Rotavirus Infection

Children’s Hospital, Zhejiang University School of Medicine

Jiang Mizu

What is Rotavirus ?Electron microscopic View of Rotavirus

What is Rotavirus ?Electron microscopic View of Rotavirus

Rotavirus particles in stool filtrate

Photo Credit : F.P. Williams, U.S. Environmental Protection Agency; Adapted from Parashar et al, Emerg Inft Dis 1998,14(4) 561–570

“Rota” in Latin

means wheel

First detected in April,

1973 by R Bishop

and team from a

biopsy of an

Australian child with

severe gastroenteritis.

Electron microscopic appearances of rotavirus

What is Gastroenteritis?What is Gastroenteritis?

• Gastroenteritis is second only to respiratory illness as a cause of childhood morbidity worldwide.

• Gastroenteritis: nausea, vomiting, diarrhea, abdominal cramping, and fever occur 6-48h after exposure.

• Most gastroenteritis is caused by viral infection; bacterial, parasitic, and protozoal illnesses are less frequent but not uncommon.

Rotavirus Gastroenteritis

• Viral gastroenteritis• Self-limited illness with nausea, vomiting,

diarrhea• Children aged 6 months to 2 years• Rotavirus can cause acute diarrhea in adults

What is diarrhea?

• Definition: increased total daily stool output (> 10g/kg/d) ， is usually associated with increased stool water content. – Loose consistency( 性状改变 ):watery diarrhea,

mucous diarrhea, bloody diarrhea– Increased stool frequency( 次数增多 )

• Duration – Acute (< 14 d)– Persistent (14 d to 2 m)– Chronic (> 2 m)

Rotavirus and diarrhea

• Viruses are the most common cause of acute gatroenteritis in developing and developed countries, such as rotavirus, astrovirus, adenovirus, and caliciviruses (Norwalk agent)

• Rotavirus, a 67-nm double-stranded RNA virus with at least eight serotypic variants, is the most common.

• As with most viral pathogens, rotavirus affects the small intestine, causing voluminous watery diarrhea without leukocytes or blood.

AA

G1P[8]

VP4VP4VP7VP7

Sub-group

Serotype

C, D, E, F, G

(2)

I

II

GG PP(1-14 ) (1-8)

G2P[4] G3P[8] G4P[8]

REOviridae Family

Group B(7) VP6VP6

病毒 - 分类

(64%) (3%) (9%)(12%)

Santos et al, Rev Med Virol 2005 Jan-Feb15(1) 29-56

G9

呼肠病毒科

Rotavirus Epidemiology

• Rotavirus is the most common diarrheal pathogen in children worldwide1

• Globally more than 125 million cases of infantile gastroenteritis2

• 440,000 deaths per year mainly in less developed countries3

1Parashar et al, Emerg Infect Dis 1998 4(4) 561–570; 2Linhares and Bresee, Pan Am J Public Health 2000 8(5) 305–331; 3Parashar et al, Emerg Infect Dis 2003 9(5) 565–572

Estimated global distribution of 440,000 annual deaths in children <5 years old caused by rotavirus diarrhea3

1 dot = 1000 deaths

Introduction

From Kapikian AZ, Chanock RM. Rotaviruses. In: Fields Virology 3rd ed. Philadelphia, PA: Lippincott-Raven; 1996:1659.

Bacteria

Unknown Rotavirus

Calicivirus

Rotavirus

Escherichia coli

Parasites

Otherbacteria

Developed CountriesDeveloped Countries

Adenovirus

CalicivirusAstrovirus

AdenovirusAstrovirus

Unknown

Less Developed CountriesLess Developed Countries

Rotavirus Epidemiology Epidemiology

Distribution of pathogens reported to cause endemic/epidemic gastroenteritis and infantile vomiting and diarrhea

Distribution of pathogens reported to cause endemic/epidemic gastroenteritis and infantile vomiting and diarrhea

All children will get at least one rotavirus infection early in life

Reproduced with permission from Velázquez et al. N Engl J Med. 1996;335:1022-1028.

1.00.90.80.70.60.50.40.30.20.1

3 6 9 12 15 18 21 24Pro

bab

ility

of

rota

vir

us

infe

cti

on

Age (months)

1st infection

2nd infection

3rd infection

4th infection

5th infection

0.0-0.1 0.6-0.9 1.0-1.9 2.0-3.40.2-0.5

Rotavirus-attributable mortality per 1000 children under 5 years of age

Epidemiology

• Outbreaks are common in children’s hospitals and child-care centers.

