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Vitamin A Supplementation Has Divergent Effects on Norovirus Infections and Clinical Symptoms among Mexican Children

  1. Kurt Z. Long1,a,
  2. Coralith García3,4,6,
  3. Jose I. Santos7,
  4. Jorge L. Rosado8,
  5. Ellen Hertzmark2,
  6. Herbert L. DuPont3,4,5 and
  7. GwangPyo Ko9
  1. 1Department of Nutrition, Boston, Massachusetts
  2. 2Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
  3. 3School of Public Health, University of Texas, Lima, Perú
  4. 4Baylor College of Medicine, Lima, Perú
  5. 5St. Luke's Episcopal Hospital, Houston, Lima, Perú
  6. 6Instituto de Medicina Tropical “Alexander von Humboldt,” Universidad Peruana Cayetano Heredia, Lima, Perú
  7. 7Hospital Infantil de México “Federico Gómez,” México City, México
  8. 8>Division of Nutrition, Universidad de Querétaro, Querétaro, México
  9. 9Institute of Health and Environment, Department of Environmental Health, School of Public Health, Seoul National University, Seoul, South Korea
  1. Reprints or correspondence: Dr. Kurt Z. Long, Div. of International and Indigenous Health, School of Population Health, University of Queensland, Herston Rd., Herston, Brisbane, Queensland 4006 Australia (k.long{at}uq.edu.au).

  1. Presented in part: Experimental Biology 2006, San Francisco, 2–6 April 2006 (abstract 399).

 
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Abstract

Background. The effect of vitamin A supplementation on viral gastrointestinal infections among young children living in developing countries remains unclear.

Methods. The effect of vitamin A supplementation on norovirus (NoV) infection among 127 Mexican children 5–15 months of age was studied in a randomized, placebo-controlled trial during June-August 1998. Stool samples collected every 2 weeks and after diarrheal episodes were screened for NoV and characterized at the genogroup level (GI and GII).

Results. Of the stool samples collected, 29.9% were positive for NoV, and NoV GI and NoV GII were found in 55.4% and 46.4% of the positive samples, respectively. Vitamin A supplementation reduced the prevalence of NoV GII infections (rate ratio [RR], 0.60 [95% confidence interval {CI}, 0.20–0.82]), increased the length of both NoV GI and GII shedding, and decreased the prevalence of NoV-associated diarrhea (RR, 0.51 [95% CI, 0.26–0.97]).

Conclusions. These findings suggest that NoV is an important cause of pediatric diarrhea in this study population and that vitamin A supplementation has divergent effects on specific outcomes of NoV infection.

Randomized clinical trials evaluating the benefits of vitamin A supplementation with respect to infectious disease outcomes among children in developing countries have generally not examined etiology-specific outcomes. Diarrhea, for example, is analyzed as a single outcome even though it is caused by an extensive and diverse group of bacterial, viral, and protozoan pathogens that initiate pathogenesis through distinct mechanisms [1]. The effect of vitamin A supplementation on pathogen-specific immune responses may also vary, with supplementation up-regulating the humoral response but down-regulating the cell-mediated and inflammatory responses [2, 3]. Grouping together etiologically distinct diarrheal episodes may ignore the diverse effects that supplementation has on pathogenspecific immune responses and clinical outcomes and may confound associations between vitamin A supplementation and diarrheal disease. This possibility may explain why vitamin A has not been found to have a consistent effect on the incidence of diarrheal disease [4–6].

Norovirus (NoV), which belongs to the Caliciviridae family, is now recognized as the leading cause of epidemic and endemic nonbacterial gastroenteritis. In industrialized countries, NoV may be responsible for 68%–93% of nonbacterial gastroenteritis outbreaks [7–9]. Studies in developing countries have shown that NoV is a major nonbacterial pathogen that causes acute diarrhea in children [10–12]. It is also an important cause of traveler's diarrhea among students fromthe United States visiting Mexico during the summer diarrheal season [13]. To date, no studies have examined the effect vitamin A may have on NoV, either in the laboratory or in clinical trials.

