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© The Children's Mercy Hospital, 2014. 03/14
2015 CAPS ID
Insights from the Red Book
Mary Anne Jackson, MD
Division Director, ID
Professor of Pediatrics UMKC-SOM
Pinch Hitter: Christopher Harrison MD
Director of CMH VTEU and ID Research
Laboratory
© The Children's Mercy Hospital, 2014. 03/14 2
• Dr. Jackson has no actual or potential
conflict of interest in relation to this
program
• CMH receives grant funding from GSK for
MMR study for which
I (Harrison) am PI, and also
from NIH for study of
various influenza
vaccines.
© The Children's Mercy Hospital, 2014. 03/14 3
Objectives • Brief history of the Red Book
– Covers established/new infectious diseases
• 4.5 cases illustrative of established vs new
1. Influenza – most common vaccine preventable infection in USA in 21st century
2. Still “Whack-a-mole” with measles
3. C difficile – Mostly Adults, now more Peds?
– Emerging pathogens in KC
4. Human parechovirus-3 (HPeV3)
5. Enterovirus (EV) D68 (mini)
© The Children's Mercy Hospital, 2014. 03/14 4
History of the Red Book
• 1930-American Academy of Pediatrics
founded
• 1936-established AAP Committee on
Immunization Procedures
• 1938-the first report of COIP published in
pamphlet form
The Red Book Through the Ages Larry K. Pickering, Georges Peter, and
Stanford T. Shulman Pediatrics 2013
© The Children's Mercy Hospital, 2014. 03/14 5
Diseases: Red Book 1938 Antimicrobial/Rx Vaccine
The common cold
Diphtheria Antitoxin Toxoid
Epidemic encephalitis Convalescent serum
Erysipelas Sulfanilamide For recurrent disease
Epidemic meningitis Sulfanilamide
Epidemic parotitis Convalescent serum
Pertussis Detoxified pertussis antigen 3 unproven
Pneumonia Sulfanilamide
Polio Convalescent serum
Rabies Post-exposure killed virus
Measles Convalescent serum
Scarlet fever Antitoxin Toxin
S aureus Antitoxin Toxoid
Tetanus Toxoid
TB BCG
Typhoid fever Vaccine
Varicella Convalescent serum Vesicle content
Variola Calf vaccine © The Children's Mercy Hospital, 2014. 03/14 6
Through the Years
• Published every 1-5 years between 1938 and
1986 and every 3 years since then
• 10 prior editors over 30 years
• 1970s-liaisons from CDC and FDA added
• 1982-associate editors added
• Inclusion of reference to AAP statements, CDC
guidelines, ACIP recommendations and IDSA,
AHA guidelines (GRADE)
• COID responsible for assembly and publication
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© The Children's Mercy Hospital, 2014. 03/14 7
2015 Edition
Primary Reviewers • 179 content experts
• 196 CDC reviewers
• 51 FDA reviewers
• 24 COID members
• 1 PhD microbiologist-Raj Selvarangan
• 30 internal AAP reviews
Grand Total-474 chapter reviewers
© The Children's Mercy Hospital, 2014. 03/14 8
Red Book 2015
• Launched in May
• All chapters updated plus new chapters (eg, Ebola)
• Format stayed the same
– 6 sections (active/passive immunization, care of
children special circumstances, summaries,
antimicrobial agents, antibiotic prophylaxis,
appendices
– Pathogen summaries
• Clinical manifestations, etiology, diagnostic testing,
treatment, isolation, control measures
© The Children's Mercy Hospital, 2014. 03/14 9
Case 1
• 10 yo: T 101.60F, RR 32, ill appearing
– Cough X 5 days, “weak in the eyes”
– Scattered rales, dull to percussion R base
– Normal CBC, Rapid flu negative
– Blood cx pending
– CXR- Bilateral air space disease, RLL patchy
consolidation
• Suspicion: CAP
– Admitted for IVF, Abx and O2 initiated
© The Children's Mercy Hospital, 2014. 03/14 10
Influenza Rapid Antigen Test
• Variable sensitivity/specificity
– Compared with viral culture or RT-PCR.
