9/24/2015 - Children's Mercy Kansas City · PDF filepamphlet form The Red Book Through ......

9/24/2015

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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.


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)


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


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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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


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


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


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


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


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


& - Rate / 100,000 population

&


>65 YO

< 5 YO

50-64 YO


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


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


http://www.journalofclinicalvirology.com/issue/S1386-6532(15)X0002-3

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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


2014-2015 Influenza Vaccine


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


Doses of Flu Vaccine

0.5 through 8 YO


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


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

http://dx.doi.org/10.1016/j.jcv.2015.07.308

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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


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


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


Measles Symptom Timeline

Conjunctivitis

Viral Shedding - Contagious

Incubation 7-21 Days


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


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


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


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


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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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


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


Clinical Manifestations

Khanna S et al. Clin Infect Dis 2013


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”


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


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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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


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


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


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


“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

http://www.ncbi.nlm.nih.gov/pubmed/?term=ENTEROVIRUS+SURVEILLANCE+1983-2005+CDC





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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 meningoencephalitis in young infants. Infect Dis Clin North Am. 2015


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


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


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


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


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

http://dx.doi.org/10.1128/JCM.05996-11



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Flu A

Flu B

Rhino/EV

Mostly EV D68


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


30th Edition

18 diseases, 8 pages


Pages of the Red Book

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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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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


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


Current Liaisons to COID


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


Disease Extent and Severity

PICU Care, CMH-KC 2014

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R/E detections PICU

Alert by IW

Batch 1:CDC

EV 68 Case Definition


Mid-August, 2014

Children’s Mercy-Kansas City

• Clinical signal

• Microbiologic signal

– Asked for confirmation from CDC

• Hospital burden particularly in PICU

9/24/2015 - Children's Mercy Kansas City · PDF filepamphlet form The Red Book Through ......

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