Meningitis and Encephalitis CME

Transcription

1 Meningitis and Encephalitis CME Supported by an independent educational grant from BioFire Diagnostics, LLC Presented through a collaboration between The American Association for Clinical Chemistry (AACC) and Medscape Education. 1

2 This article is a CME activity. To earn credit for this activity visit: Target Audience This activity is intended for physicians who practice infectious disease, critical care, pediatrics, and emergency medicine, and laboratory and point-of-care testing professionals. Goals The goals of this activity are to: Increase awareness of the strengths and limitations of rapid molecular tests for diagnosing meningitis and encephalitis Facilitate the appropriate incorporation of rapid testing methods to improve patient health outcomes and support antibiotic stewardship efforts Learning Objectives Upon completion of this activity, participants will: Have increased knowledge regarding the key distinguishing characteristics among laboratory methods for the diagnosis of meningitis/encephalitis Have greater competence related to the clinical implications of rapid molecular diagnostics for meningitis/encephalitis Demonstrate greater confidence in their ability to identify key attributes of molecular methodologies for the diagnosis of meningitis/encephalitis Credits Available Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s) Accreditation Statements In support of improving patient care, Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. For Physicians Medscape, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. For Laboratory and Point-of-Care Testing Professionals The American Association for Clinical Chemistry (AACC) will designate this activity for a maximum of 0.25 ACCENT credit hours. AACC is an approved provider of continuing education (CE) for clinical laboratory scientists licensed in states that require documentation of CE, including California, Florida, Louisiana, Montana, Nevada, North Dakota, Rhode Island, Tennessee, and West Virginia. ACCENT credit is also recognized by several organizations: AAB, ABCC, ACS, AMT,ASCLS, ASCP, ASM, CAP, IFCC, and NRCC. 2

3 Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on page 2; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on page 2. To receive AMA PRA Category 1 Credit, you must receive a minimum score of 75% on the post-test. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker. *The credit that you receive is based on your user profile. Hardware/Software Requirements To access activities, users will need: A computer with an Internet connection. Internet Explorer 8.x or higher, the latest versions of Firefox or Safari, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader. 3

4 Disclosures Faculty Anne J. Blaschke, MD, PhD Associate Professor, Pediatrics and Pediatric Infectious Diseases Director, Molecular Microbiology Laboratory University of Utah School of Medicine Salt Lake City, Utah Disclosure: Anne J. Blaschke, MD, PhD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: BioFire Diagnostics Received grants for clinical research from: BioFire Diagnostics; Gilead Sciences, Inc. Other: Holds international property for FilmArray technology from BioFire Diagnostics Dr Blaschke does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Blaschke does not intend to discuss investigational drugs, mechanical dev Editors Susan L. Smith, MN, PhD Lead Scientific Director, Medscape, LLC Disclosure: Susan L. Smith, MN, PhD, has disclosed no relevant financial relationships. CME Reviewer / Nurse Planner Esther Nyarko, PharmD Associate Clinical CME Director, Medscape, LLC Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships. Other Reviewers Dominic Rizzo American Association for Clinical Chemistry Disclosure: Dominic Rizzo has disclosed no relevant financial relationships. Lisa Dunay American Association for Clinical Chemistry Disclosure: Lisa Dunay has disclosed no relevant financial relationships. Peer Reviewer This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships. 4

5 Taryn Brill: Hello, and welcome to the first episode of Diagnosis TV: Timely Identification for Informed Patient Care in Infectious Diseases Meningitis and Encephalitis. I m Taryn Brill. Ms Brill: Even the seasoned clinician can be intimidated when confronted with a patient with suspected meningitis. Why? Because there are many causes of meningitis. Some are life-threatening and some are self-limiting, but the patient s clinical presentation offers few clues to the underlying cause. In some cases, waiting even minutes or hours to make a diagnosis and begin treatment can change the outcome for the patient. Indeed, one of the most critical unmet needs in the field of infectious diseases is the availability of diagnostic tests that can rapidly and accurately identify pathogens causing a patient s illness. [1] Reports from the Infectious Diseases Society of America and the Centers for Disease Control and Prevention have highlighted deficiencies in diagnostic methods and emphasized the critical need for culture-independent testing for specific pathogens and their patterns of susceptibility to antimicrobial agents. [2,3] These reports also called for methods that are rapid, available at the point-of-care, use direct-from-specimen analysis, and demonstrate high levels of sensitivity and specificity across a wide range of disease syndromes. Although the number of cases of bacterial meningitis in the United States is the lowest it has ever been, believed to be due in part to the increased uptake of meningococcal vaccines, [4] some forms of meningitis are medical emergencies associated with significant morbidity and mortality if not treated promptly and accurately. For example, bacterial meningitis and herpes simplex virus (HSV) encephalitis are severe infections that require prompt treatment with parenteral therapy. Death from meningococcal meningitis can occur in as little as a few hours. 5