– Sensitivities ~50-70%
– Specificities ~90-95%
• Highest sensitivity when collected early in
course, best at ≤4-5 days in adults
• Young children excrete in higher titers and
longer – so can be useful up to 8-10 days
© The Children's Mercy Hospital, 2014. 03/14 11
Rapid Antigen Test-Influenza
• Positive and negative predictive values vary
– Depends on current prevalence of influenza
• False-positive
– More likely when prevalence is low
– Occurs at beginning and end of season
• False-negative
– More likely when prevalence is high
– At height of the influenza season
• Every hospitalized child with influenza should receive
oseltamivir
© The Children's Mercy Hospital, 2014. 03/14 12
H3 Flu A
Flu A not Typed
Flu B
H1N1 Flu A
% Positive
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© The Children's Mercy Hospital, 2014. 03/14 ©2013 Children's Mercy Hospitals and Clinics. All Rights Reserved. 01/13
Flu A
Flu B
© The Children's Mercy Hospital, 2014. 03/14 14
& - Rate / 100,000 population
&
© The Children's Mercy Hospital, 2014. 03/14 15
>65 YO
< 5 YO
50-64 YO
© The Children's Mercy Hospital, 2014. 03/14 16
Children
Adults
Heart Disease
Chronic Lung Disease
Immune Deficient
Metabolic Disorder
Renal Disease
No Known Condition
Pregnancy
Obesity
Asthma
Neuromuscular Dis
Neurologic Dis
% 0 20 40 60
Confirmed Influenza Hospitalizations 2014-2015 by Condition
FluView CDC.gov
© The Children's Mercy Hospital, 2014. 03/14 17
Pregnancy Vulnerability
• IL-6 showed higher expression in pregnant
women who died.
• IFN-β and TGF-β expression were lower in
those pregnant women who died.
• Periolo et al.Pregnant women infected with pandemic influenza A(H1N1)pdm09 virus
showed differential immune response correlated with disease severity. J Clin Virol
2015 64: 52–58
© The Children's Mercy Hospital, 2014. 03/14 18
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H1N1 pnd 2009
Less Severe after 2010 • Post-pandemic years, H1N1 disease:
– Lower median age
– Less likely to have underlying condition
– Lower likelihood of intubation and ARDS
– Decreased mortality
• Rao et al. A comparison of H1N1 influenza among Pediatric Inpatients in the
Pandemic and Post Pandemic Era. J Clin Virol 2015, on line July.
• DOI: http://dx.doi.org/10.1016/j.jcv.2015.07.308
© The Children's Mercy Hospital, 2014. 03/14 20
2014-2015 Influenza Vaccine
© The Children's Mercy Hospital, 2014. 03/14 21
Influenza Vaccine for 2015–16
• IIV-3 (new H3N2 and B)
– A/California/7/2009 (H1N1)-like virus
– A/Switzerland/9715293/2013 (H3N2)
– B/Phuket/3073/2013-like (Yamagata lineage)
• IIV-4 and LAIV-4
– IIV-3 strains
– B/Brisbane/60/2008-like (Victoria lineage)
• Same 2nd B as 2013–14 and 2014–15
© The Children's Mercy Hospital, 2014. 03/14 22
Doses of Flu Vaccine
0.5 through 8 YO
© The Children's Mercy Hospital, 2014. 03/14 23
Case 2- The rash
• A 4 month old Micronesian is admitted
for suspected Kawasaki Disease.