NoVs can be divided into 5 genogroups (GI-GV), of which GI and GII cause the majority of infections in humans [14]. Each genogroup is further divided into genotypes or genetic clusters [15]. The T cell component of the immune response after challenge with NoV is weighted more toward a Th1 response, with increases in interferon (IFN)-γ and interleukin (IL)-2 production [16].

The immune regulatory effects of vitamin A led us to hypothesize that vitamin A supplementation would be associated with reductions in noninvasive infections with gastrointestinal pathogens involving a protective humoral immune response and would have a negative or minimal effect against invasive infections involving a protective cell-mediated response. To address this hypothesis, we conducted a randomized, placebocontrolled, double-blind trial of the effect of vitamin A supplementation on infections with diarrheal pathogens among children from marginalized periurban communities of Mexico City, Mexico, between January 1998 and March 1999. We report here the effect of supplementation on NoV infection during the summer months of the study. NoV is an important cause of summer diarrhea among travelers to Mexico and may be an important cause of pediatric diarrhea in this population [13, 17].

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SUBJECTS, MATERIALS, AND METHODS

Study population. A census was done for all children <2 years of age living within 9 neighborhoods (colonias) that are part of the community of La Magdalena Atlicpac, which is located along the eastern perimeter of Mexico City. Mothers of all children from 5 to 15 months of age were invited to participate in the study, as described elsewhere [18, 19]. Children were excluded if they had diseases that caused immunosuppression or any congenital or acquired alteration of the digestive tract (such as chronic diarrhea) that could alter the absorption of micronutrients. Children who were taking vitamin supplements were also excluded. For the overall study, 200 children living in this community were identified and enrolled over a 10- month period beginning in January 1998, after their parents consented to their participation.

Study design. On enrollment, each child was randomly assigned to receive vitamin A or a placebo by use of a randomized sequence generated by an epidemiologist at the National Institute of Public Health. Children <12 months of age in the vitamin A group were administered a solution containing 20,000 IU of retinol (3.3 IU is equivalent to the activity of 1 mg of retinol) at baseline and every 2 months thereafter, and children ⩾12 months of age received a solution containing 45,000 IU of retinol. Testing and preparation of the placebo and vitamin A solutions were done by personnel at the National Institute of Nutrition, to ensure similarity in taste, viscosity, and color and to assure that the field personnel and principal investigator were unaware of the regimens. The field team was in charge of administering the supplements and placebos to children from identical opaque plastic droplet bottles.

During the baseline visit, information was collected regarding the number of household members; their ages, education level, and income; household water sources and sanitation facilities; and household possessions. Information was also collected during the first visit to determine the child's feeding and weaning patterns as well as occurrences of morbidity during the previous 2 weeks. A previously validated questionnaire was used in the collection of these data by project personnel who had received training in its application.

Recruited children were followed up prospectively for up to 15 months from January 1998 until March 1999, during which time households were visited twice a week. At each visit, mothers or caretakers of children were interviewed to determine the presence of the following symptoms: diarrhea, the number and consistency of evacuations, the presence of blood and mucus in stool, fever, cough, and respiratory difficulty. A stool sample was collected twice a month among healthy children, and up to 3 stool samples were collected during a week beginning with a diarrheal episode. Project supervisors accompanied project personnel at ∼5% of all household visits to ensure quality of data collection. Children were referred to the study physician for diagnosis and treatment when field-workers or caregivers were concerned about the child's health status.