6 In those that survive, hearing loss, and long-term development and cognitive disabilities can occur. By contrast, some viral encephalitides, although more common, are usually less severe with self-limiting courses of illness, and patient care is supportive in nature. [5] To get the latest perspectives on advances in rapid diagnostics for meningitis and encephalitis, we visited Anne Blaschke, MD, PhD, Associate Professor in Pediatrics and Pediatric Infectious Diseases, the Edward B. Clark Endowed Chair in Pediatrics, Program Director for the Pediatric Infectious Diseases Fellowship Program, and Director of the Molecular Microbiology Laboratory at the University of Utah School of Medicine in Salt Lake City, Utah. We asked Dr Blaschke what first goes through her mind when she is presented with a distressed parent who has brought a 6-week old baby with lethargy and poor feeding to the emergency department. Anne J. Blaschke, MD, PhD: Infants in the first 2 months of life are at high risk for invasive bacterial infections and we often worry about meningitis, particularly if the baby is lethargic. I m most worried that it could be bacterial meningitis, which is an emergency, but it could be a viral infection or not meningitis at all. A lot of information processing and clinical decision making must occur as I first seeing the patient, and those first minutes may be critical. The initial clinical presentations of bacterial and viral meningitis or encephalitis are very similar. I cannot tell what the pathogen is or the true severity of the situation just by looking at the child, regardless of their age. Ms Brill: Dr Blaschke just described the uncertainty that faces clinicians when a patient presents with suspected meningitis or encephalitis, both potentially life-threatening syndromes that can be caused by a diverse group of pathogens. Dr Blaschke: It s important for me to drill down to the type of infection and the specific pathogen because bacterial meningitis is a medical emergency that needs immediate and appropriate antibiotic therapy. In general, I have to assume the worst and start empiric, broad-spectrum antibiotic therapy. After I start therapy I hopefully have some time to figure out what I am treating. The traditional approach to diagnosing meningitis or encephalitis can take a couple of days. 6

7 I first have to do a spinal tap and then wait for the results of bacterial cultures (which can be affected by empiric antibiotic therapy) and viral polymerase chain reaction (PCR) tests, which are done on the cerebrospinal fluid (CSF). I would admit the patient to the hospital for empiric antimicrobial therapy while cultures and other pathogen-based tests are pending. While I am waiting, I hope my patient is being treated appropriately, but I can t be sure. If the patient has bacterial meningitis and they get appropriate therapy quickly, they will likely survive. When the culture results are known, the broad-spectrum antibiotic therapy can be adjusted as needed. If the patient has viral meningitis or encephalitis, (unless the cause is HSV), his/her prognosis is generally good, but in this scenario he/she has received antibiotics that were unnecessary and could possibly have detrimental effects. There is also the unnecessary cost, not the most important concern, but nonetheless something to consider overall. It s a catch 22. Ms Brill: Although empiric antibiotic therapy may be lifesaving for patients with bacterial meningitis, Dr Blaschke brought light to the potential for what some refer to as the collateral damage of antibiotic therapy; in other words, overuse, underuse, and misuse of antibiotics, as well as their adverse effects and role in selection for antibiotic resistance, a growing public health threat in the United States. [6] Dr Blaschke: Diagnostic tests are one of the cornerstones of infectious disease practice. As clinicians, we do our best to make an accurate diagnosis as quickly as possible in an effort to get the patient on the right drug for the right bug, in other words a narrow-spectrum, targeted antibiotic, if that s what they need. But it s very challenging using our conventional approaches to diagnosis in patients with suspected meningitis because we don t have time to wait. The cost of being wrong in choosing therapy is too high. 7

