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1

Why is diarrhea so common?

Gut reabsorbs about 98% of the more than 6 L of liquid that enters it every day

If its efficiency is reduced to 96^, this doubles the amount of excreted fluid, so it does not take much to throw things out of balance—> loose stools and diarrhea

2

Clinical pearls: differential diagnosis

Enteric pathogens classically divide into three categories based on how they affect host GI physiology:

minimally invasive or enterotoxin-secreting: watery diarrhea
- enteric viruses: ETEC, EPEC, EAEC, V cholera, G lamblia, Cryyptosporidium, S aureus, and B cereus

Inflammatory diarrhea (often bloody): Inflammatory or cytotoxic destruction of mucosa of small bowel or colon leading to diarrhea with leukocytes and blood in stool
- salmonella, shigella, campylobacter, EIEC, EHEC, C. difficile , E histolytica

Systemic symptoms Penetrate through intact mucosa and access reticuloendothelial system leading to systemic illness (enteric fever syndrome)
- salmonella typhi And yersinia enterocolitica

Viruses that cause gastroenteritis result in watery diarrhea- they are not invasive

3

Differential diagnosis: acute diarrhea

90% of acute cases have infectious etiology

Viral infx by far the most common in developed countries, usually self-limited, short duration

Bacterial pathogens more commonly cause severe diarrhea more likely to cause bloody diarrhea

Epidemiological clues
- time of year - some pathogens have marked seasonality
- age of pt - children especially young children, are particularly susceptible to GI viruses, some GI viruses rare cause disease in adults
- travel history - ETEC is good example of diarrhea associated with travel; so too are pathogens that are transmitted via contaminated water ( E histolyticaa , GIardia)
- careful exposure history
- vaccination history - think rotavirus
- Hx of Abx use - think C. difficile
- nosocomial - if diarrhea occurs within a hospital setting, C diff becomes important suspect
Features of clinical presentation can be helpful in narrowing the list of possibilities

4

Viral Gastroenteritis

Caused by variety of viruses; very similar disease

Sudden onset (1 - 2d after infection)

Short duration, usually <1 week

Watery stools (no mucous or blood)

Fecal leukocytes absent or minimal

Stomach flu

Self limited in healthy well nourished persons with normal immune systems

Asymptomatic infx or mild disease very common

Serious disease can occur in those unable to rehydrate

Chronic diarrhea, increased mortality, and prolonged fecal shedding often seen in immunocompromised hosts

Viruses are the cause of most cases of acute infectious gastroenteritis; this is particularly true in developed countries but less so in developing world where bacteria nad parasites play a more prominent role

Worry about dehydration!

5

Viruses to be covered

Rotavirus - ds RNA
- major cause childhood mortality; incidence decreasing due to vaccine

Adenovirus
- most serotypes cause respiratory infx; 2 cause GI infx
- linear ds DNA

Calciviruses
- norovirus - ssRNA
- major cause of outbreaks in nursing homes, cruise ships etc
- sapovirus - ssRNA
- prob under appreciated

Astrovirus- affect GI tract, no respiratory symmtpoms

All are non-enveloped viruses, stable outside the body and transported via the fecal-oral route

6

Relative Distribution of Viral pathogens as causes of acute gastroenteritis in children

Pre rotavirus vaccine era

Rotavirus> adenovirus> norovirus> sapovirus

7

Key epidemiological features, what is the age of incidence and seasonal occurrence of

Rotavirus
Adenovirus
Norovirus
Sapovirus
Astrovirus

Rotavirus
- 6 mo to 2 yr children
- winter (temp)
- year round (trop)

Adenovirus
- infants, young children
- year round; Epidemics

Norovirus
- children and adults
- winter peak; year round occurrence

Sapovirus
- children (primarily infants and toddlers) and adults
- year round

Astrovirus
- mainly young children- year round

Children bear the brunt of viral GI disease (exception: Norovirus)

**NOROVIRUS IS THE MAJOR CAUSE OF VIRAL GASTROENTERITIS IN ADULTS**

8

Duration:Clinical/ Virological Features

Rotavirus
Adenovirus
Norovirus
Sapovirus
Astrovirus

Rotavirus
- incubation: 1 - 2d
- vomiting: 2 - 3 d
- diarrhea: 5 - 8 d
- virus shedding: 8 - 10 d

Adenovirus
- incubation is longest 8 - 10 d
- vomiting: 2 - 3d
- diarrhea 4-12 d
- virus shedding: 8 to 13 d

Norovirus and sapovirus
Incubation 1 - 2 d
- vomiting, super short: .5-1 d
- diarrhea 1 - 2 d or 4 - 6 d in the children and elderly
- virus shedding: 1 - 3 wk

Sapovirus
Astrovirus
- incubation 1 - 2 d
- vomiting 1 - 4 d
- diarrhea 1 - 4 d
- virus shedding - 8 to 19 d