• Fever for 4 days and rash, red eyes,
very irritable
• Inflammatory markers are elevated
© The Children's Mercy Hospital, 2014. 03/14 24
Differential Diagnosis Important “don’t want to miss” considerations
• Kawasaki Disease
• Tick borne infection, leptospirosis
• Seasonality, exposures
– Measles
• Key: immunization history, exposure, travel
– Staphylococcal or GAS toxin syndromes
– Drug hypersensitivity reactions
• Classic: TMP/SMX, carbamazepime
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© The Children's Mercy Hospital, 2014. 03/14 25
Irritable infant with fever, rash
and red eyes
Image courtesy Jennifer Goldman, MD © The Children's Mercy Hospital, 2014. 03/14 26
The 2014 Kansas City Outbreak
• Imported disease - Genotype B3
– 3rd largest 2014 US outbreak behind OH and CA
– Largest per population base
• May 6 - First case in Clay County, Missouri
• May 13 & 15 - 2 more cases, first infant case
– May 20….new case in a choir member
– Additional cases followed a restaurant exposure
• Data from first 22 cases:
– 2 wks old to 37 years old (median age 5 years)
– None immunized
© The Children's Mercy Hospital, 2014. 03/14 27
Another Imported Case • Measles at the “The
Happiest Place on Earth”
• Dec 2014 – Apr 2015
• 136 cases related to visit
to Disneyland and
surrounding theme parks
• B3 genotype (predominant
Philippines strain)
• 60% adults
70% not immunized, 20% hospitalized,
two other imported cases added to exposures
© The Children's Mercy Hospital, 2014. 03/14 28
What To Do If You Suspect Measles
– Know the signs/symptoms/incubation period
– Isolate suspected cases
• Highly contagious for 4 days pre- and post rash
• Airborne precautions
• Do not refer/send to healthcare facility without first calling
– Notify HD immediately and/or ID consultant on call
– Testing
• Throat swab and urine for measles PCR
• Blood sample for measles specific IgM serology
– Understand exposed unimmunized persons need PEP
© The Children's Mercy Hospital, 2014. 03/14 29
Measles Symptom Timeline
Conjunctivitis
Viral Shedding - Contagious
Incubation 7-21 Days
© The Children's Mercy Hospital, 2014. 03/14 30
5 Measles Red Flags:
High Index of Suspicion
Compatible clinical symptoms plus
1. Unimmunized against measles
2. Contact with unimmunized or international traveler
3. Travel to current outbreak area
4. Travel to US tourist destinations popular with
international travelers
• For example national amusement/theme parks
5. International travel - measles may occur anywhere
• But…..CDC specific health alerts for Philippines and Vietnam
• Other countries with measles as of June 2015
– Angola, Bosnia, Ethiopia, Germany, Kyrgyzstan
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© The Children's Mercy Hospital, 2014. 03/14 31 © The Children's Mercy Hospital, 2014. 03/14 32
What Do Two-Dose Cases Look Like?
3 C’s not present, rash not classic distribution
1. Fever 101, conjunctivitis, no cough, but did report coryza
Rash started on face, then to chest and shoulders. Did not affect to
extremities. Had traveled to China, had no known exposure
2. Subjective fever, conjunctivitis, cough, no coryza
Rash started on face, moved to chest, arms then stomach (lasted 4 days)
Exposed to measles in an UC waiting room
3. Fever 101, no conjunctivitis, cough or coryza
Rash started on face, then to body, arms, legs (lasted 3 days)
Exposed to measles in household
4. Subjective fever, conjunctivitis, no cough or coryza.
Rash spread head downward, duration unknown
Exposed on a flight to CA measles case
Exposure history critical for Dx
© The Children's Mercy Hospital, 2014. 03/14 33
Other Aspects of Rash in Immunized
Patients o Itchy rash?
oMay be itchy from day 4-7, but not itchy immediately
o Rash on palms and soles?
oMeasles rashes may be on palms and soles but not as
prominent as on face and chest
o What is the rash distribution and spread look like?
