I have nothing to disclose Em erging Issues in Ped ia tric - - PDF document

2/4/2014 1 CA R O L G L A S ER , D V M , M P V M , M D

DEPARTMENT OF PEDIATRICS DIVISION OF PEDIATRIC INFECTIOUS DISEASES UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

Em erging Issues in Ped ia tric Infections

w ith em p ha sis on

Vaccine-Preventable Illnesses

I have nothing to disclose

Em erging Issues in Ped ia tric Infections rela ted to

Va ccine-p rev enta b le d isea ses (VPD)

 Why I choose this topic



Resurgence of VPD due to failure to immunize and what it means to United States

 Measles (mainly a problem in Europe but spill over has led to problems / issue here)  Impact on others  The Pertussis Problem  Is this due to failure to immunize?  Mumps  Why are we still seeing cases?  Other vaccine-preventable illness and/ or illnesses that look like VPD

http://www.npr.org/blogs/health/2014/01/25/265750719/h

• w-vaccine-fears-fueled-the-resurgence-of-preventable-diseases

About vaccines

 Childhood rates have plummeted in Europe

following 1998 study that falsely claimed MMR was linked to autism

 Although results of 1998 study have been shown to

be false, fears about vaccine safety have remained

 What is the current impact?

2/4/2014 2

Case 1

Case

3 year old female with fever and runny nose followed by a rash 3 days later On exam child is irritable and coughs frequently. Eyes are red and erythematous MP rash whole body, most pronounced

• n trunk. No palmar erythema, no puffy hands/ feet

Labs

 CRP =2, ESR=36  CBC unremarkable  AST slight increase, ALT normal  U/ A with pyuria

Case

 Past Medical history:

• incomplete immunizations (no MMR)
• 6 older siblings, “incomplete” vaccinations
• no prior medical problems

 No animal contact  Just returned home from Philippines

Case Diagnosis

 Blood and Respiratory samples taken

 Positive Measles IgM  Positive Measles PCR  Diagnosis : Measles

 Rash illness, historically childhood infection with 2-

4 year epidemic cycle; most cases in winter / spring

 Complications may include otitis media,

pneumonia, encephalitis, miscarriage, and death

 Airborne spread - probably the most infectious

communicable disease; R0 =15-17

 Two doses of MMR vaccine offer >99% protection

from disease; however, requires very high population immunity to interrupt transmission (92- 95%)

Background

2/4/2014 3

Epidemiology

 Highly contagious viral illness – 90% of susceptible

persons who are exposed to measles will become ill

 Measles is transmitted via the airborne route  Measles patients are infectious 4 days prior to rash

• nset and 4 days after rash onset

 No endemic transmission in the U.S. at this time –

declared eliminated in 2000

 R0 = 12-18

Epidemiology

 Currently, most U.S. measles cases are related to

international travel or contact with ill travelers

 Measles is still endemic in Europe with large

• utbreaks in 2010-2011; >15,000 cases in France

in 2011 {Romania, Ireland, the UK, France, Italy, and Spain]

 Ongoing transmission in India, the Philippines and

Ethiopia, among other countries

 139,300 deaths from measles were reported in

2010 globally

Measles cases in the U.S., 2013 Imported cases of Measles in U.S., 2001-2013 Unvaccinated U.S. resident-Measles

2/4/2014 4

Clinical Features

 Prodrome – onset 8 to 12 days after exposure

(range=7-21 days)

 Stepwise increase in fever to 101º F or higher  Cough, coryza, conjunctivitis  Koplik spots (rash on mucous membranes)

Measles Clinical Features

 Rash

 2-4 days after prodrome, 14 days after exposure  Maculopapular, becomes confluent  Begins on face and head  Persists 5-6 days  Fades in order of appearance

Measles complications

Condition Percent reported Diarrhea 8 Otitis Media 7 Pneumonia 6 Encephalitis 0.1 Hospitalization 18 Death 0.2

Based on 1986-1992 Surveillance data

Choosing Not to Vaccinate

I S I T R E A L L Y A P E R S O N A L D E C I S I O N ? W H A T I S T H E I M P A C T O N O T H E R S ?