• Disease tends to be most severe in patients 6-24 mo of age, although 25% of the cases of severe disease occur after 2 yr of age, with serologic evidence of infection developing in virtually all children by 4-5 yr of age.

• Infants younger than 3 mo of age are relatively protected by transplacental antibody and possibly breast-feeding.

Epidemiology

• Transmission: fecal-oral route by contaminated food, water or toy, or respiratory droplet, only need 10 particles from person to person.

• Virus resistant to stomach acid, attaches to beta receptor• Peak season in temperate climates is winter, in the

tropics , more prevalent in times of lower humidity.• Large quantities of virus are shed in the stool during the

first week of infection, and can be last up to 2 months• The virus survives for hours on hands and for 6-60 days

on dry inanimate surfaces.

Fecal-Oral Transmission

Infected Animal

Infected Person

Water

Susceptible person

Food

Toy

Pathophysiology of rotavirus infection

• In viral infection, diarrhea is noninflammatory and results from an enteropathy in which the death of mature villus-tip cells (responsible for disaccharide digestion and monosaccharide absorption) causes an osmotic diarrhea due to the malabsorption of sugars.

Anatomy of Intestine

Pathogenesis

• Viruses that cause human diarrhea selectively infect and destroy villus tip cells in the small intestine.

• Biopsies of the small intestine show variable degrees of villus blunting and round cell infiltrate in the lamina propria.

• Pathologic changes may not correlate with the severity of clinical symptoms and usually resolve before that clinical resolution of diarrhea.

Pathogenesis Rotaviruses adhere to the GI tract epithelia

(jejunal mucosa)

Atrophy of the villi of the gut

* *

Loss of absorptive area

Flux of water and electrolytes

NSP4 viral enterotoxin

Enteric nervous system activation

VOMITING

&

DIARRHEA

*Rotavirus infection in an animal model of infection. Photographs are from an experimentally infected calf. Reproduced

with permission from Zuckerman et al, eds. Principles and Practice of Clinical Virology. 2nd ed. London: John Wiley & Sons; 1990:182. Micrographs courtesy of Dr. Graham Hall, Berkshire, UK.

Chief concern

• Acute self-limited diarrhea• Nausea• Vomiting• Most infections in newborns are asymptomatic

or mild

Clinical manifestation

• The most common cause of acute gastroenteritis in infants and toddlers.

• The peak season is in the cooler fall and winter months (year-round).

• The peak age incidence is 3 to 24 months.• The incubation period for RV is 24-48 h.• Vomiting is the first symptom in 80-90% of pts,

followed within 24 h by low-grade fever and voluminous watery diarrhea and non bloody.

Clinical manifestation

• Diarrhea is usually self-limited, abating with 4-8 days but may last longer in young infants or immunocompromised patients.

• Up to one-third have fever >39 degrees C• The white blood cell count is rarely elevated.• The stool does not contain blood or white cells.• Complication

– Dehydration– Elctrolyte imbalance

Evaluation of dehydration status

• The most common causes of dehydration in children are vomiting and diarrhea.

• Dehydration is classified by the percentage of total body water lost: mild (<5%), moderate (5-10%), and severe (>10%).

• A variety of signs and symptoms and ancillary data help to estimate the degree of dehydration.

Degree of dehydration

Clinical signs mild moderate severeDecrease in body weight 3-5% 5-10% 10-15%Skin Turgor normal decreased Markedly

decreased Color normal pale markedly decreased Mucous membranes Dry Mottled or gray;

parchedHemodynamic signs Pulse normal slight increase tachycardia Capillary refill 2-3 s 3-4 s >4 s blood pressure normal low perfusion normal circulatory collapseFluid loss urinary output mild oliguria oliguria anuria Tears Decreased absentUrinary indices specific gravity >1.020 anuria Urine [Na+] <20mEq/L anuria

Clinical dehydration scale (CDS)

• Points assigned based on 4 clinical items– General apperance

• 0, normal• 1, thirsty, restless, lethargic but irritable when touched• 2, drowsy, limp, cold, sweaty, comatose

