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Home , Coronaviridae, Torovirus

Diagnostics, epidemiology of diarrhoeal diseases of viral origin; vaccination against infection

Krisztián Bányai

ANTSZ Baranya County Institute of State Public Health Service, Regional Laboratory of Virology Historical overview Early 20th century • „pseudocholera infantum”; „winter vomiting disease” 1940s and 1950s • transmissible agent 1950s and1970s • identification of in diarrheic feces 1970s • identification of the first human enteric viruses 1980s and 1990s • identification of new, potential enteric viruses Viruses found in the gut Found in the gut but not associated with

• Polio 68-71 • Coxsackie A Coxsackie B • Echo • Hepatitis A Hepatitis E • Adenoviruses 1-39, 42-51 Reoviruses

Found in the gut as opportunistic infection • CMV VZV • HSV HIV Human enteric viruses

Virus morphology Serotypes

Rotavirus A,B,C, RNA ~70-75 nm, double-shelled particle, 11 G (, Double-stranded, ‘wheel’-like appearance 12 P Rotavirus) 11 segments Calicivirus (, RNA ~27-32 nm, featureless surface several Positive sense

Sapovirus) RNA ~33 nm, David-star surface several Positive sense RNA ~27-30 nm, 5 or 6 pointed star surface 8 (Astroviridae, Positive sense Astrovirus) Adenovirus DNA ~74 nm, classic icosahedral structure 2 (, Double-stranded ) Possible human enteric viruses

Virus Genome Virus morphology Serotypes

Aichi virus RNA ~ 28-35 nm, structured 1 ? (Picornaviridae, Positive sense surface (kobu = knob) ) RNA ~27-32 nm, featureless 3 ? (Picornaviridae, Positive sense surface Parechovirus) RNA ~ 28-35 nm, featureless ? Picotrirnavirus Double- surface (Non-classified) stranded, 2 or 3 segments RNA ~100-140 nm, torus-like 1 ? () Positive sense shape Laboratory diagnostics

•Virus detection in the faeces Cultivation Particle detection Antigen detection Nucleic acid detection •Virus-specific antibody in the serum Cultivation Category Viruses Culturable yes Confirmed Human caliciviruses (noro,sapo) NO yes Enteric adenoviruses (Group F) yes

Coronaviruses yes Possible yes Picobirna-, picotrirnaviruses NO Pestiviruses NO NO Aichi virus yes

Not confirmed (Non Group F) Adenoviruses yes Coxsackie A and B viruses yes Echoviruses yes

Atmar and Estes, Clin Microbiol Rev 14:15-37, 2001 Electron microscopy Rotavirus Astrovirus Norovirus

Parecho Aichi

Picobirna- virus Adenovirus Torovirus http://www.epa.gov/nerlcwww/images.htm Antigen-based methods

Commercial kits •EIA (RV, AdV, AstV, NV) •IF (RV) •LA (RV, AdV) •ICh (RV, AdV) Nucleic acid based methods RFLP

PAGE

4 4

2 3 2 3

2 2

Mixed Identification infections of new viruses No kits (PBV) (RT-)PCR /multiplex/ Sensitivity

EM < LA (PAGE) < EIA < (RT-)PCR < Cultivation

106-7 105-6 104-6 101-4 100-1 /ml

Limitations: quantity of shed virus particles/antigens

(e.g., RV, 1010-1012; NV, < 106-107 ml) epidemiologic background are the detected viruses infectious? Virus Routinely used methods Alternative methods Rotavirus EM PAGE, RT-PCR EIA, LA, ICh Cultivation Serology

Cailiciviruses EM Serology (Sapovirus EIA (noro) Norovirus) RT-PCR

Astrovirus EM Cultivation EIA Serology RT-PCR

Enteric adenovirus EM PCR EIA, LA, ICh RFLP Cultivation

Aichi virus Cultivation EIA RT-PCR

Parechoviruses Cultivation RT-PCR

Picobirnavirus PAGE, RT-PCR

Torovirus EM RT-PCR Epidemiology US Bangladesh Episodes/child/year 1-2 4-7 Total episodes by age 5 5-7 20-35 Agents Viruses RV 1 1 AstV 1 1 CVs 1-2 2-5 EAdV 1 1 Bacteria, parasites 1 >20 Risk of death 1 in 12,000 1 in 40

Glass et al., 2001 Endemic childhood disease Epidemic disease Viruses Rotavirus A Norovirus Astrovirus Rotavirus B Enteric adenovirus Norovirus Sapovirus

Rotavirus C Astrovirus Torovirus Rotavirus A és C

Glass et al., 2001 Kapikian et al., 2001 Differences in the epidemiology of RV

Industrial World Developing Countries

Seasonality Winter Year round

Age (% < 1 yr) 40% 80%

Serotypes 5 common Mostly common Some additional

Mixed infections Rare Common

Case fatality Low High 1 in 100 000 1 in 200 400,000 - 500,000 deaths annually !