Case 2

2/4/2014 5

Case 2

 Previously healthy, Hispanic male  6 weeks of life

 Developed upper respiratory tract symptoms  Seen in clinic for ‘stuffy nose” and told to use nasal saline

drops

 During next 8 days had 2 additional visits to PMD and then in

ER

 2nd ER visit Admitted to floor and within a few hours

transferred to PICU with pulmonary HTN

 Died the following day: Pulmonary HTN and CBC WBC

>130,000

Case 2

 Ultimately diagnosed with Bordetella pertussis

(w hooping cough)

 Several family illness with cold illness in last few

weeks

Pertussis (whooping cough)

 Caused by Bordetella pertussis, a gram negative, fastidious,

pleomorphic bacillus

 Primarily a toxin-mediated disease; bacteria attach to cilia of

respiratory epithelial cells

 Most severe disease and death occurs in infants <4 months of

age

 Highly infectious during catarrhal phase and first two weeks

• f cough

 R0 estimated to be 15-17 (similar to measles)  Has been described in writings as early as

14th c. and first isolated by Bordet and Gengou in 1906

Background

 Humans are the only host  Close contacts: aerosolized droplets  Incubation period ~ 7-10 days [5-21]  Occurs year-round but some seasonal peaks in late

summer-fall

 Neither infection or Immunization confers life-long

immunity

Epidemiology

 Prior to vaccine, >200,000 cases/ year, used to be

most common childhood illness

 Still major problem in developing countries, (among

the 10 leading causes of childhood mortality)

 Outbreaks in the US have “ballooned” in regions

across the US “breaking records”

 CA experience pertussis epidemic in 2010; incidence

declined in 2011-2012 but is now increasing again in 2013, not clear what 2014 will bring…

 Nearly all other states experienced peaks in disease

incidence in 2011-2012

U.S. Pertussis Cases: 1922-2011*

DTP Tdap DTaP

SOURCE: CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis Surveillance System and 1922-1949, passive reports to the

Public Health Service *2011 data have not been finalized and are subject to change. 2011 data were accessed on July 5, 2012.

2/4/2014 6

Only vaccine-preventable disease in the US increasing…

Europe also experiencing increase

Clinical

(outside neonatal period)  3 stages: catarrhal, paroxysmal, and convalescence  Classical presentation



coryza; no pharyngitis

 paroxysmal cough, posttussive vomiting & “whoop”  no systemic illness, no fever, no pharyngitis

 Cough often quite prolonged and severe  Adults with pertussis often report sweating episodes

and feeling as if they’re choking on something

Stages of Disease in Weeks

-3 0 2 12 8

Symptom Onset Incubation Period Catarrhal Stage Paroxysmal Stage

Convalescent

Stage Communicable Period

2/4/2014 7

Child with broken blood vessels in eyes, bruising on face (20 cough) Pertussis in Young Infants

(< 6 month)

 Infant initially looks deceptively well; coryza, no or

minimal fever, mild or no apparent cough

 Later:

 Gagging, gasping  Bradycardia or Apneic episodes  Cyanosis (parents may report red or purple face)  Post-tussive emesis  Infants can develop very high lymphocytosis  Adenovirus or RSV co-infection can occur

Mechanism for pathogenesis pulmonary hypertension in infants

Paddock C, Clin Infect Dis, 2008

Other complications in infants

 Pneumonia  Seizures  Respiratory distress  Pneumonia  Encephalopathy  Death

Pertussis Diagnostics

 Culture: considered gold standard and very specific but

insensitive, not timely

 PCR: increased sensitivity > culture, more rapid  (Ct cut off values are important; contamination of NP swabs

with pertussis vaccine DNA can lead to false positives* )

 Serology: useful for adolescents & adults in the later stages of

the disease. Is not considered valid laboratory confirmation for surveillance purposes

*See: http:/ / www.cdc.gov/ pertussis/ clinical/ diagnostic-testing/ diagnosis-pcr-bestpractices.html

Exchange transfusion as management for infants with pertussis

 Background reports

 6 reports; 13 infants ET  11/ 13 survived  5 were in cardiogenic shock but not organ failure before ET  2 fatalities  Both were in renal failure BEFORE ET initiated

2/4/2014 8

Exchange transfusion as management for infants with pertussis

 Study from Argentina

 41 infants with pertussis; 9 infants with ET  4 before 2011, considered ‘rescue Rx”; all died  5 done “preemptively” (WBC>95k), 4 of theses survived

• Taffarel P, Arch Argent Ped, 2012
• Exchange transfusion as “treatment” for

infants with pertussis

The Pediatric Infectious Disease Journal

• Volume 32, Number 6, June 2013

Exchange transfusion for management of pertussis

Source of Pertussis in Infants

 Adults transmit pertussis to infants

 Among 264 known source-cases:  Almost 50% were parents, most often mothers  51% were adults >19 years of age

Bisgard KM, et al. I nfant pertussis:

who was the source? Pediatr I nfect Dis J 2004; 23(11):985-989.

