Pediatric Pathogens and Impact on the Adult Population

Pediatric Pathogens and Impact on the Adult PopulationAPRIL KILGORE, MD, FAAP

ASSISTANT PROFESSOR OF PEDIATRICS

PEDIATRIC INFECTIOUS DISEASE

MARSHALL UNIVERSITY SCHOOL OF MEDICINE

Disclosure

My presentation does not include discussion of any commercial products or services

I will not be discussing investigational products or unlabeled uses

I have no financial interests or relationships with manufacturers or commercial products

Objectives

Participants will understand the changing epidemiology of childhood infectious disease including Respiratory syncytial virus (RSV), Human metapneumovirus (hMPV), and Bordatella pertussis

Participants will recognize the impact of these diseases on the adult population and the implications for clinical care/management

Participants will know the infection control related issues for patients in the hospital/chronic care setting

Respiratory Syncytial Virus

Background

Respiratory syncytial virus (RSV) first discovered in 1956 as respiratory pathogen in chimpanzees

1957 identified as cause of epidemic bronchiolitis in infants

Long believed to be primarily a pediatric pathogen, however increasingly recognized as important pathogen in adults

Evidence indicates second to influenza as cause of serious viral respiratory disease in adults

Virology

RNA virus of the family Paramyxoviridae Viral structure consists of a nucleocapsid

core surrounded by lipid layer 3 glycoproteins embedded in

lipid layer: G, F, SH Human RSV classified two major

groups, A and B Each contain subgroups based

on antigenic differences in G protein

Virion varies in size and shape 120-300nmhttp://phil.cdc.gov/PHIL_Images/09202002/00006/PHIL_2175_lores.jpg

Epidemiology

Yearly epidemics of respiratory illnesses during winter months in temperate climates

Epidemic curve usually broader than influenza with longer periods of activity

Primary infection almost universal by 2 years of age

http://www.cdc.gov/surveillance/nrevss/rsv/natl-trend.html

Epidemiology: Community-Dwelling Adults

Early estimates limited by diagnostic tools Reverse transcriptase polymerase chain

reaction (RT-PCR) has allowed more accurate estimates of disease

Zambon et al examined adults > 45 years visiting GP during winter for respiratory illness RSV identified in 10-22% of subjects Influenza identified in 13-42%


2001 prospective study Rochester, NY of elderly and high risk adults over 4 winter seasons 6

RSV infection confirmed in 3-7% of healthy elderly enrollees & 4-10% of high risk adults (chronic cardiopulmonary conditions) 89% were symptomatic Illness in 17-29% prompted office visits Among high risk patients, 9% visited the ED, 16%

were hospitalized and 4% died

2007 study examined hospitalizations for influenza and RSV among adult population in large HMO14

Indirect measure utilizing discharge diagnosis and ICD-9 codes for “pneumonia and influenza”

Epidemiology: Adults and Hospitalizations

Influenza and RSV associated hospitalization rates per 10,000 person-periods

Risk Group

Age (years) Viral period Pneumonia and Influenza

Low 65+ Any Flu 18.7 (10.2-27.1)

Low 65+ RSV only 5.1 (0.7-9.5)

High 65+ Any Flu 55.6 (41-70.2)

High 65+ RSV only 23.4 (13.9-32.9)Adapted from Mullooly et al. Influenza and RSV associated hospitalizations among adults. Vaccine 2007;25:846-855

Epidemiology: Community Acquired Pneumonia

Estimates of RSV contribution vary widely Falsey et al. conducted large study of

hospitalized adults with pneumonia Utilized RT-PCR for diagnosis RSV identified in 4.4% of cases 3rd most common identified pathogen after S.

penumoniae (6%) , and Influenza (5%) Composite data from the past 30 years indicate

RSV accounts for 2-5% OF CAP throughout the year 5-15% during winter months

Epidemiology: Long-Term Care Facilities

First outbreaks in nursing homes in 1970s Surveillance studies estimate5

Infection rates 1-18% Pneumonia rates 0-33% Death 0-5% of those infected

Clustering of cases suggests nosocomial spread by healthcare workers

Other closed populations at risk- senior day care centers 7

10% of acute respiratory tract infections in participants 5% of day care staff

Clinical Manifestations: Adults

No clinically distinct illness in adults Characterized by nasal congestion and cough Ranges from mild URI to severe respiratory

diseaseRelative Frequencies of Symptoms with RSV and Influenza

Symptom RSV Influenza

Rhinorrhea ++++ ++

Wheezing ++++ ++

Dyspnea +++ ++

Sputum production +++ ++

Fever + ++++

Myalgias + ++++

GI symptoms 0 ++

Adapted from Falsey, Ann. Respiratory Syncytial Virus infection in Adults. Seminars in Respiratory and Critical Care Medicine; 28(2)2007:171-181

