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Guideline for the Prevention and Control of Norovirus Gastroenteritis Outbreaks in Healthcare Settings, 2011

Evidence Table Q1 - Person characteristics / Laboratory Characteristics

Author, Yr (Ref) Study Design Quality Study Objective Population and Setting N Results Comments Ref ID_Data extracted by
Halperin, T; 200869 Prospective controlled study
 
1,3,4
To determine if norovirus genogroup II susceptibility is related to ABO phenotype. Sick soldiers and healthy contacts in military units in Israel during outbreaks during February 2003 and January 2005. All soldiers were male and 18-22 years old.
 
138 cases and 166 healthy subjects.
Symptoms
Attack rate – 20%.
Nausea and/or emesis – 75%
Diarrhea – 69%
Stomachache – 65%
Fever – 17%
 
ABO distribution
A – 36.5%
AB – 11.8%
B – 20% O – 31.6%
 
Risk Factor compared to blood type O
All results – Symptomatic infection OR (95% CI); Fever OR (95% CI)
A – 0.58 (0.33-1.01); 2.14 (0.68-6.74)
AB – 0.48 (0.20-1.14); OR N/A
B – 0.72 (0.37-1.38); 3.08 (0.89-10.67)
Cases had emesis, nausea, or stomachache.
 
Healthy contacts served in the same company as the case patients, had no GI symptoms, and were in the compound for at least the 3 days prior to the outbreak.
 
Power and sample size not reported.
5114_IL
Hutson, A; 2005 70 Prospective controlled study
 
1,2,3,4
To evaluate whether secretor status was associated with resistance to norovirus infection. Volunteers experimentally challenged with norovirus. Demographic characteristics not reported. Study was conducted in Texas.
 
51
Asymptomatic norovirus infection (following challenge)
Secretor positive vs. secretor negative – 42/43 vs. 0/8; statistical differences were not reported
 
Symptomatic norovirus infection (following challenge)
Secretor positive vs. secretor negative – 29/43 vs. 0/8; statistical differences were not reported
Norovirus infection was defined as four-fold or greater increase in norovirus specific serum antibody titer (ELISA) or norovirus antigen shedding [ELISA, radioimmunoasay (RIA) or RT-PCR]
 
Secretor genotype was assessed by testing PCR products obtained from deoxyribonucleic acid (DNA) extracted from archived sera.
 
FUT2 gene typically associated with non-secretor status (norovirus resistant) and in 20% of Caucasians. Study did not characterize participants by ethnicity, only FUT2 genotyping.
 
Power and sample size not reported
468_RA
Thorven, M; 2005 71 Prospective Controlled Study
 
1,3,4
To investigate if the FUT2 secretor gene was associated with resistance to nosocomial and sporadic outbreaks caused by genogroup II noroviruses Symptomatic and asymptomatic individuals from nosocomial and sporadic outbreaks of genogroup II norovirus. Blood donors in Sweden were used as a second control group. Patient demographics not described. Study was conducted in Sweden.
 
115
Secretor Status
Outbreak 1 (Internal Medicine Ward; N=50)
Symptomatic patients:
Homozygous secretors – 47%
Heterozygous secretors – 53%
Secretor negative – 0%
Asymptomatic patients:
Secretor negative – 19%
(Number of patients for each category was not reported)
 
Outbreak 2 (Pediatrics Ward; N=28)
Symptomatic patients:
Secretor negative – 0/7
Asymptomatic patients:
Secretor negative – 9/21
 
Outbreak 3 (Orthopedic Ward; N=18)
Symptomatic patients:
Secretor negative – 0/12
Asymptomatic patients:
Secretor negative – 3/6
 
Community Outbreaks (N=19)
Symptomatic patients:
Homozygous secretors – 7/15
Heterozygous secretors – 8/15
Secretor negative – 0/15
Asymptomatic patients:
Homozygous secretors – 2/4
Heterozygous secretors – 2/4
Secretor negative – 0/4
 
Cumulative data
Homozygous non secretor status
Symptomatic patients vs. non-symptomatic patients – 0/53 vs. 18/62; P<0.01
Symptomatic patients vs. blood donors – 0/53 vs. 21/104; P<0.01
A patient with gastroenteritis was defined as a patient with vomiting (≥ once/24 h) and/or diarrhea (≥ 2 watery stools/24 h)
 
norovirus was detected in stool using RT-PCR. The DNA from saliva was sequenced for secretor genotype using sequence-specific primers and PCR.
 