Wendelboe AM, et al. Transmission

• f Bordetella pertussis to young
• infants. Pediatr I nfect Dis J 2007;

26(4):293-299.

deGreeff SC et al. Pertussis disease

burden in the household: how to protect young infants. Clinical I nfectious Diseases 2010; 50(10):1339–1345.

Why has there been a U.S. pertussis resurgence since the 1990s?

Vaccine “refusals” and Pertussis Is this the reason for resurgence?

2/4/2014 9

Tdap in Pregnancy

 ACIP and ACOG recommend that all pregnant

women receive Tdap vaccine during each pregnancy, preferably in the third trimester, regardless of their Tdap vaccination history

 Antibodies to pertussis (PT, FHA, PRN, FIM) are actively

transported across the placenta to the baby1,2  CDC feels this is the most important strategy to

prevent infection in infants who are too young to be vaccinated

1. de Voer RM, et al. Seroprevalence and placental transportation of maternal antibodies specific for Neisseria

meningitidis serogroup C, Haemophilus influenzae type B, diphtheria, tetanus, and pertussis. Clin Infect Dis. 2009 Jul 1;49(1):58-64.

2. Gall SA, et al. Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and

neonatal serum antibody levels. Am J Obstet Gynecol 2011;204

Tdap in Pregnancy – Safe and Effective

 Data from Australia indicate that infants born to women

who received Tdap either during or after pregnancy had reduced risk of disease (OR 0.60)1

 Data from UK’s recently implemented Tdap program for

pregnant women2

 VE ~90% in preventing disease in infants up to 2 months of age  Vaccine coverage among pregnant women now ~60%  No increase in pregnancy adverse events

1.

McI ntyre. The cocoon strategy to prevent early pertussis – Australian experience. June 2013 ACI P meeting.

2.

• Salisbury. Pertussis vaccination programme for pregnant women in the UK. June 2013 ACI P meeting.

Pertussis Vaccines

 In US, whole cell vaccine (DTP) no longer available  Less reactogenic acellular vaccines widely used since (subunit,

purified inactivated components)

 DTaP (pediatric formulation)  6 weeks-7 years  (2,4,6 months, 15-18 months, 4-6 years)  Tdap (adolescent & adult formulation)  >10 years (Boostrix)  >11 years (Adacel)

 New research indicates that immunity from acellular vaccines is high

immediately following receipt but wanes quickly within a few years; may also wane faster in children who only ever received acellular vaccines

 Disease incidence continues to increase in children and adolescents

who are fully-vaccinated

Why has there been a U.S. pertussis resurgence since the 1990s?

 Acellular vaccines, which were recommended in the U.S. in

1992 for the 4th/ 5th doses and for all five doses in 1997 are less reactogenic, but less effective than whole cell vaccines

 General availability of more

sensitive laboratory tests (PCR)

 More rapid waning of vaccine-

induced immunity from acellular vaccines

 Genetic changes in B.

pertussis?

“The Pertussis Problem”

 Immunity wanes rapidly after aP* vaccine booster at

4-6 years and pre-adolescent dose

 Vaccine effectiveness high only for ~2 years

following vaccine

 wP* vaccine induces Th1 and Th2 response (and

possibly Th17) vs. aP Th2 response

 Retrospective data

 1 dose wP in infancy confers better protection vs. later

exposure vs. aP (Klein N, NEJM, 2012)

*aP=acellular pertussis, w P=w hole cell pertussis vaccine

• PLOTKIN SA, CLIN INF DIS 2013

2/4/2014 10

“The Pertussis Problem”

Is it just because of unvaccinated?

