Disclosures. Objectives. Epidemiology. Enterovirus 68. Enterovirus species 9/24/2015. Enterovirus D68: Lessons Learned from the Frontline

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1 Enterovirus D68: Lessons Learned from the Frontline Disclosures Jennifer Schuster, MD MSCI Children s Mercy Hospital Pediatric Infectious Diseases September 16, 2015 I have nothing to disclose I do not intend to talk about off label uses of drugs I was not on the frontline The Children's Mercy Hospital, 2015 Objectives Epidemiology Discuss the epidemiology of Enterovirus 68 () Discuss the 2014 outbreak Discuss outcomes and future goals Enteroviruses Enterovirus 68 Enterovirus species A B C Enterovirus serotype Coxsackie A Enterovirus (including 71) Coxsackie A serotype 9 Coxsackie B Echovirus Enterovirus Coxsackie A Poliovirus Enterovirus D Enterovirus (including 68) Identified in 1962 from 4 children with lower respiratory tract infection HRV-87 and are identified as the same Features of both rhinoviruses and enteroviruses Acid sensitive Respiratory symptoms Genetic clustering with EV70 but serologically different Adapted from Long SL ed. Principles and Practice of Pediatric Infectious Diseases, Fourth Edition Schieble et al. Am J Epi Blomqvist et al. J Clin Micro

2 Enterovirus Surveillance- United States, Occurs in Peaks 26 reports 11 in 2003 Most common age group 1-4 years 25% were 20 years 50% were outside of summer-fall 47 th most common enterovirus Increased detection in Japan, Philippines, China, Netherlands, United States True peak vs. increased utilization of PCR Khetsuriani N et al. MMWR Ostroff SM et al. MMWR Occurs in Peaks and is Under Recognized 2014 Outbreak High prevalence of antibodies Peak years occur Smura T et al. J Med Virol Meijer A et al. Virology Recognition of the CMH Outbreak Increase in Severe Respiratory Illness August 15 August 19 August 20 August 21 Recognition of cases of severe respiratory tract disease in the ED Laboratory recognition of increased enterovirus/ rhinovirus (EV/RV) respiratory pathogen panel (RPP) CDC contacted for further specimen typing Institutional Response Team established Case definition established 2

3 Number of Specimens 9/24/2015 Increase in Severe Respiratory Illness CDC Confirmation August 22 August nasopharyngeal specimens received by the CDC 19/22 specimens confirmed for 2014 Outbreak at CMH Patients with EV/RV respiratory pathogen panel Ages 0-17 years Hospitalized between August 1- September 15 Retrospective Data collected Specimens tested for at CMH 2014 CMH Outbreak 92 not admitted 662 EV/RV specimens 570 admitted Case definition established and testing recommended Enterovirus 68 Negative Positive 8 unable to be tested excluded excluded 0 1-Aug 8-Aug 15-Aug 22-Aug 29-Aug 5-Sep 12-Sep Date of Specimen Schuster JE et al. Clin Therap. In press 3

4 Demographics Demographics Age, years, median [IQR] 4.6 [ ] 2.2 [ ] <0.001 Gender, male 212 (62.5) 127 (62.6) 1.00 Race or ethnicity 0.45 White 167 (49.3) 109 (53.7) Black 95 (28.0) 52 (25.6) Hispanic or Latino 37 (10.9) 15 (7.4) Unknown/ Other 40 (11.8) 27 (13.3) Insurance status 0.16 Publicly funded 186 (54.9) 128 (63.1) High risk condition Private 127 (37.5) 64 (31.5) Self-pay 26 (7.7) 11 (5.4) Prematurity 33 (9.7) 21 (10.3) 0.82 Cardiac 18 (5.3) 8 (3.9) 0.47 Immunocompromised 3 (0.9) 9 (4.4) 0.01 Asthma 131 (38.6) 61 (30.0) 0.04 Recurrent wheeze 75 (22.1) 30 (14.8) 0.04 Clinical Symptoms Clinical Signs EVD-68 Cough 289 (85.3) 148 (72.9) <0.001 Diarrhea 21 (6.2) 17 (8.4) 0.34 Fever 151 (44.5) 94 (46.3) 0.69 Increased work of breathing/ dyspnea 286 (84.4) 142 (70.0) <0.001 Nasal congestion 153 (45.1) 76 (37.4) 0.08 Seizures 3 (0.9) 8 (3.9) 0.02 Sore throat 35 (10.3) 8 (3.9) Vomiting 102 (30.1) 59 (29.1) 0.80 Signs on initial physical examination EVD-68 O 2 saturation <95% 188 (55.5) 92 (46.2) 0.04 Retractions 249 (73.5) 107 (52.7) <0.001 Wheezing 243 (71.7) 96 (47.3) <0.001 Laboratory Findings Viral Co-infections White blood cell count* 13.0 ( ) 12.8 ( ) 0.59 Absolute neutrophil count* 8.5 ( ) 6.1 ( ) EVD-68 Absolute lymphocyte count* 1.7 ( ) 2.5 ( ) 0.02 Chest X-ray 237 (69.9) 131 (64.5) 0.19 Abnormal chest X-ray 163 (69.4) 88 (67.7) 0.74 Hyperexpansion 32 (19.6) 17 (19.3) 0.95 Lobar infiltrate 37 (22.7) 23 (26.1) 0.54 Peribronchial/perihilar infiltrates 114 (69.9) 49 (55.7) 0.02 Parainfluenza type 3 1 (0.3) 0 (0.0) 1.00 Adenovirus 2 (0.6) 8 (3.9) Mycoplasma pneumoniae 1 (0.3) 0 (0.0) 1.00 *10 3 μl 4

