Editorials implementation in the UK. J Am Med Inform Assoc 2014; 21:e226–e231 8. Weis JM, Levy PC: Copy, paste, and cloned notes in electronic health records: Prevalence, benefits, risks, and best practice recommendations. Chest 2014; 145:632–638 9. Weiskopf NG, Weng C: Methods and dimensions of electronic health record data quality assessment: Enabling reuse for clinical research. J Am Med Inform Assoc 2013; 20:144–151 10. Chan KS, Fowles JB, Weiner JP: Review: Electronic health records and the reliability and validity of quality measures: A review of the literature. Med Care Res Rev 2010; 67:503–527 11. Parsons A, McCullough C, Wang J, et al: Validity of electronic health record-derived quality measurement for performance monitoring. J Am Med Inform Assoc 2012; 19:604–609 12. Bayley KB, Belnap T, Savitz L, et al: Challenges in using electronic health record data for CER: Experience of 4 learning organizations and solutions applied. Med Care 2013; 51:S80–S86

13. Middleton B, Bloomrosen M, Dente MA, et al; American Medical Informatics Association: Enhancing patient safety and quality of care by improving the usability of electronic health record systems: Recommendations from AMIA. J Am Med Inform Assoc 2013; 20:e2–e8 14. Pickering BW, Gajic O, Ahmed A, et al: Data utilization for medical decision making at the time of patient admission to ICU. Crit Care Med 2013; 41:1502–1510 15. Ahmed A, Chandra S, Herasevich V, et al: The effect of two different electronic health record user interfaces on intensive care provider task load, errors of cognition, and performance. Crit Care Med 2011; 39:1626–1634 16. Bates DW, Kuperman GJ, Wang S, et al: Ten commandments for effective clinical decision support: Making the practice of evidencebased medicine a reality. J Am Med Inform Assoc 2003; 10:523–530 17. Bowman S: Impact of electronic health record systems on information integrity: Quality and safety implications. Perspect Health Inf Manag 2013; 10:1c

Middle East Respiratory Syndrome: The Need for Better Evidence in Severe Respiratory Viral Infections* Hani Abo-Leyah, MBChB James D. Chalmers, MD Department of Respiratory Medicine College of Medicine University of Dundee Dundee, United Kingdom

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igh contagious and deadly viruses are not new but have rarely had such a high profile. The Ebola epidemic in West Africa demonstrates the potential impact of a highly contagious virus with the capacity to spread beyond the available means to contain it. At the time of writing this outbreak continues, with now more than 14,000 laboratory confirmed cases (as of February 25, 2015) (1). Respiratory viruses also have the capacity to be rapidly transmitted and deadly. The 1918 influenza pandemic (“Spanish flu”) is reported to have killed 20–40 million people (2). The nature of genetic changes in influenza viruses, in particular, makes global pandemics of respiratory viral infections a matter of “when” rather than “if”. Public awareness of the potential for global transmission of lethal respiratory viruses is high following the 2009/2010 pandemic of H1N1 influenza, and high *See also p. 1283. Key Words: Middle East respiratory syndrome; pandemic; pneumonia; transmission; virus Dr. Chalmers consulted for Bayer HealthCare, Cempra Pharmaceuticals, and Astrazeneca. His institution received grant support from Bayer HealthCare, Aradigm Corporation, and Astrazeneca. Dr. Abo-Leyah disclosed that he does not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001008

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profile reporting of respiratory virus outbreaks, such as severe acute respiratory syndrome (SARS) and avian influenza A (3–5). Against this backdrop, this issue of Critical Care Medicine features a comprehensive update from Dr. Alsolamy (6) on the epidemiology and management to date of Middle East Respiratory Syndrome coronavirus (MERS-CoV). As of January 30, 2015, there have been 956 laboratory-confirmed cases of MERS-CoV infection with a case fatality rate of 36.7% according to the World Health Organization (7). Primary infections have all been reported from countries in the Arabian peninsula, with evidence of worldwide transmission of cases through travel (Table 1). The disease can vary in severity from asymptomatic infection, detected on contact screening, to rapidly progressive pneumonia and respiratory failure (6, 7). It should be suspected in any individual with an acute respiratory illness within 14 days of travel to Arabian Peninsula (7). Alsolamy (6) highlights the role of detection bias in the early overestimation of the high case-fatality ratio reported with MERS-CoV; nevertheless, it is clear that it can be transmitted from person to person and has the potential to be rapidly fatal. A review of recent cases in Jeddah, Saudi Arabia, has identified that a majority of new infections during 2014 were either in healthcare workers or appeared likely to have been acquired from healthcare-associated transmission (8). Supportive management of viral infections remains the dominant approach partly because of the lack of effective antiviral therapeutics. Previous experience with SARS, in particular, has influenced the treatment options used by centers in Saudi Arabia dealing with MERS. Alsolamy summarizes the available literature concerning ribavirin and interferon α therapy in MERS (6). Omrani et al (9) reported a retrospective June 2015 • Volume 43 • Number 6

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Editorials

Countries With Reported Cases of Middle East Respiratory Syndrome-coronavirus

Table 1.