8 There are pitfalls to conventional diagnostic testing in this situation. Conventional tests such as the CSF cell count can tell us that meningitis or encephalitis is present, but determining the cause may take several days. Even if the Gram stain confirms a bacterial pathogen, identifying it can take 24 to 48 hours. In addition, false-negative culture results may occur in patients who are on antibiotics. And, in many healthcare settings, molecular tests for viral pathogens need to be sent to a reference lab, which requires a relatively long turn-around time and delays diagnosis and initiation of targeted therapy. Ms Brill: We asked Dr Blaschke about new developments in rapid diagnostics for meningitis and encephalitis. Dr Blaschke: New diagnostic technologies for infectious diseases continue to emerge. These include several PCR tests, next-generation sequencing and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry, as well as multiplex molecular panels targeting 10 to 20 specific pathogens. The multiplex panels use what can be called the syndromic approach to testing. In this approach, a group of pathogens -- which may include bacteria, viruses, fungi, and even parasites -- causing a specific clinical syndrome (such as meningitis or encephalitis in this case), are combined into a single test. When the clinician identifies the syndrome, they can test for multiple pathogens at the same time. In some cases, these tests are very rapid and can be performed in as little as an hour. 8

9 Let me illustrate with a typical clinical scenario. A patient presents to the emergency department with a syndrome for which multiple pathogens could be the cause. The emergency department physician may have a suspicion about the diagnosis based on the patient s signs and symptoms and perhaps the geographic region or time of year, he/she can t be sure. So several lines of investigation must be followed. The syndromic approach, using a multiplex molecular panel, potentially eliminates many of steps that need to be taken using our conventional diagnostic methods. This saves time and could allow patients to receive appropriate treatment more quickly. Multiplex PCR amplifies multiple pathogen-specific DNA sequences simultaneously in a single test. The United States Food and Drug Administration (FDA)-approved multiplex molecular panel for meningitis and encephalitis that tests for the most common bacterial and viral pathogens directly from CSF specimens. [7-11] This test can provide results to the clinician in about 3 hours. Use of a multiplex molecular panel in conjunction with clinical judgment and CSF indices, potentially allows clinicians to quickly answer 3 very important questions: Is my patient infected? If so, what are they infected with? What is the best treatment for my patient? 9

10 Ms Brill: We asked Dr Blaschke to walk us through a typical case using a multiplex molecular panel test for meningitis and encephalitis. Dr Blaschke: Let s say my patient is a 15-year-old boy brought in by his mother. He came home from school feeling sick and complaining of a severe headache. His mother felt his forehead and said he was burning up. She took his temperature, which was 103 F. He vomited on the way to the hospital. He has a stiff neck and is lethargic. Using the conventional approach, I would to do a spinal tap and get a CSF sample (with white blood cell count, glucose, and Gram stain). Presuming the cell count is consistent with a central nervous system (CNS) infection (but even if it is not, given his presentation) I cannot afford to hold off on therapy or choose a narrow-spectrum antibiotic. So I would treat him with a broad-spectrum antibiotic because I am very worried about bacterial meningitis. I would admit him to the hospital, possibly to the intensive care unit. If it turns out he has bacterial meningitis I hopefully have treated him in time and with a therapy that is active against the pathogen causing his disease. But until the cultures come back I can t be sure and he has to remain on broad-spectrum antibiotic therapy in the hospital. There is really no room to be judicious in the antibiotic choice when the disease is so serious and the cause is unknown. In this same patient, the diagnosis could have been enteroviral meningitis, which is self-limiting and does not require antibiotic therapy. I could have chosen to watch him and possibly have avoided a hospital admission if he were stable enough to go home. With conventional tests it is difficult to know whether it is a bacterial or viral diagnosis for 24 to 48 hours, and so we often have to treat toward the worst diagnosis. And we are even more cautious with babies and toddlers. These cases are very difficult. Ms Brill: To provide more insight, we asked Dr Blaschke which patients would potentially benefit the most from syndromic testing for meningitis and encephalitis. Dr Blaschke: In my view, patients who would benefit the most are those who are very sick with the probable diagnosis of bacterial meningitis and who need to be treated emergently with the right antibiotic within a very narrow window of time. Other patients who can benefit are actually those on the other end of the spectrum, those with probable viral meningitis who could possibly be discharged home if we could feel certain with that diagnosis. A result in an hour or so could prevent them from being admitted to the hospital and receiving unnecessary antibiotics. We know that the introduction of molecular testing for viral illness when evaluating young infants for sepsis has led to changes in their management. It has been shown in a number of studies that rapid detection of enterovirus, for example, can decrease unnecessary use of antimicrobials, hospital length of stay, and hospital costs. [12-15] We performed a retrospective evaluation of clinical and outcome data for 145 infants 1 to 60 days old at 3 clinical sites enrolled in the performance evaluation for the FDA-approved multiplex molecular panel that detects and identifies 14 pathogens that can cause meningitis and/or encephalitis, including 7 viruses, 6 bacteria, and 1 yeast. 10