Identification of NoV in stools. The analysis of the effect of vitamin A supplementation on NoV infection was restricted to children monitored during the summer months (June through August) of 1998. A previous study by Ko et al. [13] suggested that NoV infections are an important cause of traveler's diarrhea during the summer and so may also be an important cause of pediatric diarrheal episodes that peak during this season [20]. Fresh stool samples collected from children during the summer months were placed in sealed test tubes on ice and then frozen within 4 h of their collection at -20°C. NoV was detected by reverse-transcriptase polymerase chain reaction (RT-PCR) [13]. Viral RNA was extracted from 140 µL of a 10% stool suspension by a spin column technique, in accordance with the instructions in the QIAamp Viral RNA Mini Kit handbook (Qiagen). Viral RNA was assayed in a generic RT-PCR with 2 sets of primers, G1SKF/G1SKR and G2SKF/G2SKR, to detect the capsid region of NoV GI and GII, respectively [21]. Viral RNA was reverse transcribed for 60 min at 42°C, followed by 15 min at 95°C to activate the Taq polymerase. Thermocycling conditions for PCR consisted of 40 cycles of 1 min at 94°C, 1 min at 40°C, and 1 min at 72°C, with a final extension for 10 min at 72°C. Amplified products were analyzed on ethidium bromide-stained 2% agarose gels. To prevent any possible cross-contamination, standard operating procedures were strictly adhered to for RT-PCR, as described elsewhere [17]. All RT-PCR products positive for NoV were purified by use of the QIAquick PCR Purification Kit (Qiagen), in accordance with the manufacturer's protocol, and were then sequenced on an ABI 3730XL sequencer by a commercial company (SeqWright). Stool samples were also screened for enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli (ETEC), Shiga toxin-producing E. coli, enteroinvasive E. coli, and Giardia lamblia.

Outcome definitions. The primary end points for the study were the prevalence of infections with the 2 genogroups, NoV GI and GII, and the duration of NoV shedding during the summer months of June, July, and August. Secondary outcomes were the prevalence and duration of diarrhea and fever episodes associated with infections. A NoV infection was defined as a NoV-positive stool sample. Duration of shedding was defined as the time between the first and last sequentially collected stool samples positive for NoV. A diarrheal episode was defined as a mother's reporting of symptoms in a child, confirmed by the passage of 3 or more liquid stools in 1 day. Episodes of fever or diarrhea were considered to be associated with NoV if the episode occurred within 7 days (before or after) of the collection of a positive stool sample. Duration of a diarrheal episode was defined as the number of reported days of diarrhea in a child preceding 3 or more symptom-free days.

Statistical analysis. Stool samples collected from children monitored during the summer months were used in this analysis. Rate ratios (RRs) for NoV prevalence among all children randomized to the 2 groups were first estimated by fitting Poisson regression models to counts of NoV-positive stool samples. RRs for the prevalence of NoV-associated diarrhea and fever were estimated by fitting Poisson regression models to counts of diarrhea and fever episodes among children with NoV-positive stool samples [22]. The duration of pathogen shedding and pathogen-associated diarrhea was then compared between the 2 groups by use of parametric regression survival-timemodels with a Weibull distribution. Variables for age, breast-feeding status, and coinfections with EPEC, ETEC, and G. lamblia were included in the model, to control for the modifying effect that they may have on associations between vitamin A supplementation and each analyzed outcome. Statistical significance was set at a probability level of <.05 and <.1 for interactions. The GENMOD and LIFEREG procedures from SAS software (version 8.2; SAS Institute) were used in the Poisson regression and hazard analyses, respectively.

Sample sizes for the original study were calculated on the basis of the assumption that the study population has a diarrheal disease rate of 3 episodes/child/year and that the vitamin A supplement would reduce this rate by ∼20%, as reported by Barreto et al. [6] in their vitamin A trial in Brazil. A sample size of 100 per group was calculated as being necessary to detect a 20% difference between the control and treatment group, with a power of 80%, a significance level of 95%, and an expected loss to follow-up of 20%.

The study was approved by the ethical review committees of the National Center for the Health of Infants and Adolescents of Mexico and the Harvard School of Public Health.

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RESULTS

In the overall study, 188 children were monitored for up to 15 months [18]. A total of 127 children enrolled in this larger community trial were included in the analysis of NoV infections restricted to the summer months (June through August) of 1998. The distribution of sociodemographic characteristics of study children and households was similar between children in the vitamin A and placebo groups (table 1). Forty-two to 45 percent of households had no access to piped water, ∼65% had no indoor toilets, and 25%–30% of children were stunted at baseline. The duration of follow-up for children in the 2 treatment groups was similar (mean ± SE, 11.5 ± 5.5 months for the vitamin A group and 11.9 ± 5.6 months for the placebo group; P = .56). Of the planned 1120 doses of vitamin A or placebo, 1035 were given by project personnel to study for a compliance rate of 92%.