o Even if disease is modified the order of appearance
(face and head) and direction of spread is the same
o Timing of fever in relation to rash not defined
© The Children's Mercy Hospital, 2014. 03/14 34
Use All Opportunities to Give
MMR – Target pediatric age groups in your practice
• Be aware daycare or schools with low vaccination coverage
– Two MMR vaccines (first @ 12 months and 2nd dose may be
administered if 28 days has elapsed)—99% protective
– Accelerate vaccine for travelers
• 6 through 11 months – give dose 1
• Give dose #2 to any child 12 months or older who is 28 days
post dose #1
– Recommend vaccine to anyone born during or after 1957
– HCW workers need two vaccines if without serologic evidence
© The Children's Mercy Hospital, 2014. 03/14 35
Case 3-Diarrhea in a 10 year old
• Starts amoxicillin for sinusitis after a URI
symptoms persist for 10 days
• Day 4 on antibiotic
– Abdominal pain and watery diarrhea
• Day 6
– Diarrhea worse, cramping – Abx stopped
• Day 11
– Stools become bloody
© The Children's Mercy Hospital, 2014. 03/14 ©2013 Children's Mercy Hospitals and Clinics. All Rights Reserved. 01/13
CDC Threat Report
• 250,000 Americans suffer from C. difficile
infection annually
• >85% of reported cases are adults
• Recent data conflicting on pediatric C diff
disease vs. asymptomatic “carriage”
http://www.cdc.gov/drugresistance/threat-report-
2013/
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© The Children's Mercy Hospital, 2014. 03/14 37
Introduction
• Clostridium difficile
• Gram-positive
anaerobic bacillus
• Can exist in vegetative
or spore form
• Causes hospital and
community-acquired
diarrhea
Am J Dis Child. 1935;49(2):390-402
© The Children's Mercy Hospital, 2014. 03/14 ©2013 Children's Mercy Hospitals and Clinics. All Rights Reserved. 01/13
Epidemiology
C. difficile colonization
– Become colonized in by 1-3 months of life
– Up to 73% of 6 month olds
– Colonization decreases in 2nd and 3rd year of life
– Up to 3% can have asymptomatic carriage at 3 years
of age (similar to adults)
– Can be colonized with toxigenic or non-toxigenic
strains
Donta and Myers. J Pediatr 1982 Mar;100(3):431-4
© The Children's Mercy Hospital, 2014. 03/14 ©2013 Children's Mercy Hospitals and Clinics. All Rights Reserved. 01/13
Clinical Manifestations
Khanna S et al. Clin Infect Dis 2013
© The Children's Mercy Hospital, 2014. 03/14 40
Candidate for C diff Testing?
A. 6 month old with streaky blood in stool for 5 days
B. 2 year old with mucous and blood in stool for one day
C. 6 year old with abdominal pain and diarrhea for 4 days,
formed stool today
D. 10 year old with IBD has diarrhea for 10 days while
hospitalized for TPN
E. 12 year old completing metronidazole after C diff
diagnosis as “test of cure”
© The Children's Mercy Hospital, 2014. 03/14 41
Diagnostics-correct test in
correct situation
• C. difficile could be cultured using selective media
but this won’t identify if toxin present
• Testing is targeted to identifying the toxin
• 2 step testing
1. ELISA for C. difficile glutamate dehydrogenase (GDH) antigen
2. If GDH positive then test for toxin A and B antigens
• PCR testing for toxin genes
Schutze and Willoughby with AAP COID. Policy Statement: Clostridium difficile
Infection in Infants and Children Pediatrics 2013; 131:1 196
© The Children's Mercy Hospital, 2014. 03/14 42
CMH Cdiff Test Order Algorithm
* https://www.childrensmercy.org/Health_Care_Professionals/Medical_Resources/Clinical_Practice_Guidelines/Clostridium_Difficile/Clostridium_Difficile/
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© The Children's Mercy Hospital, 2014. 03/14 43
Treatment
• Classify disease severity
– Oral metronidazole
– Oral vancomycin
– Oral, PR vancomycin plus IV
metronidazole
• FMT for refractory C. difficile
– Administer stool via enema,
colonoscopy, NG
– DIY follows IDSA guidelines
for choosing “donor”
Cohen SH et al. Clin Infect Dis 2010
Powerofpoop.com
© The Children's Mercy Hospital, 2014. 03/14 44
Case 4 – R/O sepsis infant
• 2 week old presents in August:
– History
• Fever 101.2 F at home
• Poor feeding, Very irritable
• Transient truncal rash
– PE
• Abdominal distension, is irritable
– Lab
• Leukopenia with lymphopenia
• Normal CSF exam
© The Children's Mercy Hospital, 2014. 03/14 45
SBI IN YOUNG INFANTS
• Non-infectious etiologies - e.g. volvulus
• UTI most common and E coli predominates
• CNS infections
– Viral agents (HSV, enteroviruses, others)
– Bacterial pathogens
• Group B streptococcus
• Less common: E coli, other gram-negatives,
Listeria monocytogenes
• S pneumoniae and N meningitidis
© The Children's Mercy Hospital, 2014. 03/14 46
Enteroviruses
• 10-15 million children infected yearly
• 100 different viruses
• Polioviruses and non-polio viruses
• Non-Polioviruses
– Echoviruses
– Coxsackie viruses A and B
– Numbered enteroviruses
© The Children's Mercy Hospital, 2014. 03/14 47
“Typical” Enteroviruses • Summer-fall
• Typical clinical presentations
– Nonspecific febrile illness
– HFMD-classically Coxsackie A-16; atypical cases Coxsackie A-6
– Enterovirus meningitis- classically echoviruses
• Rare but distinct associations
– Enterovirus 71-acute flaccid paralysis
Khettsuriani, et al. MMWR Surveill Summ.