Glass et al., 1998 Endemic childhood disease Epidemic disease

Viruses Rotavirus A Astrovirus Rotavirus B Enteric adenovirus Norovirus Sapovirus

Rotavirus C Astrovirus Torovirus Rotavirus A és C Coronavirus

Glass et al., 2001 Etiology of gastroenteritis outbreaks (1998-2002; N=829)

Salmonella

Shigella

Campylobacter

Other/More bacteria Non-bacterial

Krisztalovics et al., 2004 Etiology of non-bacterial gastroenteritis outbreaks (1998-2002; N=490)

Adenovirus

Rotavirus

Calicivirus

Non-bacterial, no further tested

Krisztalovics et al., 2004 Total no. of calicivirus (CV) and non-bacterial gastroenteritis outbreaks - laboratory surveillance (1998-2002)

CV Non-bacterial

Krisztalovics et al., 2004 Settings

9%

11% Kórházak,Hospitals, nursing szoc. homesotthonok 43% Éttermek,Restaurants, fogadások catered meals 11% Iskolák,Schools, dayóvodák care centers VakációVacation settings EgyébOther

26%

CDC, 1996-1997 Glass et al., 2000 Source of infection

21%

Élelmiszer-közvetítettFood Személyes kontaktus 43% Infected person KagylófogyasztásShellfish 11% VízWater közvetített IsmeretlenUnkown 6% NincsNo data adat 3% 16%

CDC, 1996-1997 Glass et al., 2000 Endemic childhood disease Epidemic disease

Mode of transmission direct contact food aerosol water contaminated surfaces personal contact aerosol

Reservoir humans humans animals animals Immunity high seroprevalence seroconversion by age of 5 y during the outbreak

good short-lived

Glass et al., 2001 Transmission through ‘aerosol’ Moreno-Espinosa et al., 2004 Endemic childhood disease Epidemic disease

Mode of transmission direct contact food aerosol water contaminated surfaces personal contact aerosol

Reservoir humans humans animals animals Immunity high seroprevalence seroconversion by age of 5 y during the outbreak

good short-lived

Glass et al., 2001 Animals as reservoirs of rotavirus strains

B4106 (P[14]G3) Belgium (11 LA) AU-1, Ro-5829 (P3[9]G3) 116E (P8[11]G9) Japan, Israel (11 FE) India (10 HU / 1 BO)

I321 (P8[11]G10 India (2 HU / 9 BO) Ro1845, HCR3 (P5[3]G3 )

Israel, USA (11 FE / CA) PA151 (P3[9]G6) PCP5 (P3[9]G3) (7 HU / 4 BO)

Br1054 (P[8]G5) US1205 (P[8]G9, P[6]G9) S-Am (8 HU / 3 PO) Global (10 HU / 1 PO) Endemic childhood disease Epidemic disease

Mode of transmission direct contact food aerosol water contaminated surfaces personal contact aerosol

Reservoir humans humans animals animals Immunity high seroprevalence seroconversion by age of 5 y during the outbreak

good short-lived

Glass et al., 2001 Endemic childhood disease Epidemic disease

Virus variants limited in a given area several genotypes various in different areas Clinical might be mild, self-limiting manifestation severe (life threatening)

Prevention vaccination (Rotavirus A) outbreak control safer food handling water surveillance

Glass et al., 2001

100 Baranya County, 1984-2000

90

80

70 G1 60 G2 50 G3 G4 40 G6 G9 30

20

10

0

1984-19851985-19861986-19871987-19881988-19891989-19901990-19911991-19921992-19931993-19941994-19951995-19961996-19971997-19981998-19991999-2000

100 Budapest, 1988-2003 90 80 70 G1 60 G2 G3 50 G4 40 G6 G9 30 20 10 0

1988-19891989-19901990-19911991-19921992-19931993-19941994-19951995-19961996-19971997-19981998-19991999-20002000-20012001-20022002-2003 Endemic childhood disease Epidemic disease

Virus variants limited in a given area several genotypes various in different areas Clinical might be mild, self-limiting manifestation severe (life threatening)

Prevention vaccination (Rotavirus A) outbreak control safer food handling water surveillance

Glass et al., 2001 Endemic childhood disease Epidemic disease

Virus variants limited in a given area several genotypes various in different areas Clinical might be mild, self-limiting manifestation severe (life threatening)

Prevention vaccination (Rotavirus A) outbreak control safer food handling water surveillance

Glass et al., 2001 Kapikian et al., 2001 Estimated no. of rotavirus infections accordig to the disease severity

400 000 - 500 000 deaths

2 000 000 hospital admission

25 000 000 medical visit

111 000 000 home treatment

Parashar et al., 2003 Why is vaccination What benefits are needed? expected?

•high mortality •prevention of severe outcome infections •high morbidity decreasing the no. •high costs of treatment of hospitalizations and •limited influence of public deaths health interventions and •reduction of costs improvemments in water assoc. with the supply treatment •regional inequalities in health care systems •lack of antiviral therapy Animal strains

Animal-human reassortant strains

Attenuated human strains

Alternative approaches Santos and Hoshino, 2004 Parental strains

Reassortant progenies Animal strains

Animal-human reassortant strains

Attenuated human strains

Alternative approaches Santos and Hoshino, 2004