Figure 1.
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Figure 1.

Duration of norovirus (NoV) infections and diarrheal episodes, by treatment arm. Shown are cumulative hazard functions for duration of NoV infections in children in the vitamin A (dashed line) and placebo (solid line) groups. A, NoV genogroup 1 (GI) infections; B, NoV genogroup 2 (GII) infections; C, NoV GI-associated diarrheal episodes; D, NoV GII-associated diarrheal episodes. Shorter or longer infections and episodes are associated with higher or lower cumulative hazards, respectively.

Table 1.
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Table 1.

Socioeconomic characteristics of the study children and households during the summer months (June through August) of 1998.

NoV was isolated from 114 (30.5%) of 374 stool samples collected during the summer months. NoV GI and NoV GII were found in 62 (54.4%) and 52 (45.6%) of the 114 positive samples, respectively. Twenty-five (21.9%) of the 114 NoVpositive samples had coinfections: 7 (6.1%) were coinfected with EPEC, 10 (8.8%) with ETEC, and 7 (6.1%) with G. lamblia. In the Poisson regression analysis, vitamin A supplementation was associated with reductions in the prevalence of NoV GII infections (RR, 0.51 [95% confidence interval {CI}, 0.27–0.97]) (table 2). There was no association between supplementation and the prevalence of NoV GI infections or all NoV infections.

Table 2.
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Table 2.

Impact of vitamin A supplementation on the prevalence of norovirus (NoV) infections.

The effect of vitamin A supplementation on the duration of shedding of NoV GI, NoV GII, and all NoV combined was determined by fitting parametric regression models to the measured durations. In this analysis, children who received vitamin A supplementation had significantly longer durations of all NoV shedding and the shedding of GI and GII than did children in the placebo group (mean ± SE, 7.11 ± 0.54 vs. 4.26 ± 0.22, 5.87 ± 0.51 vs. 3.08 ± 0.21, and 12.85 ± 3.12 vs. 5.24 ± 1.16 days, respectively) (table 3 and figure 1). The lower values for the cumulative hazard among children in the vitamin A group relative to children in the placebo group (illustrated in figure 1) indicates that there is a lower probability that the shedding of NoV GI and GII will end in the former group than in the latter group.

Table 3.
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Table 3.

Impact of vitamin A supplementation on duration of norovirus (NoV) shedding.

Thirty-seven (33.0%) of 112 NoV infections were associated with an episode of diarrhea. Twenty-two (35.5%) of 62 NoV GI infections and 12 (23.1%) or 52 NoV GII infections were associated with diarrheal episodes. Children in the vitamin A group had a significantly decreased incidence of all NoV-associated diarrheal disease and diarrhea associated with GI and GII infections (RR, 0.51 [95% CI, 0.26–0.97], 0.53 [95% CI, 0.30–0.96], and 0.38 [95% CI, 0.14–1.02], respectively) (table 5 and figure 1).

Table 4.
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Table 4.

Impact of vitamin A supplementation on the prevalence of norovirus (NoV)-associated diarrhea and fever.

Table 5.
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Table 5.

Impact of vitamin A supplementation on duration of norovirus (NoV)-associated diarrheal episodes.

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DISCUSSION

The present study provides unique information about the epidemiology of NoV infection and the effect that vitamin A supplementation has on this infection among children living in periurban communities of Mexico City. First, we have found a high prevalence of NoV infections during the summer months. Second, we have found divergent effects of vitamin A supplementation on NoV-associated outcomes, with supplementation reducing the rate of NoV GII infection only but increasing the duration of shedding of overall and genogroupspecific NoV. Supplementation was also associated with a decrease in rates and durations of overall and genogroup-specific NoV-associated diarrhea. To our knowledge, this study is the first to report on the relationship between vitamin A supplementation and NoV infection.