Diagnosis

Diagnosis on clinical grounds difficult in adults Four methods diagnosis

Viral culture Sensitivity 20-45%

Enzyme immune assay (rapid tests) Sensitivity 50-90%

Varies on prevalence of RSV in community

RT-PCR Most sensitive and specific method available

Detects 30% more infections than viral isolation techniques

Serology Limited by pre-existing antibodies and need for acute and

convalescent

Treatment

Symptomatic supportive care Fluids, oxygen, and antipyretics mainstay

of care No FDA approved anti-viral medications

for adults Published reports of ribiviran use in

elderly patients with severe disease

Infection Control

From Tang J, Nicolle A, Pantelic J, Jiang M, Sekhr C, Cheong D, Tham K (2011). "Qualitative Real-Time Schlieren and Shadowgraph Imaging of Human Exhaled Airflows: An Aid to Aerosol Infection Control

Infection Control

Viral shedding in infants up to 21 days Shedding in young adults averages 3-6

days with range 1-12 days Shedding in older adults not well studied

Presumably shorter in healthy adults Longer in patients with COPD

Spread via contact with contaminated secretions via large droplets or fomites Can survive on surfaces for many hours

Infection Control Infection control practices1,20

Hand washing key to prevention Contact isolation with use of gown and gloves

recommended Mask use per standard precautions Patients with known infection single room or cohorted

HAI1,20

During community outbreaks can consider Screening of symptomatic patients Cohorting of infected patients and staff Excluding visitors with current or recent respiratory tract

infections Excluding staff with respiratory tract illness from caring for

susceptible patients Emphasizing contact precautions and hand hygiene Limiting sibling visitation

Infection Control

When can they come out of isolation? Immunocompromised adult and pediatric

patientsOfficial guidelines warn of extended shedding but

give no duration recommendations

What have we done to address this? If prolonged hospitalization and primary team wishes

to discontinue PCR, isolation can be discontinued when patient has been asymptomatic for at least 5 days AND respiratory PCR is negative

Human Metapneumovirus (hMPV)

Background

2001 first described as respiratory pathogen by van den Hoogen and colleagues in the Netherlands

Identified in specimens collected over a 20 year period from patients with respiratory tract disease during the winter months

The then unidentified isolates caused cytopathic effects largely indistinguishable from RSV

Serologic studies show high rate of antibodies in populations worldwide and evidence circulating dating back to 1958

Virology

RNA virus of the Paramyxoviridae family with lipid bilayer envelope of host cell origin

Genetically related to avian pneumovirus (AVP) aka turkey rhinotracheitis virus Causes URI in turkeys and other avian species Suggestive of origination from bird species

Epidemiology

Predominantly in winter months in temperate climates

May exhibit yearly variation

2 Major genotypes that often co-circulate

Almost all children infected by 5 years of age

Older age at primary infection than RSV

http://www.cdc.gov/surveillance/nrevss/hmpv/natl-trend.html


Less well studied than epidemiology of RSV Estimates of symptomatic infection generally <

5%8

2001 study in the Netherlands hMPV infection rate 3% in adults with symptomatic respiratory illnesses16

2003 two year prospective study in Rochester NY9

Cohorts of young and older adults studied 4.5% of illnesses associated with hMPV infection Significant yearly variation with rates of 1.5% and 7%

during years 1 and 2 of the study period respectively High risk adults had more severe disease and more

hospitalizations

Epidemiology: Long Term Care Facilities

Multiple reports in the literature of outbreaks

June-July 2006 outbreak in Sacramento California in 148 bed facility13

26 residents and 13 staff with acute respiratory illness

31% ill residents developed pneumonia and 5 % hospitalized

RT-PCR confirmed hMPV in 5 of 14 specimens and no other cause identified

Epidemiology: Long Term Care Facilities

January-February 2006 outbreak of severe disease in facility in Canada 2

27% of residents developed respiratory or constitutional symptoms

Attack rate on most affected ward 72% Fatality rate 50% among confirmed cases (3/6) and

9.4% among possible cases (9/96) Spring Summer 2011 outbreak in facility in

Oregon11

Attack rate 36% among residents 3 health care workers affected Fatality rate of confirmed and possible cases 31%

