Disclosures. Curry Clinical Microbiology Updated 3/12/17

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1 Clinical Microbiology 2017: Useful and Useless New Tests in Primary Care Scott Curry, MD Assistant Professor of Medicine Division of Infectious Diseases 12 March 2017 Disclosures I have no commercial relationships to the pharmaceutical industry or medical device manufacturers. 1

2 Learning objectives 1. Review the potential impact of nucleic acid testing for respiratory viruses in the treatment of upper respiratory tract infections/rhinosinusitis. 2. Review updates in use of nucleic acid testing for the evaluation of gastroenteritis/foodborne illness. 3. Understand recent updates in C. difficile testing. Case of recurrent sinusitis: Case of Mr. X 62 yo male with history of recurrent sinusitis Takes fexofenadine for seasonal allergies and PRN fluticasone spray Presents to PCP in clinic with 3-week history of URI symptoms: Feels subjectively feverish + facial pain Nasal discharge is thicker and more purulent over the last week Does not smoke Past rash reaction to ampicillin. Patient attributes onset of symptoms to exposure to a long-haired dog Exam shows 99.6 F temperature R>L maxillary tenderness No active nasal drainage Normal TMs Does this patient need an antibiotic? Libman H. Ann Intern Med Feb 7;166(3):

3 Grand Rounds at BI Deaconess Dr. B (internist): Give doxycycline 100 mg PO BID x 5-7 days Mucopurulent nasal discharge Worsening after 10 days of mild symptoms Unilateral maxillary pain/ exam findings Low-grade fever Dr. G (ID doc): Give nothing Animal dander exposure (raises risk of allergic etiology) All above signs/symptoms not specific for bacterial etiologies Evidence that antibiotics alter course of bacterial sinusitis is poor Libman H. Ann Intern Med Feb 7;166(3): Appropriate Antibiotic Use for Acute Respiratory Tract Infection in Adults: Advice for High-Value Care From the American College of Physicians and the Centers for Disease Control and Prevention High-Value Care Advice 3: Clinicians should reserve antibiotic treatment for acute rhinosinusitis for patients with 1. persistent symptoms for more than 10 days, 2. onset of severe symptoms or signs of high fever (>39 C) and purulent nasal discharge or facial pain lasting for at least 3 consecutive days 3. onset of worsening symptoms following a typical viral illness that lasted 5 days that was initially improving (double sickening). High-Value Care Advice 4: Clinicians should not prescribe antibiotics for patients with the common cold. Harris AM et al. Ann Intern Med 2016; 164:

4 Pathogenesis of acute rhinosinusitis: data from the era of PCR testing Prospective cohort study of 50 Finnish military recruits with acute rhinosinusitis: 39/50 (78%) had viral DNA recovered from NP swab 17 (34%) influenza A 14 (34%) adenovirus 19 (38%) rhino/enterovirus (picornavirus) 7 (14%) coronavirus 1 (2%) other viruses 28/50 (56%) had non-typeable H. influenzae in middle meatus cultures collected by laryngoscopy (no correlation with clinical outcomes) Autio TJ et al. Laryngoscope Jan;125(1):E1-7 Pathogenesis of acute URIs during flu season (San Francisco 2002) All Influenza A/B Rhino* RSV hmpv HCoV Para Adeno No pathogen Total Clinician diagnosis Bronchitis Pharyngitis PNA Sinusitis URI Other Louie JK et al. Clin Infect Dis Sep 15;41(6):

5 Treating acute bacterial rhinosinusitis Prospective, multicenter, randomized, double-blind trial 5 days moxifloxacin vs placebo for patients with bacterial sinusitis (screened by clinical criteria, confirmed by sinus puncture) Primary endpoint: clinical response at 1-3 days after end of therapy Results: 57/73 (78%) moxifloxacin 30/45 (67%) placebo P=0.19 CONCLUSION: Are we kidding ourselves? Hadley JA et al. Laryngoscope May;120(5): Patient demographics and baseline characteristics from mitt moxi vs placebo Moxifloxacin n=73 Placebo n=45 Mean age Male sex 26 (36%) 19 (42%) Duration of infection, d 13.1± ± 4.7 Pathogen isolated at baseline, no (%) S. pneumoniae 32 (43.8) 13 (28.9) Moraxella catarrhalis 7 (9.6) 12 (26.7) Haemophilus influenzae 28 (38.4) 15 (33.3) Streptococcus pyogenes 2 (2.7) 2 (4.4) S. aureus 11 (15.1) 5 (11.1) Hadley JA et al. Laryngoscope May;120(5):