– Eyes• 0, normal; 1, slightly sunken; 2, very sunken

– Mucous membranes (tongue)• 0, moist; 1, sticky; 2, dry

– Tears • 0, present; 1, decreased; 2, absent

• CDS classifies children into 3 degrees of dehydration– 0 points, no dehydration– 1-4 points, some dehydration– 5-8 points, moderate/severe dehydration

Electrolyte Disorders

• Sodium disorders

Isotonic dehydration: [Na+] 130-150mmol/L

Hypotonic dehydration: [Na+] <130mmol/L

Hypertonic dehydration: [Na+] >150mmol/L• Potassium disorders

Hyperkalemia: [K+] >5.5mmol/L

Hypokalemia: [K+] <3.5mmol/L

Metabolic Acidosis

According to AG= [Na+] - ([HCO3-] + [Cl-])

• Normal type: 8-16mmol/L [HCO3- ]• Increased type: >16mmol/L [H+]

According to [HCO3-] • Mild [HCO3-] 18-13mmol/L• Moderate [HCO3-] 13-9mmol/L• Severe [HCO3-] <9mmol/L

Diagnosis

• In most cases, a satisfactory diagnosis can be made on the basis of clinical and epidemiologic features.

• Specific identification of rotavirus in not required in every case, especially in outbreaks.

• Stool for ELISA, which offer approximately 70-80% sensitivity and 71-100% specificity.

• Blood tests: blood gas and electrolytes, blood count, blood urea nitrogen, creatinine

• Perform microbiological stool studies if bloody diarrhea or severe illness.

• Additional tests: abdominal X-ray, stool (culture, electron microscopy, PCR)

Stools studies

Findings ImplicationsGross examination Blood, mucus, pus Bacterial infection

Microscopic examination >5 WBC/hpf Bacterial infection

Chemical examination– Stool pH pH<5 Viral infection, Carbohydrate

malabsorption– Stool-reducing substances + Viral infection, Carbohydrate

malabsorption

Differential diagnosis

• In infancy, the differential diagnosis of acute gastroenteritis includes diarrhea associated with other infections such as urinary tract infection, otitis media, sepsis, and pneumonia.

• Depending on the geographic location, enteric adenoviruses or caliciviruses are the next most common viral pathogens in infants.

• Other potentially pathogenic viruses include astroviruses, corona-like viruses, Coxsackis viruses, and other small round viruses.

Norovirus

• A calicivirus, is a small RNA virus that causes epidemic outbreaks of gastroenteritis

• Affects school-age children, adolescents, and adults. • After a 24-h incubation period (range,12-72h), patients

characterized by fever, vomiting, diarrhea, and often malaise and myalgias.

• Stools are loose, watery, and without blood, mucus, or leukocytes.

• The duration of symptoms is short, usually 12-60 hours.

一些胃肠道病毒的特征 病毒 基因结构 主要发病人

群季节 诊断试验 治疗

轮状病毒Group A

双股分节段 RNA

< 3 岁儿童 冬 ELISA, PAGE

•口服补液•疫苗

腺病毒types 40 & 41

双股 DNA < 3 岁儿童 全年 ELISA •口服补液

杯状病毒 单股 RNA 小儿 不明 Experimental & EM

•口服补液

星状病毒 单股 RNA 小儿免疫功能低下者

冬 Experimental & EM

•口服补液

诺如病毒 单股 RNA 儿童 / 成人 , 流行 / 散发

冬 Experimental & EM

RT-PCR

•口服补液

Management

• The goals– Control the diarrhea, Prevent vomiting, Control other

symptoms– Recognition, prevention, and treatment of dehydration– Maintenance of the nutritional status of the patients.

• Supportive treatment– Replacement of fluid and electrolyte deficits and

ongoing losses is critical, especially in small infants. – The use of oral rehydration solution (ORS) is

appropriate in most cases.

Oral rehydration solution (ORS)

Component （低渗 ) g/L （标准 ) g/L

NaCl 2.6 3.5 Glucose 13.5 20

KCl 1.5 1.5

Sodium citrate 2.9 2.9

Total weight 20.5 27.9

Management of dehyration

• For children with mild or moderate dehydration– Rapid fluid replacement with oral rehydration therapy

(ORT) recommended• Estimated amount of ORS 75ml/kg within first 4 hr• ORT by mouth or nasogastric (NG) tube may have similar

overall safety and efficacy as IV rehydration therapy.