9

Viral Gastroenteritis Transmission

Fecal oral route from person to person

Contaminated fomites (eg shared eating utensils, surfaces, toys in playrooms, door knobs, elevator buttons, bed rails, toilet seats)
- possible bc it is a non-enveloped virus so it is stable on all kinds of surfaces

Contaminated for or water
- food typically in touch with water
- shellfish

Possibly respiratory secretions

Healthcare associated spread common; particularly for rotavirus and norovirus

10

Transmission of GI viruses is efficient

Physical hardiness of GI viruses
- stable over wide pH and temperature ranges and even after drying, heating, or freezing
- stable on human hands and objects for extended times

High virus concentration in stools

Highly contagious; small infectious dose

Resistant to inactivation by various standard cleaning soles

Not easily inactivated by antiseptic agents that contain high concentrations >40% of alcohols (eg Purell and Lysol) and by bleach

11

Pathogenesis of viral gastroenteritis

Viral replication occurs in mature enterocytes at the tips of villi of the small intestine

Infection leads to shortening of the villi, exfoliation, elongation of the crypts, and an increase in mononuclear cells in the lamina propria

Pathological changes are usually patchy

Diarrhea is multifactorial, representing a number of viral and host effects. There are malabsorption and secretory components to the diarrhea, as well as effects related to villus ischemia and intestinal motility. NSP4 of rotavirus may even act as an enterotoxin to induce a secretory state

12

Rotavirus

Leading cause of severe dehydrating diarrhea necessitating hospitalization in infants and young children worldwide

Respiratory enteric orphan

Naked (nonenveloped)

Triple layered icosahedral capsid

Double stranded segmented RNA genome

Resembles wheels slide 14

13

Rotavirus Serologic Classification

Human disease is mostly A

Groups B - G primarily infect animals; group B and C cause infections in swine but have occasionally been associated with food borne or water borne outbreaks of human disease in China (B) and Japan (C)

Genetic diversity- reassortment between animal and human strains and Ag drift necessitates surveillance and possible future changes in rotavirus vaccine

14

Rotavirus: morbidity in Us before 2006

3 million cases/yr in Us; 125 mill in developing countries

Nearly every US child infected before 5 y

Responsible for 4 - 5% of all pediatric hospitalizations

Accounted for 50% of AGE hospitalizations during winter months

15

Rotavirus: Global Epidemiology

Risk of dying from Rotavirus by Age 5y increases as SES decreases

By age 5 nearly every child will have an episode of rotavirus gastroenteritis

16

Rotavirus Episodes by Age

Severe rotavirus infx occur in infants and children between 4 and 24 months of age

17

Annual spread of rotavirus

SEasonality in temperate climates; cool, dry weather appears to promote spread

Activity usually starts in the fall in the southwest US and moves sequentially to the northeast US by spring

In temperate climates like the US, rotavirus activity is most prevalent during cooler months of fall winter and spring

18

Rotavirus Epidemiology

Person may excrete 1 trillion infectious particles/ml of stool

Infants <3. Months old protected by passive maternal antibody

Readily spread in daycare centers, neonatal units, families (~20% of adult household contacts of infected infants will develop symptomatic infx) **

Older children and adults can be infected throughout life, most are subclinical

Chronic diarrhea, increased mortality and prolonged fecal shedding of virus seen in immunocompromised and repeated infx throughout live are subclincial

19

Rotavirus clinical syndromes

Fever, explosive water diarrhea and vomiting (up to 40 times/day )
- virus replicates quickly—> shortening and blunting of villi and a mononuclear infiltrate into the lamina propria (if polys suspect bacterial infection but mononuclear cell infiltrates are more characteristic of viral)

Rapidly dehydrating
- isotonic dehydration—> balanced depletion of water and sodium causing extracellular fluid loss

Don’t really see fecal leukocytes and blood in stool this is more bacterial

Systemic infection with viremia and spread to extraintestinal tissues sometimes happens, particularly in immunocompromised children
- lymphatic mode of spread
- enteric rotavirus clinical symptoms
- unclear whether vaccine protects against this

20

Rotavirus Vaccine

Rhesus rotavirus tetravalent vaccine (Rotachield) but withdrawn due to inussusception

Bovine rotavirus pentavalent live vaccine (RotaTeq, Merck) licensed for use among US infants
- live, oral (ready to use)
- 3 doses (2, 4, 6 mo(
- FDA licensed
- G1-4 serotypes

Rotarix
- live, oral, preparation needed
- 2 doses: 2 and 4 months
- FDA licensed
- G1, 3, 4, 9

Safe and effective in children

Must induce mucosal immune response (IgA in lumen of gut) to be protective; intestinal ab but not serum Ab correlate with protection

Herd immunity possible- can be transmitted to non-vaccinated contacts

Estimated to prevent - 45% of deaths due to rotavirus gastroenteritis

21

Impact of vaccine on rotavirus incidence

2006 vaccination recommended; 72% children vaccinated in 2013

Peak rotavirus season is delayed each year and is less severe

Prior to the vaccine, virtually all children infected by rotavirus

See less and less rotavirus,m peak suppressed in magnitude although still spring seasonality