6 Acute URI management: the great unknown(s) Is there a role for more aggressive diagnostic testing for viruses in the management of URIs? Pharyngitis (doubtful) Bronchitis (maybe!) Sinusitis (yes during flu season, maybe other times) PROs Patient satisfaction / antibiotic avoidance Diagnoses specific viral etiologies Diagnoses treatable illness (influenza) CONs Cost ($ ) Misses co-infections and secondary bacterial infections Diagnoses untreatable illnesses (rhino/coronavirus) Things FDA-cleared tests can test for using multiplex PCR on NP swabs Virus Syndrome Demographic Influenza A (H1 / H3) Influenza A 2009 H1N1 Influenza B URTI with fever All ages Respiratory syncytial virus A LRTI in infants Respiratory syncytial virus B URI/ILI in adults Infants/children/aged Human metapneumovirus Bronchiolitis Infants/children/aged Parainfluenza Virus 1 / 2 / 3 Croup, PNA, Bronchiolitis Infants>Children>Adults Immunocompromised Rhino-Enterovirus URIs All ages Adenovirus URIs, Conjunctivitis All ages Coronavirus URIs All ages Atypical bacterial pathogens (Chlamydophila, Mycoplasma, Bordetella pertussis) Varies Mostly children and young adults 6

7 Etiologies that FDA-cleared NP swab tests don t test for: Agent Legionella spp. Bocavirus Parainfluenza type 4/5 Measles/Mumps Epstein-Barr virus CMV MERS/SARS & other emerging respiratory viruses Respiratory Virus Testing at MUSC: (since December 2011) 7

8 Respiratory Virus Testing: What it Looks Like in the Lab Respiratory Virus PCR FAQs Q) What are typical causes of false negative results? Concurrent antiviral/antibacterial therapy Amount of organism in specimen is less than detectable level Presence of assay inhibitors, technical errors, sample mix-up Infection caused by an organism not covered by RVP PCR Alterations in the virus sequence in the region targeted by the assay Q) Can RVP be used to determine when pt. no longer infectious? No, viral & bacterial nucleic acid may persist independently of organism viability. Detection of organism target(s) does not imply that the organisms are infectious or are the cause of clinical symptoms. 8

9 Laboratory limit of detection data for FilmArray RP Organism Strain identification Limit of Detection (TCID 50 /Ml*) Enterovirus Echovirus 6 30,000 Human rhinovirus A1 1 A/Brisbane/59/ Influenza A/H1 A/New Caledonia/20/99 2,000 Influenza A/2009 H1 A/SwineNY/03/ A/Wisconsin/67/ Influenza A/H3 A/Port Chalmers/1/73 50 *50% tissue culture infectious dose Laboratory sensitivity varies widely even within viruses /cdrh_docs/pdf10/k pdf 27% sensitivity of point of care Ag testing for influenza Ukeyi TM et al. Clin Infect Dis (2009) 48 (9): e89-e92. 9

10 Respiratory viral panel testing summary: when/how to order All patients with URI symptoms and fever during flu season All patients with community acquired pneumonia Consider for outpatients with bronchitis/sinus symptoms of any duration demanding antibiotics Should be collected by MDs or trained personnel Use flocked nasopharyngeal swab Insert like you would a feeding tube Wear a mask! Case study: 42 yo female with no significant medical history presents to ER with fever, emesis of food contents, and profuse diarrhea 6 hours after consuming a restaurant meal shared with her husband (still well). No sick contacts. She has 37.9 temperature and otherwise non-toxic. GI PCR panel is positive for norovirus and C. difficile. She has not taken any antibiotics in >1 year. No hospitalizations in same time frame. What is the diagnosis? What is going on here? 10

11 CDC 2011 Estimates for incidence of gastroenteritis in the U.S. Pathogen Illnesses Hospitalizations Deaths Norovirus* 20,865,958 56, Salmonella, nontyphoidal 1,229,007 23, Clostridium perfringens 969, Campylobacter spp. 1,322,137 13, Staphylococcus aureus 241,994 1,067 6 Giardia spp.** 1,221,564 3, Listeria monocytogenes 1,662 1, E. coli (STEC/EHEC) 265,232 3, *only 26 % foodborne **7% foodborne Community-acquired C. difficile? setting year # cases % cases Rate per 100,000 personyears* abx exposu re (3 mos.) exposed to healthcare facilities Connecticut ? % 29 % Manitoba % 23.4?? VA/Durham NC % % > 50% Reading, UK ? % 27.8 % MMWR 57(13); , Infect Control Hosp Epidemiol. 30(10):945-51, Emerg Infect Dis. 16(2): , J Infect Public Health. 2010;3(3):