 Local collections of unvaccinated children

But also;

 Strain changes (different ways: change in circulating organisms in alleles for each

antigen, replacement of older promoters of PT allele, pertactin-deficient strains}

 Decrease efficacy aP* relative to wP*  Predilection of vaccine to induce Th2 response

(rather than Th1)

 ?aP doesn’t protect against pertussis infection in a

baboon model



*aP=acellular pertussis, w P=w hole cell pertussis vaccine

• PLOTKIN S, Clin Inf Dis 2013

Baboon study and Pertussis vaccine

 Developed non-human primate model (baboons)  Disease very similar to severe clinical pertussis in

humans

 2 week ‘heavy respiratory colonization’  WBC; 30-80k  Paroxysmal cough illness (average > 2 weeks but <

children)

 Characterization of airborne transmission of B. pertussis from

infected  naïve animals  Test Hypothesis; aP fails to prevent B. pertussis

colonization (thus enabling transmission)

• Warfel JM, PNAS, 2013

What did baboon study tell us about Pertussis vaccine?

 Conclusion from baboon study

 Vaccine protects against severe disease  However, does not protect against carriage/ infection

 Implications for humans

 Need additional study but this suggests  “Plausible” explanation for resurgence  No ‘herd immunity’ and therefore vaccinated individuals could

be infected (not know it) and transmit it…

 (Potential) Implications for  Cocooning  Health care w orked  Still too soon to know

• Warfel JM, PNAS, 2013

Treatment & Prophylaxis

 Treatment effective for limiting infectivity, but

useful for ameliorating symptoms only if started very early in course of disease (catarrhal stage)

 Prophylaxis

 Identifying contacts difficult  Long infectious period  Large Ro  One strategy is to target prophylaxis to those at highest risk

• f severe disease (infants <1 year of age) or those in contact

with infants

Case 3

2/4/2014 11

Case 3

 14 month old male presents with ~ 1 week + of fever,

headache, fatigue and loss of appetite

 And ~ 2 days of progressive swelling and tender

salivary glands

Case 3

 Past medical history

 Previously healthy  UTD on all vaccine including MMR  Serology was drawn and respiratory sample  Mumps IgM “positive”  Respiratory sample : PCR positive for Para-influenza virus type 3  So…

Is this mumps or not?

Mumps

 Caused by mumps virus, a paramyxovirus  Symptoms typically appear 16-18 days after infection

(12-25 days)

 Typical course

 Fever, headache, muscle aches, fatigue, and decrease appetite  A few days later, salivary gland enlargement (unilateral of

bilateral) (aka chipmunk cheeks)

Mumps

RNA virus in the Paramyxoviridae family

• same family as measles, RSV, parainfluenza,

Hendravirus Modes of transm ission

 transmitted by contact with respiratory secretions

• r

 droplets from the respiratory tracts of infected

persons

 e.g., sneezing, coughing, kissing, talking,

breathing…

Mumps epidemiology Mumps

Exposure

 face-to-face (<3 feet) contact with an infectious

person for at least 5 minutes Incubation period

 Usually 16 to 18 days, but cases may occur 12 to 25

days after exposure Period of com m unicability

 Highly infectious R0 10-12  90-92% needed for herd immunity  Communicability is highest from 2 days before to 5

days after onset of parotitis; mumps virus has been isolated in saliva from 7 days before through 9 days after onset of swelling

2/4/2014 12

Mumps; differential

 Only cause of epidemic parotitis  Sporadic parotitis –

 Cytomegalovirus  Parainfluenzae virus types 1 and 3  Influenza A virus  Coxsackieviruses and other enteroviruses,  lymphocytic choriomeningitis virus  human immunodeficiency virus  Staphylococcus aureus, and  nontuberculous Mycobacterium

Journal Infect Dis, 20 13 Journal Infect Dis, 20 13 What they found; 10 1 specim ens (all) [<18 years] What they found; 10 1 specim ens (all) [<18 years]  EBV (23)[8]  HHV-6B (10)[8]  HPIV-2 (3)[3]  HPIV-3 (1)[0]  Human bocavirus (1)[1]  No mumps or EV

Parotitis in the United States Mumps: Clinical

 Up to 20% of infections asymptomatic  40-50% of infections may: nonspecific or respiratory

symptoms only

 Prodromal symptoms are nonspecific

 Prodromal symptoms nonspecific: myalgia, anorexia, malaise,

headache and low-grade fever

 most common manifestation is unilateral or bilateral swelling of one

• r more of the salivary glands, usually the parotid glands (parotitis),

which occurs in 30%-40% of infected persons

 Parotitis tends to occur within the first 2 days and may be first noted

as earache and tenderness on palpation of the angle of the jaw

 Symptoms decrease after 1 week and usually resolve after 10 days

Complications

 Central nervous system (CNS) involvement is

common(15%)

 Meningitis  Encephalitis

 Other rare complications include arthritis, mastitis,

glomerulonephritis, myocarditis, endocardial fibroelastosis, thrombocytopenia, cerebellar ataxis, transverse myelitis, ascending polyradiculititis, and hearing impairment.