Power and sample size not reported
400_RA
Lindesmith, L; 2003 72 Prospective controlled study
 
1,2,3,4
To investigate the role of secretor status and acquired immunity in Norwalk virus infection. Volunteers received doses of Norwalk virus inoculum ranging from 10 to 3 × 108 PCR detectable units. Volunteers dosed with Norwalk virus. 49% male; 71% white, 23% black and 6% other races; average age 30 yrs (range 20-49). Study was conducted in North Carolina.
 
77
Asymptomatic norovirus infection (following challenge)
Secretor positive vs. secretor negative – 34/55 vs. 0/22; P<0.01
 
Blood types
Among O blood type
Secretor positive – RR 1.56; P<0.05
Secretor negative – No events; P>0.05
Overall – RR 1.89; P<0.05
 
Among A blood type
Secretor positive – RR 0.79; P>0.05
Secretor negative – No events; P>0.05
Overall – RR 0.54; P<0.05
 
Among B blood type
Secretor positive – RR 0.66; P>0.05
Secretor negative – No events; P>0.05
Overall – RR 0.82; P>0.05
 
Among AB blood type
Secretor positive – No events; P>0.05
Secretor negative – No events; P>0.05
Overall – P>0.05
 
Symptomatic norovirus infection
O blood type. P>0.05
Norovirus infection was defined as viral RNA detected in stool or a .4-fold increase in Norwalk-virus specific serum IgG. Symptomatic infection was defined as an infected subject with vomiting or diarrhea (>2 unformed stools in 24 hours).
 
Secretor genotype was determined through PCR amplification of DNA extracted from saliva.
 
Data on immunity was not not extracted as it was not clinically relevant (antibody titers)
 
Comparison group for RR unclear.
 
Power and sample size not reported
830_RA
Hutson, A; 2002 73 Prospective controlled study
 
1,2,3,4
To investigate the role of ABO phenotype in norovirus susceptibility Volunteers experimentally challenged with norovirus. Demographic characteristics not reported. Study was conducted in Texas.
 
51
All results OR (95% CI); P value by Fisher’s exact for the presence of blood type and the risk of infection
 
Asymptomatic norovirus infection (following challenge)
O – 11.80(1.3-103.00); 0.01
A – 0.63(0.14-2.70); 0.70
B – 0.27(0.04-1.90); 0.21
AB – 0(0-1.10); 0.03
A/AB combined – 0.25(0.05-1.20); 0.13
B/AB combined – 0.10(0.02-0.56); 0.01
 
Symptomatic norovirus infection (following challenge)
O – 0.89(0.23-3.40); 1.0
A – 3.90(0.72-21.00); 0.16
B – 0(0-0.99); 0.03
Norovirus infection was defined as four-fold or greater increase in norovirus specific serum antibody titer (ELISA) or norovirus antigen shedding (ELISA, RIA or RT-PCR)
 
Asymptomatic infection was defined as the absence of vomiting and/or diarrhea and a low overall symptom score (abdominal cramps, chills, body ache, headache, nausea and fever)
 
Comparison group for OR unclear.
 
Power and sample size not reported
954_RA
Graham DY, 1994 74 Prospective controlled study
 
1,3,4
To evaluate the clinical features and virologic and immunologic responses following oral administration of Norwalk virus. 8 volunteer studies between July 1985 and January 1990 where medical students and staff of the Texas Medical Center were administered norovirus.
 
21 women, 30 men 19-39 years old 43 white, 6 black, 1 Hispanic, and 1 East Indian.
 
N=50 subjects
Infection status measured by serum antibody response
After norovirus challenge, 9 (18%) uninfected vs. 41 (82%) infected.
Of those infected, 82% with vs. 60% without preexisting antibody; p>0.2.
Of those infected, Group 4 subjects had higher preexisting antibody titers than uninfected subjects; p=0.004
Uninfected subjects had lower preexisting antibody titers than infected subjects; p<0.001
Of those infected, there were increases in geometric mean titers after infection (p<0.01) and the increase in convalescent titers were higher in subjects with vomiting (Groups 3 and 5 vs. 2 and 4; p=0.016) or with vomiting and diarrhea (Group 5 vs. 2-4, p=0.02)
 