11 In our study, the panel identified a potential CNS pathogen in 37 of 145 (26%) infants, while conventional testing identified a CNS pathogen in 21 infants (14%). [16] In 2 cases, the panel results were likely false positives. Thirty-six (25%) infants in this study had CSF positive for a viral pathogen. Enterovirus was the most common virus detected, followed by human parechovirus. [16] Because results of the panel were not given to clinicians in this study, we could not evaluate directly how care might have changed with rapid testing. However, management decisions for infants with clinically-positive enterovirus could suggest how rapid diagnosis might impact care. In our study, more than half of the infants with enterovirus detected by conventional methods in our study were discharged in 48 hours or less, and nearly 20% were discharged in less than 24 hours. It is likely that infants discharged in less than 24 hours were discharged at the time that their enterovirus PCR tests came back positive, as the median turn-around time for that test was 17.3 hours. Although in the past, infants were hospitalized and treated empirically with antibiotics for up to 72 hours while awaiting results of sterile site (eg, CSF) cultures, many infants are now discharged in less than 24 hours if they are clinically well and found to have a viral illness, and some are managed expectantly, without antibiotics. It is possible that the availability of more rapid molecular tests with large pathogen panels could lead to further improvements in management. Ms Brill: But, as Dr Blaschke points out, there are limitations to these technologies. The FDA-approved multiplex molecular panel for meningitis and encephalitis covers the most common etiologies; it takes us a long way, but there are limitations. Bacterial meningitis is very uncommon, so any test that you use, including multiplex molecular panel tests, can give false-positive results. 11

12 When you are dealing with a very low-incidence disease like bacterial meningitis and you use a test with very high sensitivity, there will be false-positive test results, and we have to determine how to deal with that. In part, it requires clinical judgment in deciding which patients are appropriate to test. On the other hand, not all pathogens that can cause meningitis and encephalitis are on the panel. A patient could have bacterial meningitis with an uncommon organism and the multiplex molecular panel test would be negative. A cell count, Gram stain and cultures are still needed and, as discussed, clinical judgment is important in deciding whether to test and when it is appropriate to stop therapy. In addition, serology is still needed to test for some causes of encephalitis, such as arthropod-borne vectors. Finally, there are some pathogens on the multiplex molecular meningitis/encephalitis panel that we don t fully understand. For example, human herpes virus 6 (HHV-6) is on the panel, but it is not clear what it means when HHV-6 is detected in CSF. In some cases, it may be the cause of the patient s illness and in others and it is an incidental finding. As these tests are used more, we will likely gain better understanding of these types of results. Ms Brill: As Dr Blaschke pointed out, it is important to make a definitive diagnosis of meningitis or encephalitis as quickly as possible because the treatment differs depending on the cause, and the patient s outcome may depend on rapid initiation of an appropriate therapy. The availability of a rapid, sensitive, and relatively comprehensive test for the most common pathogens may decrease the time it takes to start appropriate therapy and could improve outcomes, such as lower morbidity and mortality, shorter hospital stays, and less cost. We asked Dr Blaschke how these tests can equip clinicians to be good stewards of antibiotics? 12