12 Prospective study of C. difficile contribution to outpatient diarrheal illness All outpatients with acute diarrheal illnesses at Yale and Hopkins ER and clinics May 2001-Sept /1091 (3.9%) participants with + EIA tests for CDI Only 7 had no recognized risk factors Only 3 (0.27%) had no risk factors and no co-infection (rotavirus, norovirus, C. perfringens) An evolving picture of widespread, frequent CDI among outpatients without risk factors should be tempered by these findings. Hirshon et al. EID 17 (10) , 2011 Gastroenteritis/foodborne illness: diagnostics: Pathogen Previous diagnostics available in 2000 Molecular test available 2017 Norovirus* None Yes Salmonella, nontyphoidal Stool culture Yes Clostridium perfringens None No Campylobacter spp. Stool culture Yes Staphylococcus aureus None No Giardia spp.** Antigen testing Yes Listeria monocytogenes None No E. coli (STEC/EHEC) Culture* Yes Plesiomonas Culture* Yes Yersinia Culture* Yes Vibrio spp. Culture* Yes *by special request only 12

13 GI panel PCR testing Target detected Bacteria Viruses Parasites Campylobacter spp. Norovirus Cryptosporidium Plesiomonas shigelloides Sapovirus Cyclospora cayetanensis Salmonella spp. Astrovirus Entamoeba histolytica Vibrio spp. Rotavirus A Giardia lamblia Vibrio cholerae Adenovirus F 40/41 Yersinia enterocolitica STEC (Shiga-like toxin-producing E. coli) Shigella / Enteroinvasive E. coli EAEC / EPEC / ETEC C. difficile toxin A/B PCR multiplexing: all tests for all people Enteropathogenic E.coli (EPEC): no proved role in adult diarrhea Enteroaggregative E. coli (EAEC): no proved role in adult diarrhea Vibrio cholerae: rare in US C. difficile: COLONIZATION COMMON!!! 13

14 7/106 (6.7%) healthy subjects with toxigenic C. difficile Allegheny County, PA 2012 Positive subject Visit Toxigenic culture CFU/g C. difficile NAAT (illlumigene) tcdc genotype 1 POS 2.7 x 10 3 NEG tcdc 5 2 NEG 3 NEG 1 POS < 10 tcdc 20 2 NEG 1 POS 8.7 x 10 3 NEG tcdc 19 2 POS 4.9x10 4 POS tcdc 19 1 POS 3.0 x 10 4 POS tcdc NEG 3 NEG 5 1 POS <10 tcdc Galdys et al. J Clin Microbiol 2014 Jul; 52(7): POS 8.0x10 4 NEG tcdc 3 2 NEG 1 POS 1.1x10 3 NEG tcdc 10 2 POS 1.6x10 6 POS tcdc 10 Lab sensitivity of C. difficile testing Strain PCR limit of detection Culture limit of detection CD3330* 400 CFU/ml 10 CFU/ml CD CFU/ml 10 CFU/ml *epidemic BI/NAP-1/027 lineage Curry SR et al. J Clin Microbiol Nov; 49(11):

15 Time to conversion of CDI test to negative while on therapy, by test type (n=20) Proportion positive Sunkesula V C K et al. Clin Infect Dis. 2013;57: Time to conversion of CDI test to negative while on therapy, by treatment(n=20) Proportion positive Sunkesula V C K et al. Clin Infect Dis. 2013;57:

16 Are we overdiagnosing C. difficile with molecular tests? Prospective analysis of 12,420 stool samples tested for CDI Planche TD et al. Lancet Inf Dis 2013:

17 PCR test + / Cytotoxin negative patients Planche TD et al. Lancet Inf Dis 2013: What about EIA tests vs nucleic acid tests? OBJECTIVE To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox /PCR+) for CDI 17

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19 Duration of Diarrhea Polage CR, et al. JAMA Intern Med. 2015;175(11):

20 Polage CR, et al. JAMA Intern Med. 2015;175(11): So are we over-diagnosing CDI? Yes, particularly in patients with low pre-test suspicion of CDI No antibiotics in preceding 90 days No inpatient / healthcare exposures in preceding 90 days Longstanding non-infectious diarrhea Testing for other typical causes of gastroenteritis positive Maybe Patients with colonization only (current molecular diagnostics cannot distinguish) Patients with intact albumin, normal WBC, mild diarrhea 20

21 GI PCR pearls If C. difficile wasn t on your Ddx when sending stool cultures, DO NOT TREAT it if it comes back positive Especially if it s positive for a virulent pathogen Norovirus Campy, Salmonella, Shigella etc There is NO laboratory test that can distinguish C. difficile colonization from C. difficile infection. IGNORE the results for EPEC, EAEC, ETEC Self-limited diseases Colonization is common Conclusions Respiratory viral PCR panel may be a useful test for limiting unnecessary antibiotic use for URIs. PCR for C. difficile identifies both CDI patients and C. difficilecolonized ones GI PCR panels are now identifying patients colonized with C. difficile and non-pathogens in adults BUT GI PCR allows for rapid diagnostic capacity to identify the main causes of foodborne illness and gastroenteritis. 21