Clinical Manifestations

Vary based on age and health status Clinical symptoms indistinct from other

viral respiratory infections Patients requiring hospitalization

typically elderly with chronic cardiac or lung disease

Clinical characteristics of young versus older adults with hMPV

Clinical Feature Elderly (n=13) Young (n=11)

Hoarseness 46% 91%

Dyspnea 69% 9%

Wheezing 62% 9%

Length of stay 17.4 ± 9.4 8.5 ± 3.4

Adapted from Falsey, Ann et al. Human metapneumovirus infections in young and elderly adults. JID 2003;187(1-March):785-790


Evidence of role in COPD exacerbations, pneumonia in immunosuppressed patients, and severe illness with ARDS

Most common diagnoses of patients admitted with hMPV are exacerbation of COPD, bronchitis, and pneumonia8

Diagnosis

Serology Limited by pre-existing antibodies and need for acute

and convalescent testing Viral culture

Difficult to perform and can take up to three weeks to see cytopathic effects

Immunofluorescence Rapid testing available Sensitivity approaches that of RT-PCR

RT-PCR Testing modality with greatest sensitivity and

specificity

Treatment

Symptomatic supportive care Fluids, oxygen, and antipyretics mainstay

of care No FDA approved anti-viral medications Susceptible in vitro to Ribavirin but no

controlled clinical data to assess benefit

Infection Control

Route of transmission not established Likely similar to RSV since closely related and similar

epidemiology Infection probably through direct or close contact with

contaminated secretions Infection control practices1,20

Contact precautions for duration of illness Masks according to standard precautions Patients with known infection single room or cohorted

HAI Problematic as symptoms in staff and patients may be mild Emphasis on hand hygiene and adherence to contact

precautions

Bordatella pertussis

Background

In 1679 Syndenham named the illness pertussis which means violent cough

In 1900 Bordet and Gengou discovered the organism which causes whooping cough and by 1906 they had developed media to support culture and detailed morphology and virulence

Pertussis is caused by a fastidious, strictly aerobic gram negative coccobacillus

“The lung is so irritated that, in its attempt by every effort to cast forth the cause of the trouble, it can neither admit breath nor easily give it forth again. The sick person seems to swell up, and, as if about to strangle, holds his breath clinging in the midst of his jaws. …” DeBaillou describing the first documented whooping cough epidemic in 1578

Epidemiology

Humans are the only known hosts of B. pertussis Transmission occurs by close contact with cases

via aerosolized droplets Cases occur year round with peaks in late

summer/autumn In immune-naïve population, it is estimated a

primary case will result in 17 secondary cases18

In households up to 80% of immunized contacts of symptomatic cases acquire infection 4

Mild or unrecognized atypical disease to classic pertussis

Epidemiology

Prior to routine vaccination large burden of disease and high mortality rates in infants

The first whole-cell vaccine introduced in 1940s Very successful and resulted in tremendous

decrease in disease incidence In pre-vaccine era, natural infection(s) resulted in

boosted immune response Since routine vaccination and reduction in natural

disease, now see waning immunity over time Result is increase in cases in people > 10 years of age Waning maternal immunity and transplacental antibody Increase in pertussis in very young infants

Epidemiology

Currently approximately 50% of cases reported are in adults and adolescents4

Reservoir of infection for infants who are unimmunized or partially immunized

Based on epidemiologic studies, most infants infected by adolescents or adults in the household

Highest rates of mortality among infants and elderly4,17

Case fatality rates approximately 1% in infants < 2 months and <0.5% in infants 2-11 months17

Recent studies have highlighted risk in elderly17

Older patients with longer hospitalizations for pertussis Although pertussis related deaths rare in adults, most in

persons > 50 years of age and majority > 65

Clinical Manifestations: 3 Stages Classic Disease

Catarrhal Nonspecific sings and symptoms following 7-10 day incubation

period Often mistaken for viral URI

Paryoxysmal Typically starts second week of illness Hallmark coughing spells Cough paroxysm low lung volumes vigorous inspiration Post-tussive emesis and syncope reported

Convalescent Slow transition after 2-3 months of paroxysmal stage Persistent cough that is less frequent and less severe