2006 Sep 15;55(8):1-20 © The Children's Mercy Hospital, 2014. 03/14 48
Atypical HFMD
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© The Children's Mercy Hospital, 2014. 03/14 49
Human parechoviruses (HPeV)
• Single-stranded, non-enveloped RNA viruses Picornaviridae family
• Types 1 and 2 were initially designated echovirus 22 and 23 within
the Enterovirus (EV) genus
• HPeV type 3 (HPeV-3), identified in 2004, and 16 HPeV types are
now known
• 2-3 year cycle of late summer-fall outbreaks
– Mostly like EV meningitis
– But…meningoencephalitis and severe disease may occur in neonates
• Differential Dx includes HPeV vs enterovirus vs HSV
• Diagnosis confirmed by PCR detection in CSF
Romero, JR, Selvarangan, R. The Human Parechoviruses: An Overview. Adv Pediatr. 2011; 58: 65-85.
Renaud C, Harrison CJ. Human Parechovirus 3: The most common viral cause of meningo- encephalitis in young infants. Infect Dis Clin North Am. 2015
© The Children's Mercy Hospital, 2014. 03/14 50
0
20
40
60
80
100
120
140
160
2006 2007 2008 2009 2010 2011 2012 2013 2014
EV 81 86 156 55 141 55 42 53 65
HPeV 4 54 0 66 4 5 47 8 43
# d
ete
cte
d
3
All
EV and HPeV Cases
CMH-KC 2006-2014
Courtesy Dr. Raj Selvarangan
2014 EV not including EV-D68
© The Children's Mercy Hospital, 2014. 03/14 51
HPeV vs Enterovirus
• Hx of Abdominal pain
• Sepsis appearance
• Lymphopenia
• Absence of CSF pleocytosis
• Longer duration of fever
• Prognosis generally good but
severe disease with white
matter lesions, sequelae
Verboon-Maciolek, et al. Ann
Neurol 2008;64:266–273
Diffuse in high signal intensity in white
matter, diffuse high signal intensity in the
periventricular white matter on DWI
Sharp, et al Pediatr Infect Dis J.
2013 Mar;32(3):213-6
© The Children's Mercy Hospital, 2014. 03/14 52
Case 5-What else?
• August 2014: an outbreak of asthma like
illness in children requiring PICU care
– 3 signals: physician alert, microbiology
records, PLUS “us too”
– Prompted request for CDC typing
– The emergence of EV68 in KC and the rest of
the states
© The Children's Mercy Hospital, 2014. 03/14 53
FilmArray™ for Molecular ID
Respiratory Pathogens
• Has the ability to potentially identify 19
respiratory pathogens
• “FilmArray RP utilizes a combination of PCRs
that can detect rhinovirus or that may more
broadly detect rhinovirus/enterovirus without
distinguishing between the two”
– Biased toward recognition of rhinovirus
J Clin Microbiol. Feb 2012; 50(2): 364–371.
doi: 10.1128/JCM.05996-11
© The Children's Mercy Hospital, 2014. 03/14 54
Figure 1 Weekly entero/rhino detections
2013 compared to 2014; week 33
5-7/week 30/week
for prior
2 wks
Courtesy Dr. Rangaraj Selvarangan
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© The Children's Mercy Hospital, 2014. 03/14 ©2013 Children's Mercy Hospitals and Clinics. All Rights Reserved. 01/13
Flu A
Flu B
Rhino/EV
Mostly EV D68
© The Children's Mercy Hospital, 2014. 03/14 56
2014 EV D-68 Outbreak • Largest outbreak of EV D68 severe respiratory illness across the US
– In KC, we confirmed 333 cases with 61 to the PICU
• Spectrum of infection uncertain
– Severe bronchospasm with respiratory failure
– ? Extent of mild disease
• Severely ill EV D-68 positive children were older (5-10 YO), more
likely to have history of asthma/wheeze, high rate respiratory failure
• Don’t’ miss “the forest for the trees” – especially in high risk hosts
– 36% of strains submitted to CDC confirmed
– 60% confirmed from CMH PICU patients
• Unusual EV68 manifestations ?