22

Family Caliciviridae slide 24

Genetically diverse group

Small round viruses

SsRNA

Nonenveloped (naked)

4 distinct genera

2 human genera
- norovirus- most important
- sapovirus

Single major capsid protein (VPI)

Norovirus and sapovirus infect humans

23

Noroviruses vs Sapoviruses

Noroviruses
- cup like indentations
- small round structured viruses
- Norwalk virus
- IV (GI, GII, and GIV contain human strain)
- all ages
- vomiting and diarrhea
- high outbreak potential
- transmission: fecal oral; direct person to person, contaminated food, water or fomites; droplet spread from vomitus


Sapoviruses
- cup like indentations in EM
- Sapporo virus
GI-V
- children mainly
- mild gastroenteritis with less vomiting
- low outbreak potential
- transmission - fecal-oral direct person to person spread

Both are genetically diverse

24

Human Caliciviruses

Noroviruses are currently considered the most widely recognized agents of infectious gastroenteritis in adults and older children in both developed and developing countries
- leading cause of viral gastroenteritis ina adults
- second leading cause of severe diarrheal disease in young children worldwide (should pass rotavirus soon)
- responsible for both outbreaks and sporadic disease

Sapoviruses - found in 3# of children hospitalized for diarrhea and 3% of children in day care centers, outbreaks in institutional settings

25

Norovirus Clinical Syndrome

Not a serious illness

Incubation period 24 - 48 hrs

Duration of illness: 12 - 60 hrs

Prominent features
- nausea
- nonbloody diarrhea
- vomiting
- abdominal cramps

Children> vomiting; adults> diarrhea

Virus shedding may last for. 3 weeks or more

Duration of illness can last longer ( 4 - 6 d) than previously recognized in young children and elderly adults

Chronic diarrhea in immunocompromised; prolonged virus shedding for months to years

Duration of illness can last longer

26

Norovirus Outbreak Characteristics

Public health concern
- account for 60 - 90% of nonbacterial food borne and waterborne outbreaks of gastroenteritis

Restaurants are the second most common source for norovirus outbreak

Leading cause of illness from contaminated food

Year round but most common in the winter

Most cruise ship outbreaks
- 90% of diarrheal disease outbreaks on cruise ships are caused by norovirus, virus can persist on surfaces and is resistant to many common disinfectants

27

Norovirus transmission

Consumption of contaminated food or water

Person to person contact

Contaminated environmental sources

Symptomatic or asymptomatic passengers can bring the virus on board as well

Food: shellfish, salads, celery, frosting, sandwiches, raspberries, cakes etc (those that require handling, but not subsequent cooking)

Water: groundwater supplies, community water systems, swimming pools, recreational lakes, ice

Aerosolization of vomitus; ppl without norovirus can vomit violently without warning

Direct contact: with infectious persons and fomites; secondary transmission

Sick foodhandler is a big deal! Largest food borne outbreaks occurred in Minneapolis St. Paul when a single food handler had vomiting and diarrhea and messed up all the icing

Philly VA nursing home outbreak

28

Why are norovirus infections so common?

Highly contagious; low infectious dose

Resistant to disinfection; stable in the environment
- resists heat, chlorine, being frozen

Large human reservoir; prolonged virus shedding, even after symptoms resolve

Strain specific immunity is short term and not cross protective

Multiple routes of transmission ( fecal-oral, person to person, infectious aerosol, contaminated food and water)

Strain diversity; genetic plasticity
- norovirus appears to evolve by Ag drift and evading the immune system causing waves of global epidemics much like influenza

Lastly considerable genetic variability exists, because of strain diversity, a person can be infected with norovirus more than once; being infected with 1 type doesnt prevent infx from another type later on

29

Enteric Adenoviruses

Adenovirus = gland

First isolated from adenoidal tissue

Nondeveloped (Naked)

DsDNA

Icosahedral capsid, composed of three major proteins - herons (serotypes), Peyton’s, and fibers (subgroups)

30

Adenovirus: classification

Divided into 7 subgroups (A through G)
- based on hemagglutination characteristics (mediated by fiber proteins)
- subgroups with different tissue tropism

57 human serotypes
- characterized by resistance to neutralization by antibodies to other known Adenoviruses
- subgroup F consists of serotypes 40 and 41
- associated with gastroenteritis, especially in infants
- fastidious non cultivatable
- causes 2 - 22% of pediatric diarrhea

Cause endemic diarrhea and outbreaks of diarrhea in hospitals, orphanages, and child care centers; cause 2 - 22% of pediatric diarrhea in inpatients and outpatients

Second to rotavirus in causing pediatric gastroenteritis, they are more important causes of viral gastroenteritis in infants less than 6 mo of age than in older children; infections occur year round with periodic outbreaks