 Pancreatitis (2-5%)  Orchitis (testicular swelling) is a common complication and

may occur in as many as 30-50% of postpubertal males

 Females can develop inflammation of ovary-tender

abdomen

Diagnosis

 Mumps infection can be laboratory confirmed by:  positive serologic test for serum mumps IgM

antibody; OR

 four-fold rise between acute and convalescent

titers in mumps IgG antibody; OR

 isolation of mumps virus; OR  detection of viral RNA by reverse transcription

polymerase chain reaction (RT- PCR)

2/4/2014 13

Diagnosis

 Specim en collection  Collection of a serum specimen for serologic detection of mumps

antibody in conjunction with obtaining a buccal swab for molecular determination is helpful in the laboratory confirmation of a mumps case.

 IgM/ IgG testing  Collect 7-10 ml of blood in a red top or serum separator tube (SST).  Serum should be collected as soon as possible after onset of parotitis for

IgM testing or as the acute-phase specimen for determining seroconversion.

 If initial testing is negative and mumps is strongly suspected, a

convalescent serum sample should be collected 2-3 weeks after symptom onset.

Diagnosis

Mumps infection can be laboratory confirmed by:

 Mumps serum IgM positivity; OR  Four-fold rise between acute and convalescent

titers in mumps IgG antibody; OR

 Isolation of mumps virus; OR  Detection of viral RNA by reverse transcription

polymerase chain reaction (RT- PCR) – preferred m ethod (buccal sw ab)

Diagnosis - serology can be problematic…

 In vaccinated persons:

 IgM may be falsely negative in infected persons

May be transient, late occurring, or missing in persons

who have had any doses of mumps-containing vaccine.

 Presence of IgG prior to infection does not

necessarily indicate immunity

 In unvaccinated persons:

 IgM antibody detectable within 5 days of onset, reaches a

maximum level about a week after onset, and remains elevated for several weeks or months.  False positive mumps IgM results can occur from:

 parainfluenza virus 1, 2, and 3, Epstein-Barr virus, adenovirus,

and human herpesvirus 6 infections

Back to the case… ..

 This case had no known contact with other mumps

cases probably wasn’t mumps

 however there have been recent cases and outbreaks

• f mumps

Recent outbreaks

 Midwest outbreak 2006

 6,584 cases in 11 states  Predominantly Midwestern college students, especially those

living in dorms.

 Most (90%) had a history of 2 MMRs  79% had received 2nd MMR >10 years prior

 New York/ New Jersey outbreak 2009-2010

 >2,700 cases  Primarily Hasidic Jewish communities

Mumps in Europe (& beyond)

2/4/2014 14

Case 4

Case 4

9 year old male previously healthy child

 developed upper respiratory infection with

rhinorrhea, fever and pharyngitis

 4th day of illness, presented wit left arm weakness

with progressed over the next 48 hours

 Exam

 L flaccid paralysis L Arm and should  Sensation to touch, temperature, vibration and

proprioception; intact

 Cr N WNL

 Over period of cc developed flaccid paralysis

Case 4

 CBC ~ normal except with increase PNMs 75%  CSF

 81 WBCs  0 RBCs  Protein and Glucose unbreakable

 CBC-normal except for 74% PMNs

Case 4; Spinal MRI Case 4

 The patient was treated with

 methylprednisolone 20mg/ kg x 7 days followed by  IVIG x 4 days  As well as azithromycin and then ciprofloxacin

 Follow-up several months later

 Minimal recovery

Could this be polio?

2/4/2014 15

No… however..

 It is ‘polio-like’  Other recent viruses that have emerged to cause such

as syndrome in recent years

 Enterovirus 71  West Nile

 Testing for these agents have been negative

AFP cases; call for cases

Appendix

Reference for Reproduction Numbers