Primary Infections in the Arabian Peninsula

Countries With Travel-Associated Infections

Saudi Arabia

Europe

United Arab Emirates

 United Kingdom

Qatar

 France

Oman

 Italy

Jordan

 Greece

Kuwait

 Austria

Yemen

 Netherlands

Lebanon

 Turkey

Iran

 Germany Asia  Malaysia  Philippines Africa  Tunisia  Egypt  Algeria North America  United States of America

cohort of patients with MERS-CoV, where 20 patients received ribavirin and interferon α-2α with 24 patients receiving only supportive treatment. Although there was a significant difference in survival at 14 days (70% survival in the treatment group compared with 29% in the comparator group; p = 0.004), the difference was no longer statistically significant at 28 days (6). During the SARS epidemic, most patients were treated with high-dose glucocorticoids and ribavirin, but most experts now agree that neither treatment had a clear beneficial effect. Immediate and late toxicities were common (10, 11). Other modalities such as monoclonal antibodies and a vaccine are only presently in the development stage for these novel coronoviral infections. The need for randomized trials is clear, but how do you design randomized controlled trials in the context of epidemics and pandemics? It is challenging for the research community to respond to the onset of an epidemic or pandemic. Critical Care trials, in particular, are challenging in terms of feasibility and ethics. This is magnified in the context of a rapidly evolving pandemic. Study design, ethical approvals, drugs supply, and establishment of trial networks take time, by which time a window may be lost to inform therapy for the next epidemic. This is particularly true of influenza, where innovative approaches such Critical Care Medicine

as “hibernating trials” should be considered. Such approaches involve setting up all aspects of studies which then go into hibernation ready to be initiated with the onset of an epidemic or pandemic. Improved technologies for viral detection have allowed us to clarify the role of respiratory viruses more generally. We now know that at least 1 of 3 of patients with community-acquired pneumonia have detectable respiratory viruses, and indeed in the recent Centre for Disease Control Etiology of Pneumonia in the Community study of the etiology of pneumonia in the United States, Human Metapneumovirus beat Streptococcus pneumoniae to top spot as the most frequent cause of pneumonia (12). Viral infections are now increasingly recognized as frequent causes of exacerbations of chronic respiratory disease. The absence of effective antiviral therapies, therefore, not only affects the response to epidemics and pandemics but also in daily practice. The ability to improve outcomes from severe pneumonia more generally may depend on the development of improved antiviral drugs and vaccines (13). A Cochrane review of the evidence for osteltamivir and zanamivir, the most widely used antiviral drugs in clinical practice particularly following the 2009 H1N1 pandemic, suggests that we are not there yet. This review found that antiviral drugs reduce the duration of symptoms by half a day but could not find convincing evidence that antiviral drugs could reduce hospital admission or reduce the risk of developing pneumonia (14). It unfortunately goes without saying that no trial evidence was available to inform whether there was any effectiveness in critically ill patients with influenza-associated pneumonia. We desperately need more data and the capacity to conduct trials of antivirals including for viruses other than influenza. What about isolation? A key point reviewed by Alsolamy (6) is that nearly 20% of infections so far reported with MERScoV have been in healthcare workers. Indeed, the outbreak began in an ICU in Jordan where 8 of 11 people affected were healthcare workers (6). The subsequent work from Jeddah seems to confirm a high proportion of disease is healthcare associated (8). The Centre for Disease Control has helpfully provided guidance for healthcare professionals on the management of patients with potential MERS-CoV (7), but on a daily basis we are faced with patients with severe respiratory infections, with or without recent foreign travel, who have a high likelihood of having infections with more typical respiratory viruses. Testing is not immediate, and both in MERS and in the H1N1 pandemic, it was observed that polymerase chain reaction on upper airway swabs may be insensitive compared with lower airway specimens. Are we moving toward a situation where barrier precautions and viral screening are mandatory for all patients with severe acute respiratory infections? At present, this is often reserved for patients judged to be at high risk of viral infection but, as has been clearly shown, diagnosis of viral infections is unreliable using clinical parameters alone (15). We know that nosocomial transmission of viruses occurs frequently with MERS-coV because we have looked for it. Because more viruses are identified in respiratory infections both inside and outside the ICU, it will be important to www.ccmjournal.org

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investigate potential for nosocomial transmission to protect both patients and staff. For those working outside the Arabian Peninsula, MERS-CoV may seem a remote problem. Nevertheless, it is clear that globalization means that physicians internationally need to be aware of this potential diagnosis is travelers from the region. Closer to home, as we pass through a winter in the United Kingdom in which H3N2 influenza was largely responsible for a more than 30% increase in winter mortality, we are reminded that respiratory viruses are common, increasingly recognized, preventable but ultimately in urgent need of therapeutic development.

