%. There is also the added threat of resistant strains being ‘selected’ to thrive in vivo in immunocompromised hosts carrying relevant tissue concentrations of antifungal drugs.4 A new oral antifungal agent, isavuconazonium sulphate (a prodrug, converted to isavuconazole), is now licensed in the UK for the treatment of invasive mould infections. Its interest lies in its readily absorbed formulation, its favourable pharmacokinetic/pharmacodynamic characteristics, its more predictable activity against the often resistant Mucorales and its lower potential for drug interactions compared with other azole drugs, especially voriconazole. Licensing trials have demonstrated equivalence; whether it is more effective than previous generations of azoles, and in what situations, remains to be established, although to date its safety/toxicity profile seems very favourable.
MEDICINE 45:10
Diagnostics Newer, faster and more accurate diagnostics for recognition of sepsis, the organisms responsible for it and rapid resistance determination have been promised for well over a decade. No high-performance test has emerged. Available platforms claim to detect and speciate microorganisms within several hours, but how good they are, and how useful they might be, needs more independent work. The initial promise of clinically useful, accessible, rapid, easily performed and rapid biomarker assays has yet to be delivered. Paradoxically, this has prompted renewed interest in whether the procalcitonin test might deliver a rule-out test for bacterial infection, allowing for all-important antibiotic de-escalation. A KEY REFERENCES 1 Tackling drug-resistant infection globally: final report and recommendations. The review on antimicrobial resistance chaired by Jim O’Neill. Accessible at: https://amrreview.org/sites/default/files/ 160525_Final%20paper_with%20cover.pdf. 2 Alevizakos M, Gaitanidis A, Andreatos N, Arunachalam K, Flokas ME, Mylonakis E. Colonisation with extended-spectrum b-lactamase-producing Enterobacteriaceae and risk for infection among patients with solid or haematological malignancy: a systematic review and meta-analysis. Int J Antimicrob Agents 2016; 48: 647e54. 3 Heidenreich D, Kreil S, Nolte F, Hofmann WK, Miethke T, Klein SA. Multidrug-resistant organisms in allogeneic hematopoietic cell transplantation. Eur J Haematol 2017; 98: 485e92. 4 Vermeulen E, Lagrou K, Verweij PE. Azole resistance in Aspergillus fumigatus: a growing public health concern. Curr Opin Infect Dis 2013; 26: 493e500. 5 Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). J Am Med Assoc 2016; 315: 801e10.
607
Ó 2017 Published by Elsevier Ltd.