Adults and adolescents with prior infection/immunization highly variable presentation Often mild and atypical Most common symptom is a persistent cough Frequently pertussis not suspected by

clinician and therefore not diagnosed Pertussis estimated to be the cause in 12-32%

of adolescents and adults with prolonged cough (> 3 weeks)4

Laboratory Diagnosis

Culture B. pertussis fastidious and requires special culture media

resulting in false negatives Delay in transport and plating, as well as duration of illness at

time of collection, and prior antibiotics contribute to high rate false negatives

Sensitivity only 30-60% PCR

Able to detect small number of organisms Unaffected by prior antibiotics Used more frequently due to better sensitivity and specificity

Challenges in testing Must obtain specimen from ciliated respiratory epithelium of

posterior nasopharynx Cotton swabs toxic to organism and calcium alginate interfere

with PCR, so dacron swabs preferred

Treatment

If considering testing then should also consider treating

Treatment during catarrhal phase may decrease duration of illness

Treatment at later stages does not affect duration of illness but reduces shedding and spread

Macrolides preferred and usually eradicate B. pertussis in 5 days

Infection Control Considerations

Untreated may remain contagious for > 1 month Post exposure prophylaxis 1

Household and close contacts If unimmunized or under immunized: age appropriate vaccine

and chemoprophylaxis If immunized but in household with high risk individual :

chemoprophylaxis Monitor closely for symptoms 21 days after last contact and

evaluate and treat when appropriate Child care

Prophylaxis for household and close contacts Providers and exposed children observed for 21 days after last

contact Children and providers with confirmed pertussis excluded until

completed 5 days of antimicrobial therapy or 21 days if untreated


Post exposure prophylaxis1

SchoolsStudents and staff with pertussis excluded until

completed 5 days antimicrobial therapy or 21 days from onset of symptoms if untreated

Immunization status reviewed and age appropriate vaccines given

Consider excluding persons with cough illness pending eval by physician

Infection Control Considerations Post exposure prophylaxis1

Health Care SettingsTdap may not preclude need for antimicrobial prophylaxisAntimicrobial prophylaxis recommended for ALL health care

workers (HCW) regardless of immunization status who have unprotected exposure to pertussis AND are likely to have contact with high risk patient

Other HCW should receive antimicrobial prophylaxis or be monitored for 21 days and treated at first sign symptoms

Patients and caregivers who are close contacts or high risk contacts of patient or HCW with pertussis should receive antimicrobial prophylaxis and if appropriate, vaccination

HCW with suspected pertussis or cough illness within 21 days of exposure should be excluded pending 5 days of antimicrobial therapy or 21 days if refuse treatment


Isolation1,20

Droplet precautions for until patient has completed 5 days of effective therapy

If appropriate therapy not given then droplet precautions until 3 weeks after onset of cough

Measles

Background

Recorded epidemics of measles date back to the 10th century

Repeated epidemics have occurred throughout the ages in Europe, Asian, and ultimately America

The first live attenuated measles vaccine licensed for use in 1963

2001 Measles declared eradicated from the US with the only cases imported

Virology

Large RNA virus of the family Paramyxoviridae

Virion composed of outer lipoprotein envelope and internal nucleocapsid

Labile and inactivated rapidly by heat, UV light, and lipid solvents

•Photo Credit: Cynthia S. Goldsmith•Content Providers(s): CDC/ Courtesy of Cynthia S. Goldsmith; William Bellini, Ph.D.

Epidemiology

Although declared eradicated in 2001, importation of cases continues15

From 2001-2012 median number of cases annually in US was 60

This year to date 159 cases have been reported in 16 states

82% cases unimmunized and 9% unknown immunization status Of those unimmunized, 79% had

philosophical objections and 13% were infants too young to be immunized

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6236a2.htm#fig2

Epidemiology

2013 outbreaks15

11% required hospitalization

4 patients diagnosed with pneumonia

No deaths reported Source of outbreaks

continues to be WHO European Region

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6236a2.htm#fig2


Prodrome Onset characterized by fever, cough, coryza,

conjunctivitis Koplik spots, bluish white spots on bright red

mucosal surface, usually appear on approximately day 10 and are pathognomonic

Exanthem stage Characteristic rash appears on day 14 after

exposure Rash starts on hairline and spreads from head to

feet in centrifugal manner Exanthem begins to clear on day 3-4 of rash and

typically lasts 6-7 days

Clinical Manifestations: Complications Pneumonia10

Very common and reported in 50-75% Young infants have clinical picture of bronchiolitis Clinical course can progress to severe pulmonary disease and ARDS

Encephalitis10

0.5 to 1 per 1000 cases 20-40% of patients with encephalitis have evidence of brain damage