All results: No (%) subjects with pre-existing Norwalk virus antibody titers of levels <10 vs. 10 vs. 40 vs. 160 vs. 640 vs 2560 who have the characteristic of interest
Seroconversion: 3/5 (60) vs. 4/7 (57) vs. 13/17 (76) vs. 16/16 (100) vs. 4 /4(100) vs. 0/1; p value=0.065
Viral shedding: 2 (40) vs. 2 (29) vs. 12 (70) vs. 16 (100) vs. 3 (75) vs 1 (100); p value=0.0012
Diarrhea: 2 (40) vs. 1 (14) vs. 10 (59) vs. 7 (44) vs. 3 (75) vs. 1 (100); p value=NS
Vomiting: 2 (40) vs. 1 (14) vs. 7 (41) vs. 5 (31) vs. 1 (25) vs 0; p value=NS
Nausea: 2 (40) vs. 1 (14) vs. 11 (65) vs. 10 (62) vs. 4 (100) vs. 0; p=0.065
Cramps: 2 (40) vs. 1 (14) vs. 12 (70) vs. 10 (62) vs. 2 (50) vs. 0; p value=NS
Headache: 4 (80) vs. 3 (42) vs. 12 (70) vs. 9 (56) vs. 3 (75) vs. 0; p value=NS
Chills: 1 (20) vs. 0 vs. 5 (29) vs. 3 (19) vs. 1 (25) vs. 0; p value=NS
Fever: 1 (20) vs. 0 vs. 4 (23) vs. 3 (19) vs. 1 (25) vs. 0; p value=NS
 
Virologic parameters of infection
64% patients with symptomatic infection vs. 32% with asymptomatic infection had stools with positive antigen
Earliest positive sample occurred at 15 hours
Peak of stool viral shedding 25-72 hours after inoculation
Most infected volunteers shed viral antigen continuously from their first positive sample until the last sample obtained
Longest antigen shedding was 7 days after inoculation and 1 asymptomatic subject shed antigen 6 days after inoculation
 
All results No. positive/no. tested stool samples (%); Mean no. stools/person/day in Uninfected vs. Infected (asymptomatic) vs. Infected (symptomatic) patients at different time points
Day 0: 0/5; 0.6 vs. 0/7; 0.5 vs. 0/10; 0.4
Day 1: 0/6; 0.7 vs. 0/16; 1.2 vs. 12/51 (24); 1.8
Day 2: 0/7; 0.8 vs. 9/17 (53); 1.3 vs. 81/109 (74); 3.9
Day 3: 0/13; 1.4 vs. 5/9 (56); 0.7 vs. 40/44 (91); 1.6
Day 4: 0/1; NC vs. 2/3 (67); NC vs. 16/22 (73); NC
Day 5: 0/4; NC vs. 1/3 (33); NC vs. ½ (50); NC
Day 6: 0/2; NC vs. 1/1 (100); NC vs. 5/5 (100); NC
Day 7: 0/1; NC vs. NS; NC vs. 2/2 (100); NC Total: 0/39; NC vs. 18/56 (32); NC vs. 157/245 (64); NC
NC - not calculated because not all stools collected after subjects discharged
NS – no samples received.
 
Clinical features of subjects relative to infection status
Incubation time to onset of symptoms: 24-38 hours
Duration of illness: 2-3 days
Diarrhea: occurred earliest at 15 hours and latest at 55 hours after inoculation.
 
All results: No. (%) subjects with antibody responses 0 vs. 4 vs. 16 vs. 64 vs. 256 fold with the characteristic of interest; total No. subjects with antibody response
Diarrhea: 1/10 (10) vs. 0/3 vs. 9/15 (60) vs. 11/17 (65) vs. 3/5 (60); 24/50 (59); p value=NS
Vomiting: 0 vs. 0 vs. 4 (27) vs. 9 (53) vs. 3 (60); 16 (39); p value=0.02
Nausea: 1 (10) vs. 0 vs. 10 (67) vs. 13 (76) vs. 4 (80); 27 (66); p value≤0.02
Cramps: 0 vs. 1 (33) vs. 10 (67) vs. 12 (71) vs. 4 (80); 27 (66) ; p value=NS
Headaches/body aches: 4 (40) vs. 0 vs. 11 (73) vs. 12 (71) vs. 4 (80); 27 (66); p value=0.04
Chills: 0 vs. 0 vs. 4 (27) vs. 5 (29) vs. 1 (20); 10 (24); p value=0.08
Fever: 0 vs. 0 vs. 3 (20) vs. 3 (18) vs. 3 (60); 9 (22) ; p value=NS
 