– Association with polio like cases still under investigation
© The Children's Mercy Hospital, 2014. 03/14 57
30th Edition
18 diseases, 8 pages
© The Children's Mercy Hospital, 2014. 03/14 58
Pages of the Red Book
0
100
200
300
400
500
600
700
800
900
1000
1938
1940
1943
1945
1951
1955
1961
1966
1971
1977
1986
1991
1997
2003
2009
2015
© The Children's Mercy Hospital, 2014. 03/14 59 © The Children's Mercy Hospital, 2014. 03/14 60
Red Book Timeline
Activity
Aug 28 to Oct 8, 2012 Finalize AEs and primary reviewers
Oct 8 to Dec 17, 2012 Primary reviewers review chapters
Dec 21, 2012 to Feb 4, 2013 AEs to incorporate primary reviewer edits
March 4 to June 3, 2013 CDC, FDA, and Internal Reviewers review chapters
June 24 to Oct 7, 2013 AEs to incorporate CDC, FDA, and Internal Reviewer edits
Nov 1, 2013 to Feb 3, 2014 COID and liaison primary and secondary reviews
Feb 17 to March 10, 2014
AEs review primary and secondary COID and
liaison reviewers’ edits
March 11 to March 13, 2014 Marathon Meeting
March 13 to April 9, 2014 AEs to incorporate Marathon Meeting edits
April 9 to Aug 11, 2014 Copy editing (Shaw) and final editing (Kimberlin)
Aug 11, 2014 to Feb 16, 2015
Board review (from Word documents), Editor
Review (Kimberlin), and typesetting (Peg Mulcahy)
Feb 16 to March 16, 2015 Indexing (outside company, coordinated through Marketing)
March 16 to March 30, 2015 Shaw and Kimberlin cross-check index
March 30 to April 27, 2015 Print
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© The Children's Mercy Hospital, 2014. 03/14 61
10 Editors of the Red Book over
30 years • John Toomey first 8 editions
• John J. Miller, Jr (2), Aims McGuinness (1), Edward C.
Curnen, Jr (1), Alex J. Steigman (3), Franklin H. Top, Sr.
(3)-1951-1977
• Jerry Klein in 1982-appointed the first associate editors
• George Peter and Larry Pickering 10 editions between
1986 and 2012
• David Kimberlin, editor 2015 edition
© The Children's Mercy Hospital, 2014. 03/14 62
COID Members + Liaisons
13 Voting-Michael T. Brady, Carrie L. Byington, H. Dele Davies, Kathryn M. Edwards, Mary Anne Jackson,
Yvonne A. Maldonado, Dennis L. Murray, Walter A. Orenstein, Mobeen Rathore, Mark Sawyer,
Gordon E. Schutze, Rodney E. Willoughby, Theoklis E. Zaoutis; 4 Non-voting-David W. Kimberlin,
Sarah S. Long, Henry H. Bernstein, H. Cody Meissner, + 12 Liaisons
© The Children's Mercy Hospital, 2014. 03/14 63
Current Liaisons to COID
© The Children's Mercy Hospital, 2014. 03/14 64
Enterovirus D-68 Confirmation
• Samples to CDC August 19
• Confirmation of EV D-68 in clinical samples August 26
• EV D-68- identified in 1962 in respiratory samples from CA cases (Schieble, et al, Am J Epidemiol 1967)
• Rare reports next 36 years
• Since 2008, small clusters
– MMWR 2011-disease could be missed b/o misidentification as a rhinovirus
© The Children's Mercy Hospital, 2014. 03/14 65
Disease Extent and Severity
PICU Care, CMH-KC 2014
0
5
10
15
20
25
30
35
40
45
1-A
ug
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
2
4
6
8
10
12
14
17
19
21
23
R/E detections PICU
Alert by IW
Batch 1:CDC
EV 68 Case Definition
© The Children's Mercy Hospital, 2014. 03/14 66
Mid-August, 2014
Children’s Mercy-Kansas City
• Clinical signal
• Microbiologic signal
– Asked for confirmation from CDC
• Hospital burden particularly in PICU
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