Subacute Sclerosing Panencephalitis (SSPE)10

Rare, incidence in pre-vaccine era after infection with wild type measles 1 case per 100,000 population

Stage 1 progressive psychointellectual disturbances Stage 2 convulsive and motor disorders Stage 3 pre-terminal stage with rapid decrease in cortical activity ultimately

progression to vegetative state Progression over months to years

Laboratory Diagnosis

Viral culture PCR

Can be performed on throat swab specimens

Serology Acute and convalescent titers Single positive IgM suggests diagnosis

Treatment

Supportive care for typical measles Vitamin A supplements recommended in

certain situations 1,10

Reduced morbidity in Vitamin A deficient children

Enhanced IgG and total lymphocyte numbers Children 6 months to 2 years who require

hospitalization Children > 6 months with suspected vitamin A

deficiency


Transmitted by direct contact with infectious droplets or airborne spread

Airborne transmission precautions indicated for 4 days after onset of rash in healthy children and duration of illness in immunosuppressed 1,20

Negative airflow room with 6-12 changes per hour

Susceptible HCW should not enter patient rooms If susceptible persons must enter then N-95

mask should be worn People with documented immunity do not need

to wear a mask


Vaccination recommended for all people who work or volunteer at health care facilities and who may be in contact with patients with measles1

Adequate evidence of immunity 1

Documentation of 2 doses live-virus measles vaccine

Laboratory evidence of immunity or confirmation of disease

Birth before 1957

References

1. American Academy of Pediatrics. RedBook: The report of the committee on infectious diseases 2012

2. Boivin, G. et al. An outbreak of severe respiratory tract infection due to human metapneumovirus in a long-term care facility. CID 2007;44(1-May): 1152-1158

3. Caram et al. Respiratory Syncytial Virus outbreak in a long-term care facility detected using reverse transcriptase polymerase chain reaction: an argument for real-time detection methods. J Am Geriatric Soc 2009;57:482-485

4. Cornia, P et al. Does this coughing adolescent or adult patient have pertussis? JAMA 2010;304(8):890-896

5. Falsey, Ann. Respiratory Syncytial Virus infection in Adults. Seminars in Respiratory and Critical Care Medicine; 28(2)2007:171-181

6. Falsey AR. Et al. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;28:1749-1759

7. Falsey AR et al. Acute respiratory tract infection in daycare centers for older persons. J Am Geriatr Soc 1995;45:30-36

References

8. Falsey, Ann. Human metapneumovirus infection in adults. The Pediatric Infectious Disease Journal 2008;27(10):s80-s83

9. Falsey, Ann et al. Human metapneumovirus infections in young and elderly adults. JID 2003;187(1-March):785-790

10. Feigan and Cherry’s Textbook of Pediatric Infectious Diseases 6th edition. Saunders Elsevier Philadelphia PA 2009

11. Liao, R. et al. An outbreak of severe respiratory tract infection due to human metapneumovirus in a long-term care facility for the elderly in Oregon. Journal of Clinical Virology 2012;53:171-173

12. Liss, HP, Bernstein, J. Ribavirin aerosol in the elderly. Chest 1998;93:1239-1241

13. Louie, J. et al. A summer outbreak of human metapneumovirus infection in a long-term-care facility. JID 2007;196(1-September):705-708

14. Mullooly et al. Influenza and RSV associated hospitalizations among adults. Vaccine 2007;25:846-855

15. MMWR. Centers for Disease Control and Prevention. September 13, 2013 / 62(36);741-743

References

16. Osterhaus A, Fouchier R. Human metapneumovirus in the community. Lancet 2003;111:1407-1410

17. Ridda, I. et al. The importance of pertussis in older adults: A growing case for reviewing vaccination strategy in the elderly. Vaccine 2012; 30: 6745-6752

18. Schellekens, J. Et al. Pertussis sources of infection and routes of transmission in the vaccination era. Pediatr Infect Dis J 2005;24: S19-S24

19. Senzilet, L et al. Pertussis is a frequent cause of prolonged cough illness in adults and adolescents. CID 2001;32(15 June): 1691-1697

20. Siegel, J et al. 2007 guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings. The Healthcare Infection Control Practices Advisory Committee

21. Zambon et al. Contribution of influenza and respiratory syncytial virus to community cases of influenza-like illness: an observational study. Lancet 2001;358:1410-1416

Pediatric Pathogens and Impact on the Adult Population

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