Antigen vs. antibody detection
All results: Patients with given clinical scores who had the following antigen response/antibody response (+/+ vs -/+ vs +/- vs. -/-)
Clinical score 0-2 (uninfected): 0 vs 0 vs 0 vs 9
Clinical score 0 (asymptomatic infection): 4 vs 4 vs 0 vs 0
Clinical score 1-4 (mild symptomatic infection): 4 vs 1 vs 0 vs 0
Clinical score 5-24: 26 vs 1 vs 1 vs 0
Total: 34 vs 6 vs 1 vs 9
 
Antibody detection may be more sensitive than antigen detection
ELISA to detect norovirus specific antibodies and antigen in stool. Biotin-avidin ELISA, RIA, RT-PCR, and dot blot hybridization to detect antigen in stool.
 
Norovirus infection defined as ≤ 4 fold increase in serum antibody titer or excretion of virus.
 
Diarrhea defined as watery stools (unformed stools not considered diarrhea).
 
Asymptomatic infection defined as no vomiting or diarrhea and a symptom score of ≤4 in an infected subject.
 
Symptomatic infection defined as a composite symptom score of ≥ 5 in an infected subject. Patients who vomited or had diarrhea had symptomatic infection.
 
Subjects divided into 5 groups:
Group 1 - uninfected
Group 2 - asymptomatic or mildly symptomatic (no vomiting or diarrhea)
Group 3 - symptomatic (vomiting but no diarrhea)
Group 4 - symptomatic (no vomiting but watery diarrhea)
Group 5 - symptomatic (vomiting and watery diarrhea)
 
Clinical scores: symptoms were graded using a 5 point score with 0 (absence of symptom) and 5 (most severe iscomfort with symptom). Compositescores tabulated for 72 hour period after inoculation (maximum score 35).
 
Power and sample size not reported.
1563_IL
Nakata, S; 1985 75 Prospective controlled study
 
1,2,3
To determine if clinical illness correlates with pre-existing CaCV serum antibody. Human CaCV outbreak in a Japanese orphanage during October 1982.
 
41
Symptomatic infection
Preexisting serum CaCV antibody – present 3/18 vs. absent 18/23; p<0.01
All patients except one, who only had vomiting, had diarrhea.
 
Power and sample size not reported.
1960_IL
Parrino, TA; 1977 76 Prospective controlled study
 
1,2,3,4,5
To examine immunity in viral gastroenteritis. Male volunteers, 30-47 years of age, were challenged with Norwalk virus and had symptoms, jejunal biopsies, and serum antibodies evaluated.
 
12
Baseline
All subjects had normal baseline biopsy samples.
 
First challenge
6/12 developed gastroenteritis.
4/5 symptomatic volunteers who had antibody levels checked had increase in serum Norwalk antibodies that waned over time.
3/3 asymptomatic patients who had antibodies checked did not have increase in serum antibody.
3/5 symptomatic volunteers had abnormal biopsies.
2/5 asymptomatic volunteers had normal biopsies.
 
Second challenge (27-42 months later)
6/12 who were symptomatic after the first challenge were symptomatic again with jejunal lesions after the second challenge. 6/12 who were previously asymptomatic were asymptomatic without jejunal lesions.
3/3 asymptomatic patients who had antibody levels checked did not have increase in serum antibody.
 
Third challenge
Only performed in 4/6 volunteers who twice became symptomatic; 4-8 weeks after second challenge
1 was symptomatic.
3 were asymptomatic.
Patients were considered clinically ill if they had vomiting and/or diarrhea with one or more associated signs and symptoms. Two investigators characterized subjects as clinically ill without knowledge of serologies or small bowel biopsy results.
 
Two investigators characterized subjects without knowledge of serologic findings and prior to biopsy results.
 
Immune-electronmicroscopy technique was performed for measurement of Norwalk serum antibody using the 8FIIa Norwalk filtrate as antigen.
 