13 Dr Blaschke: It is difficult to be a good steward of antibiotics when it is so important to start treatment right away. But we don t want to misuse antibiotics; over treatment, under treatment, or mistreatment all have consequences such as adverse effects of therapy, selection for resistance, and cost. With a rapid multiplex molecular panel test, a clinician may be able to get an answer back about a specific bacteria or virus and then proceed to targeted therapy. One example is group B streptococcus, which is a common pathogen of meningitis in young infants. This bacterium is very sensitive to the narrowspectrum antibiotic ampicillin. With rapid testing we can know very quickly if that this is what we are dealing with, and initiate targeted therapy quite early. Ms Brill: This brings us to the close of episode 1. We hope you found it to be informative and helpful to your practice. As Dr Blaschke discussed, one of the greatest unmet needs in infectious diseases is availability of rapid and precise diagnostic tests. In out next episode, we will continue our discussion of the use of molecular diagnostic tests in patients who present with acute gastroenteritis. To proceed to the online CME/CE test click on the earn CME/CE credit link on this page. And thank you for watching. 13

14 Abbreviations CSF = cerebrospinal fluid CNS = central nervous system FDA = United States Food and Drug Administration HHV = human herpes virus HHV-6 = human herpes virus 6 HSV = herpes simplex virus MALDI-TOF = matrix-assisted laser desorption/ionization time of flight PCR = polymerase chain reaction Related Links Clinical Pearls on the Management of Immune-Related Adverse Events Affecting the CNS AAP Recommends Flu Shot Over Nasal Spray for Influenza Season Children With Vomiting and Muscular Weakness: What s the Diagnosis? 14

15 References 1. Blaschke AJ, Hersch AL, Beekman SE, et al. Unmet diagnostic needs in infectious disease. Diagn Microbiol Infect Dis. 2015;81: Caliendo AM, Gilbert DN, Ginocchio CC, et al. Better tests, better care: Improved diagnostics for infectious diseases. Clin Infect Dis. 2013;57:S Pillai SK, Beekmann SE, Santibanez S, et al. The Infectious Diseases Society of America emerging infections network: bridging the gap between clinical infectious diseases and public health. Clin Infect Dis. 2014;58: Centers for Disease Control. Meningococcal disease. Accessed October 10, MacNeil Jessica R, Blain AE, Wang X, et al. Current epidemiology and trends in meningococcal disease -- United States, Clin Infect Dis. 2018;66: Centers for Disease Control. Antibiotic resistance threats in the United States Accessed August 5, Hanson KE. The first fully automated molecular diagnostic panel for meningitis and encephalitis: How well does it perform, and when should it be used? J Clin Microbiol. 2016;54: Leber AL, Everhart K, Balada-Llasat J-M, et al. Multicenter evaluation of BioFire FilmArray meninigitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbiol. 2016;54: Liesman RM, Strasburg AP, Heirman AK, et al. Evaluation of a commercial multiplex molecular panel for diagnosis of Infectious meningitis and encephalitis. J Clin Microbiol. 2018;56:e Messacar K, Breazeale G, Robinson CC, et al. Potential clinical impact of the FilmArray meningitis encephalitis panel in children with suspected central nervous system infections. Diagn Microbiol Infect Dis. 2016;86: Wootton SH, Aguilera E, Salazar L, et al. Enhancing pathogen identification in patients with meningitis and a negative Gram stain using the BioFire FilmArray Meningitis/Encephalitis panel. Ann Microbiol Antimicrob. 2016;15: Verstrepen WA, Kuhn S, Kockx MM, et al. Rapid detection of enterovirus in cerebrospinal fluid specimens with a novel single-tube real-time reverse transcription-pcr assay. J Clin Microbiol. 2001;39: Rabenau HF, Clarici AM, Mühlbauer G, et al. Rapid detection of enterovirus infection by automated RNA extraction and real-time fluorescence PCR. J Clin Virol. 2002;25: Bennett S, Harvala H, Witteveldt J, et al. Rapid simultaneous detection of enterovirus and parechovirus RNAs in clinical samples by one-step real-time reverse transcription-pcr assay. J Clin Microbiol. 2011;49: Giulieri SG, Chapuis-Taillard C, Manuel O, et al. Rapid detection of enterovirus in cerebrospinal fluid by a fully-automated PCR assay is associated with improved management of aseptic meningitis in adult patients. J Clin Virol. 2015;62: Blaschke AJ, Holmberg KM, Daly JA, et al. Retrospective evaluation of infants aged 1-60 days with residual CSF tested using the FilmArray meningitis/encephalitis (ME) panel. J Clin Microbiol Jun 25;56:e