• For children with severe dehydration– Immediate and rapid IV rehydration recommended.

• Children with acute diarrhea should continue to be fed.

No or minimal signs of dehydration

• Home based fluid management recommended– Increase fluid intake to compensate for losses and

prevent development of dehydration– If possible, replace fluid after each episode of

diarrhea or vomiting• 50-120ml in children<2 yr• 100-240ml in children aged 2-10 yr

– Encourage ORS– Avoid commercial juices and carbonated beverages– Continuing usual feeding– Encourage caretakers to bring child to healthcare

facility if sings of dehydration arise

Mild and moderate dehydration

• Rapid fluid replacement with ORT at health facility – Provide 50-100ml/kg ORS over first 4 hr (giving

frequently in small amounts)– Considerations for ORT– Consider NG administration of ORS in child with normal

mental status who is unable to drink or who vomits persistently with oral ORS

– Consider IV therapy in child with decreased consciousness or if unresponsive to oral or NG administration of ORS

– Start IV therapy immediately if child shows signs of severe dehydration or clinical deterioration

– Encourage home fluid management after dehydration corrected

Severe dehydration

• Start rapid IV infusion with a 10-20ml/kg bolus of normal saline (NS) over 20 to 30 min.– Assessing their fluid status – Obtain blood for electrolytes, blood urea nitrogen (BUN),

creatinine, glucose, and urinalysis

• If there is a poor response to the initial bolus, repeat the infusion.

• If there is a poor response to two IV boluses, consider other associated organ disease (septic shock or metabolic, cardiac, and neurologic diseases) or the need for central venous monitoring before giving a third bolus.

• Edema of eyelids and extremities may indicate overhydration

Diet therapy

• Children having semisolid or solid foods should continue usual diet during diarrhea episodes

• Offer child food every 3-4 hr• Feeding considerations in infants

– Breastfed infants should continue to nurse on demand– Formula-fed infants should continue usual formula upon

rehydration– Infants should continue usual diet during diarrhea diet afterward

• Food should never be withheld; • Food should not be diluted• Breastfeeding should always be continued

– Lactose-free milk or infant formula does not appear to improve outcomes in most young children with acute diarrhea.

• Dietary considerations for children in developing coutries

Medications

• Probiotics: such as lactobacillus species has been shown to reduce somewhat the intensity and duration of illness.

• Zinc supplementation• Racecadotril, an enkephalinase inhibitor with

antisecretory actions• Smectitie• Glutamine

No medications

• No role for antiviral drug treatment.• No benefit for antibiotics • No benefit from antiemetics or antidiarrheal

drugs, and there is a significant risk of serious side effects.

• Antimotility agents should be avoided.

Prevention of rotavirus infection

• Good hygiene (regular disinfection of play areas and toys) reduces the transmission of RV.

• Frequent hand washing and isolation procedures can help control nosocomial outbreaks.

• Breast-feeding in prevention or amelioration of RV infection may be small.

• Repeat infections occur but are usually less severe.

• Development of rotavirus vaccines

Rotavirus vaccination

• Mimic the immune response of natural rotavirus infection to:– Protect against moderate/severe disease– Prevent hospitalization and death– Reduce morbidity and socioeconomic burden– Attenuate severity and duration of illness

Asian rotavirus health burden

Outcome

Without Vaccination

With Vaccination

Events

Averted

Deaths 170,960 61,640 109,320

(-64%)

Hospitalizations 1,914,891 535,603 1,379,288

(-72%)

Outpatient visits 13,503,114 5,838,838 7,664,275

(-57%)

CDC, unpublished data

Summary

• Rotavirus is the most common cause of vomiting and diarrhea in children worldwide

• An estimated 440,000 deaths occur annually, mainly in less developed countries

• Outer viral capsid proteins VP7 and VP4 define the serotype of rotaviruses (G and P type respectively), that are critical to vaccine development

• Four Group A rotavirus serotypes predominate globally: G1P[8], G2P[4], G3P[8] and G4P[8], with most disease attributable to G1[P8]

• Serotype G9 emerging as the fifth globally important serotype

• Vaccination is the most likely intervention to impact significantly on the global incidence of severe disease