5 Therapies Used Outcome Supplemental oxygen 294 (86.7) 132 (65.0) <0.001 Hours on oxygen 13.0 [ ] 10.0 [ ] 0.31 Albuterol 309 (91.2) 133 (65.5) <0.001 Continuous albuterol 221 (71.5) 84 (63.2) 0.19 Hours of continuous albuterol 2.0 [ ] 2.0 [ ] 0.19 Corticosteroids 281 (82.9) 119 (58.6) <0.001 Magnesium 109 (32.2) 35 (17.2) <0.001 Antibiotics 54 (15.9) 60 (29.6) <0.001 Length of stay 38.0 [ ] 38.0 [ ] 0.56 Discharge medications Antibiotics 21 (6.2) 17 (8.4) 0.34 Corticosteroids 239 (70.5) 96 (47.3) <0.001 Albuterol 286 (84.4) 121 (59.6) <0.001 Readmission (7 days) 2 (0.6) 8 (3.9) Readmission (30 days) 5 (1.5) 20 (9.9) <0.001 Children with Asthma and Recurrent Wheeze N=206 N=91 ICU stay 40 (19.4) 10 (11.0) 0.07 Length of ICU stay (hours) 26.5 [ ] 23.0 [ ] 0.54 Oxygen 191 (92.7) 75 (82.4) Hours on oxygen 13.0 [ ] 9.0 [ ] 0.12 Albuterol 204 (99.0) 84 (92.3) Continuous albuterol 159 (77.9) 64 (76.2) 0.75 Hours on continuous albuterol 3 [2-4] 2 [2-3] 0.03 Corticosteroids 200 (97.1) 83 (91.2) 0.04 Children with Asthma and Recurrent Wheeze N=206 N=91 Magnesium 88 (42.7) 27 (29.7) 0.03 Aminophylline 15 (7.3) 0 (0.0) Length of stay (hours) 37.5 [ ] 35.0 [ ] 0.57 Risk Factors for Severe Disease Risk Factors for Severe Disease ICU N=60 Non-ICU N=279 P OR 95% CI Univariate analysis Multivariate analysis Age, years, median [IQR] [ ] [ ] Age 5 years Gender, male 39 (65.0) 173 (62.0) 0.66 High risk condition Prematurity 5 (8.3) 28 (10.0) 0.69 Cardiac 1 (1.7) 17 (6.1) 0.22 Immunocompromised 0 (0.0) 3 (1.1) 1.00 Asthma 30 (50.0) 101 (36.2) Recurrent wheezing 10 (16.7) 65 (23.3) 0.26 P ICU N=60 Non-ICU N=279 P value Race or ethnicity 0.58 White 25 (41.7) 142 (50.9) Black 20 (33.3) 75 (27.0) Hispanic or Latino 8 (13.3) 29 (10.4) Unknown/ Other 7 (11.7) 33 (11.8) Ct, median 21.7 [ ] 23.7 [ ]

6 Seroprevalence Outcome Age (years) N Fermon* 18949* 18952* 18953* (5.5) 100 (5.83) 76 (3.17) 91 (4.17) (6.17) 100 (7.83) 93(7.83) 91 (6.17) (5.83) 100 (7.83) 98 (8.50) 95 (6.50) (8.5) 100 (8.5) 99 (9.17) 98 (7.17) > (10.5) 100 (8.83) 99 (9.5) 99 (6.83) Total (6.83) 100 (7.83) 89 (8.34) 97 (6.50) *Sero (median titer) Harrison C et al. ASM Clinical Virology Symposium. Poster presentation August 8- September 15, children with acute neurologic illness Extremity weakness, cranial nerve dysfunction, or both Median age 8 years Preceding febrile illness and often URI symptoms Non-enhancing gray matter spinal cord lesions in multiple levels Non-enhancing brainstem lesions Lymphocytic CSF pleocytosis Pastula DM et al. MMWR children had NP specimens 6 were EV/RV 4 Stool specimens for polio Pastula DM et al. MMWR CDC case definition 1. Patients 21 years of age 2. Acute onset of focal limb weakness 3. On or after August 1, MRI showing a spinal cord lesion largely restricted to gray matter Ayscue P et al. MMWR Division of Viral Diseases et al. MMWR

7 88 cases in 32 states 81% had a respiratory illness 8/41 (20%) were from upper respiratory tract samples None were fully recovered 48 patients in Colorado and California 25 acute flaccid myelitis 16 encephalitis/ aseptic meningitis and for enterovirus 5 URTI 2 enterovirus-associated encephalitis Division of Viral Diseases et al. MMWR Greninger AL et al. Lancet Infect Dis Summary Greninger AL et al. Lancet Infect Dis Children with are older than those with other common respiratory viruses. Children with asthma and recurrent wheeze may require aggressive bronchodilator therapy and ICU care. An increased recognition of acute flaccid myelitis cases occurred concurrently with increased detection. Future Directions Acknowledgements Active respiratory surveillance for Association of with acute flaccid myelitis Effective therapeutics against Mary Anne Jackson, MD Rangaraj Selvarangan, PhD Ferdaus Hassan, PhD Lindsay Hays CDC Steve Oberste, PhD Allan Nix Shannon Rogers Kayla Briggs Jenna Miller, MD Barbara Pahud, MD Hank Puls, MD Mary Ann Queen, MD Marita Thompson, MD Gina Weddle, DNP 7