Power and sample size not reported.
2228_IL
Fretz, R; 2005 77 Retrospective controlled study
 
1,2,3,6,7
To identify risk factors for sporadic norovirus infections. All patients of general practitioners in German-speaking parts of Switzerland. Cases (mean age 32.7 years; median age 34 years; range 1.1-69.3 years) were subjects who resided in the study area who had an episode of diarrhea and/or vomiting, consulted a practitioner in the study area, had stool samples negative for Campylobacter, Shigella, Salmonella, and other gastroenteric pathogens, had stool samples positive for norovirus genogroup I or II. Cases excluded subjects <6 months or >75 years, patients with possible nosocomial disease, and patients who were part of a norovirus outbreak.
 
Controls (mean age 33.2 years; median age 37.1 years; range 1.3-70.1 years) were identified through each patient, were the same sex and age group (defined as 5 year intervals over 5-20 years and 10 year intervals over 20-60 years), lived within 10 kilometer (km) of the case, and had not consulted a general practitioner for gastrointestinal illness or symptoms in the month prior to the questionnaire.
 
126 cases met study inclusion criteria. 73 matched case-control pairs
Symptoms (study duration 2 years)
Diarrhea - 124/126 (98.4%).
Vomiting – 84/126 (66.7%).
Nausea – 85/126 (67.5%)
Fever – 57/126 (45.2%)
Headache – 45/126 (35.7%)
Abdominal cramps – 87 (69%)
Other – 46 (36.5%)
 
Mean duration of symptomatic illness
7.3 days (SD, 6.2 days; range 0.25-28 days)
 
Symptomatic norovirus infection
Multivariable analysis
Consumption of food and beverages OR (95% CI); p value
Mineral water – 1.00 (0.46-2.16); 1.00
Salad – 1.25 (0.34-2.65); 0.74
Raw berries – 0.75 (0.17-3.35); 0.71
Tap water – 1.33 (0.56-3.16); 0.51
Sweet beverages – 1.06 (0.55-2.05); 0.87
 
Personal contacts OR (95% CI); p value
Household with children ≤2 years) – 1.00 (0.29-3.45); 1.00
Household with children ≤ 5 years – 0.75 (0.26-2.16); 0.59
Household with children ≤ 10 years – 0.75 (0.26-2.16): 0.59
Household with children ≤ 65 years – 0.75 (0.17-3.35); 0.71
Household with children > 1 person – 1.50 (0.53-4.21); 0.44
Household with children > 2 person – 0.77 (0.34-1.75); 0.53
Household with children > 3 person – 0.71 (0.32-1.61); 0.53
Household with children > 4 person – 1.14 (0.41-3.15); 0.53
 
Symptomatic norovirus infection
ABO histo-blood group OR (95% CI); p value - conditional logistic regression
Type A: 1.34 (0.55-3.42); 0.49
Type B: 0.33 (0.07-1.65); 0.15
Type O: 1.00 (0.40-2.52); 0.49
Type AB: 1.50 (0.25-8.98); 0.65
Type A/AB: 1.44 (0.62-3.38); 0.39
Type B/AB: 0.63 (0.20-1.91); 0.40
 
Symptomatic norovirus infection
ABO histo-blood group OR (95% CI); p value – random effects logistic regression
Type A: 1.20 (0.55-2.61); 0.64
Type B: 0.28 (0.07-1.13); 0.07
Type O: 1.11 (0.51-2.45); 0.79
Type AB: 1.89 (0.35-10.2); 0.46
Type A/AB: 1.39 (0.64-3.00); 0.40
Type B/AB: 0.59 (0.21-1.70); 0.32
Power and sample size reported as 70 matched case-control pairs to detect an OR of 2.9 (alpha 0.05; power 0.80; 0.5 probability of an event in the exposed group). Period between the start of symptoms and completion of the patient questionnaire averaged 29 days (median 24 days). 506_IL
Meyer, E; 2004 78 Retrospective controlled study
 
1,2,3,4
To determine if O phenotype is more commonly found in patients from norovirus outbreaks compared to blood donors. Cases were subjects with vomiting, nausea, and/or diarrhea from two nosocomial norovirus outbreaks at a German university hospital. Controls were blood donors in Southwest Germany.
 
95 cases and 45 controls.
Symptomatic norovirus infection
% blood donors vs. % outbreaks with particular ABO phenotype; p value
Type O – 41.2 vs. 22; 0.01
Type A – 43.3 vs 58; 0.52
Type B – 10.7 vs 11; 1.00
Type AB – 4.8 vs 9; 0.34
Power and sample size not reported. 729_IL

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