Community-based studies in both industrialized and developing countries have established that NoV is an important cause of endemic gastroenteritis [23, 24]. Farkas et al. [25] reported that ∼19% and 8% of diarrheal stool specimens and nondiarrheal stool specimens, respectively, collected from a cohort of children were positive for calicivirus in periurban communities of Mexico City. Virus exposure can occur early during childhood in developing countries in which there is poor sanitation, as is reflected by the high prevalence of serum antibody to NoV [12, 26, 27]. In our study, ∼30% of all stool samples collected from children were positive for NoV and, of these, 33% were associated with an episode of diarrhea. Approximately 55% of the isolates obtained were NoV GI, whereas ∼46% were NoV GII. These findings are surprising, because high rates of NoV infection or shedding are typically not found during the summer months and because a majority of studies have reported that NoV GII is the predominant genogroup [28]. However, recent studies have identified summer peaks of NoV-related illness and have suggested that winter outbreaks are restricted more to health care institutions [29–31]. Similarly, strains belonging to different genogroups can cycle through a population and, thus, be predominate at different periods [32]. Parks et al. [33] have, in fact, found a greater number of NoV GI strains than GII strains in their study conducted in periurban communities of northeastern Brazil.

No comparable studies have evaluated the effect of vitamin A supplementation on NoV-associated health outcomes. However, the role the innate and adaptive immune responses play in NoV infection and the reported effects of vitamin A on these responses may provide insight into our results. Studies have shown that infected individuals develop short-term systemic IgG and fecal IgA immunity to homologous virus [34–36]. Lindesmith et al. [16], for example, reported that the IgG elicited in response to Snow Mountain virus, a genogroup 2 NoV, after challenge is cross-reactive to other NoV GII strains but not to GI strains. The T cell response was weighted more toward a Th1 response, with increases in IFN-γ, IL-2, and serum IgG1 production. However, there also was a significant increase in IL-5 production, a marker for the Th2 response. A strictly serum Th1 response with IFN-γ production was reported after the administration of Norwalk virus-like particles to volunteers [36, 37]. A predominant Th1 intestinal immune response with increased IL-2 and IFN-γ was also found among travelers infected with NoV, but a mixed Th1/Th2 response was found when coinfections with ETEC were present [38]. A mixed Th1/ Th2 response was also found after the administration of recombinant GII virus-like particles to mice along with the ETEC heat-labile toxin as an adjuvant [35].

Vitamin A status has been shown to have a number of immune effects relevant to the present study. Vitamin A deficiency is associated with reduced cytotoxic activity of NK spleen cells [39], reduced T lymphocyte proliferation and functionality [40], and a reduced response to specific antigens [41]. Vitamin A deficiency also induces a polarized Th1 response, whereas retinoid treatment up-regulates a Th2 response [2]. These findings would appear to not support our findings that supplementation reduced the prevalence of NoV GII infections given the more-dominant Th1 response produced after NoV infections. However, a Th2 response may protect against NoV infection as well, given the significant increase in IL-5 production reported by Lindesmith et al. [16]. IL-5 is important in the up-regulation of mucosal IgA production by B lymphocytes and so may be involved in the prevention of NoV infection [42]. The up-regulation of the Th2 response may explain why children receiving vitamin A had increased lengths of NoV shedding, given that a Th1 response may be more important for eliminating viral infections.

The decrease in the rate and duration of diarrheal symptoms among children receiving vitamin A supplementation may result from the down-regulation of the Th1 and inflammatory responses. We previously reported that vitamin A supplementation is associated with reductions in fecal monocyte chemoattractant protein-1 levels, a chemokine that is involved in the inflammatory response and the up-regulation of the Th1 response [43]. This effect may have reduced the gastrointestinal inflammatory response and the onset of symptoms in the children who received vitamin A supplementation.

