Rotavirus Infection

1. Rotavirus Infection Children’s Hospital, Zhejiang University School of Medicine Jiang Mizu

2. What is Rotavirus ?Electron microscopic View of Rotavirus “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. 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

3. Electron microscopic appearances of rotavirus

4. 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.

5. 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

6. 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)

7. 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.

8. REOviridae Group B VP6 C, D, E, F, G (7) Family I Sub-group II (2) Serotype VP7 VP4 G P (1-14 ) (1-8) G1P[8] G2P[4] G3P[8] G4P[8] 病毒- 分类 呼肠病毒科 A G9 (64%) (12%) (3%) (9%) Santos et al, Rev Med Virol 2005 Jan-Feb15(1) 29-56

9. Introduction 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 Estimated global distribution of 440,000 annual deaths in children <5 years old caused by rotavirus diarrhea31 dot = 1000 deaths 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

10. Developed Countries Less Developed Countries Parasites Unknown Rotavirus Unknown Rotavirus Otherbacteria Escherichia coli Bacteria Adenovirus Adenovirus Astrovirus Calicivirus Astrovirus Calicivirus Epidemiology Rotavirus Epidemiology Distribution of pathogens reported to cause endemic/epidemic gastroenteritis and infantile vomiting and diarrhea From Kapikian AZ, Chanock RM. Rotaviruses. In: Fields Virology 3rd ed. Philadelphia, PA: Lippincott-Raven; 1996:1659.

11. All children will get at least one rotavirus infection early in life 1.0 1st infection 0.9 0.8 2nd infection 0.7 0.6 Probability of rotavirus infection 0.5 3rd infection 0.4 0.3 4th infection 0.2 0.1 5th infection 9 12 15 18 21 24 3 6 Age (months) Reproduced with permission from Velázquez et al. N Engl J Med. 1996;335:1022-1028.

12. Rotavirus-attributable mortality per 1000 children under 5 years of age 0.0-0.1 0.2-0.5 0.6-0.9 1.0-1.9 2.0-3.4

13. 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.

14. 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.

15. Fecal-Oral Transmission Infected Person Infected Animal Toy Water Food Susceptible person

16. 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.

17. Anatomy of Intestine

18. 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.

19. 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 VOMITING & DIARRHEA NSP4 viral enterotoxin Enteric nervous system activation *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.

20. Chief concern • Acute self-limited diarrhea • Nausea • Vomiting • Most infections in newborns are asymptomatic or mild

21. 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.

22. 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

23. 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.

24. Degree of dehydration Clinical signs mild moderate severe Decrease 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; parched Hemodynamic signs Pulse normal slight increase tachycardia Capillary refill 2-3 s 3-4 s >4 s blood pressure normal low perfusion normal circulatory collapse Fluid loss urinary output mild oliguria oliguria anuria Tears Decreased absent Urinary indices specific gravity >1.020 anuria Urine [Na+] <20mEq/L anuria

25. 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

26. 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

27. 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

28. 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)

29. Stools studies Findings Implications Gross 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

30. 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.

31. 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.

32. 一些胃肠道病毒的特征

33. 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.

34. Oral rehydration solution (ORS) Component（低渗) g/L （标准) g/L NaCl 2.6 3.5 Glucose13.5 20 KCl1.5 1.5 Sodium citrate2.9 2.9 Total weight20.5 27.9

35. 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.

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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.

42. 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

43. 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

44. Asian rotavirus health burden CDC, unpublished data

45. 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