REFERENCES

1. Centre for Disease Control 2014 Ebola Outbreak in West Africa Case counts. http://www.cdc.gov/vhf/ebola/outbreaks/2014-westafrica/case-counts.html. Accessed February 25, 2015 2. Gagnon A, Miller MS, Hallman SA, et al: Age-specific mortality during the 1918 influenza pandemic: Unravelling the mystery of high young adult mortality. PLoS One 2013; 8:e69586 3. Lee N, Hui D, Wu A, et al: A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003; 348:1986–1994 4. Singanayagam A, Singanayagam A, Wood V, et al: Factors associated with severe illness in pandemic 2009 influenza a (H1N1) infection: Implications for triage in primary and secondary care. J Infect 2011; 63:243–251 5. Subbarao K, Klimov A, Katz J, et al Characterisation of an avian influenza A (H5N1) virus isolated from a child with fatal respiratory illness. Science 1998; 279:393–396

6. Alsolamy S: Middle East Respiratory Syndrome: Knowledge to Date. Crit Care Med 2015; 43:1283–1290 7. Rasmussen SA, Gerber SI, Swerdlow DL: Middle East Respiratory Syndrome-Coronavirus (MERS-CoV): CDC update for clinicians. Clin Infect Dis 2015; in press 8. Oboho IK, Tomczyk SM, Al-Asmari AM, et al: 2014 MERS-CoV outbreak in Jeddah-a link to health care facilities. N Engl J Med 2015; 372:846–854 9. Omrani AS, Saad MM, Baig K, et al: Ribavirin and interferon alfa-2a for severe middle east respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect Dis 2014; 14:1090–1095 10. Chiou HE, Liu CL, Buttrey Mj, et al: Adverse affects of ribavirin and outcome in severe acute respiratory distress syndrome: Experience in two medical centers. Chest 2005; 128:263–272 11. Lv H, de Vlas SJ, Liu W, et al: Avascular osteonecrosis after treatment of SARS: A 3-year longitudinal study. Trop Med Int Health 2009; 14(suppl 1):79–84 12. Balk R, Self WH, Woodworth A, et al: Association of pathogens detected in community-acquired pneumonia (CAP) with serum procalcitonin (PCT) among adults: Preliminary results from the CDC Etiology of Pneumonia in the Community (EPIC) study. Am J Respir Crit Care Med 2013; A1153 13. Riquelme R, Jiménez P, Videla AJ, et al: Predicting mortality in hospitalized patients with 2009 H1N1 influenza pneumonia. Int J Tuberc Lung Dis 2011; 15:542–546 14. Jefferson T, Jones M, Doshi P, et al: Oseltamivir for influenza in adults and children: Systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348:g2545 15. Ruiz-González A, Falguera M, Vives M, et al: Community-acquired pneumonia: Development of a bedside predictive model and scoring system to identify the aetiology. Respir Med 2000; 94:505–510

Time for Tailored Antimicrobials: Adapted Bacteriophages in the ICU* Martin Witzenrath, MD Department of Infectious Diseases and Pulmonary Medicine Charité-Universitätsmedizin Berlin SFB-TR84 “Innate Immunity of the Lung” Berlin, Germany

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ccording to the World Health Organization, pneumonia is the third most frequent cause of death worldwide and the most frequent life-threatening infection in ICUs. Mortality of pneumonia in the ICU is considerably high despite the availability of potent antimicrobial agents in most cases. Unfortunately, antimicrobial resistance increasingly concerns hospital-acquired pneumonia (HAP), and mortality is further enhanced when pneumonia is caused by drug-resistant bacteria.

*See also p. e190. Key Words: antimicrobial resistance; bacteriophage; hospital-acquired pneumonia; ventilator-associated pneumonia Dr. Witzenrath’s institution received grant support from Deutsche Forschungsgemeinschaft (unrestricted scientific grant). Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001038

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According to the Centers for Disease Control and Prevention, an estimated 2 million infectious diseases and 23,000 deaths annually are associated with drug-resistant bacterial infections in the United States, which cost an estimated $20 billion for healthcare and $35 billion for lost productivity each year (1). Initial empiric therapy of HAP in the ICU mostly consists of broad-spectrum antibiotics as the causative pathogen is not immediately known. As soon as pathogen and resistance profile are detected, narrowing of the therapeutic spectrum is important to reduce the unwanted effects. For example, broadspectrum antibiotic treatment eradicates commensal bacteria, thereby opening niches for pathogens including Clostridium difficile and Candida albicans. Increasing evidence also suggests that loss of commensal microbiota impairs innate immunity, which generally paves the way for secondary infections (2). Thus, pathogen-specific therapy would be the perfect choice in this situation, particularly when detection of multidrugresistant pathogens precludes from considerable narrowing of the antibiotic spectrum. Bacteriophages are viruses that infect bacteria and control the bacterial synthesis machinery to replicate thousands of progenies per cell, which then lyze the bacterial cell wall in order to free themselves. If more bacteria are available, the newly produced June 2015 • Volume 43 • Number 6

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Middle East respiratory syndrome: the need for better evidence in severe respiratory viral infections.

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