Currently, there are no studies that might explain the intriguing finding that the effect of vitamin A supplementation is specific to NoV GII. Susceptibility to specific NoV strains, determined by the ability of these strains to bind to specific human histoblood group antigens (HBGAs), may offer one explanation. The different binding abilities might lead to qualitatively distinct immune responses to each strain [44, 45]. However, it remains to be seen whether these HBGA-binding profiles correlate with genetic clusters within a NoV genogroup [46]. There is evidence that IgG and cytokine responses to one NoV GII strain cross-react with other GII strains but not to GI strains [47, 48]. The generation of these distinct responses may be differentially regulated by vitamin A and so underlie the genogroup-specific effect of vitamin A supplementation found in our study. We have found that vitamin A supplementation has a very different effect on specific cytokines after infection with these 2 genogroups (K.Z.L., unpublished data).

One limitation of the present study is that we have no indicators of the children's vitamin A status, because no blood samples were collected from children. Differences in the initial status of study children could determine the effectiveness of supplementation. A probabilistic national survey conducted in Mexico has shown that overt and subclinical vitamin A deficiency among children living in Mexico City is minimal but that low levels of serum retinol are prevalent [49]. A second limitation may have been that the study was not sufficiently powered to address the genogroup-specific effect of vitamin A supplementation. However, that the effects associated with vitamin A supplementation were restricted to GIIassociated outcomes only suggests that this may not be such an important issue.

We have found that vitamin A supplementation produces divergent outcomes for genogroup-specific NoV infections and clinical symptoms among Mexican children. We have argued that these outcomes are the result of the differential regulation of the innate and adaptive immune responses by vitamin A, each of which plays a distinct role in these specific outcomes. If our findings are confirmed, public health efforts to reduce NoV infections through the development of new vaccines may optimally be coordinated with vitamin A supplementation programs to maximize the beneficial effects of supplementation on specific NoV genogroups.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: Instituto de Nutrición Danone, CONACYT (National Council of Science and Technology of Mexico); National Institutes of Health (grant K01 DK06142-02); University of Texas Health Science Center (unrestricted grant); Korea Research Foundation (grant E00080 to GP.K.).

  • ↵a Present affiliation: Division of International and Indigenous Health, School of Population Health, University of Queensland, Brisbane, Australia.

  • Received January 17, 2007.
  • Accepted March 14, 2007.
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References

  1. 1.↵
    1. Evans AS,
    2. Brachman PS
    1. DuPont HL,
    2. Mathewson JJ
    . JJ. Escherichia coli diarrhea. In: Evans AS, Brachman PS, editors. Bacterial infections of humans: epidemiology and control. 3rd ed. New York: Plenum Medical Book; 1998. p. 269-83.
  2. 2.↵
    1. Cantorna MT,
    2. Nashold E,
    3. Hayes C
    . Vitamin A deficiency results in a priming environment conducive for Th1 cell development. Eur J Immunol 1995;25:1673-9.
    MedlineWeb of Science
  3. 3.↵
    1. Kim BH,
    2. Kang KS,
    3. Lee YS
    . Effect or retinoids on LPS-induced COX- 2 expression and COX-2 associated PGE2 release from mouse peritoneal macrophages and TNF-alpha release from rat peripheral blood mononuclear cells. Toxicol Lett 2004;150:191-201.
    CrossRefMedlineWeb of Science
  4. 4.↵
    1. Dibley MJ,
    2. Sadjimin T,
    3. Kjolhede CL,
    4. Moulton LH
    . Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. J Nutr 1996;126:434-42.
    Abstract/FREE Full Text
  5. 5.
    1. Ramakrishnan U,
    2. Latham MC,
    3. Abel R,
    4. Frongillo EA Jr.
    . Vitamin A supplementation and morbidity among preschool children in south India. Am J Clin Nutr 1995;61:1295-303.
    Abstract/FREE Full Text
  6. 6.↵
    1. Barreto ML,
    2. Santos LM,
    3. Assis AM,
    4. et al
    . Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Lancet 1994;344:228-31.
    CrossRefMedlineWeb of Science
  7. 7.↵
    1. Fankhauser RL,
    2. Monroe SS,
    3. Noel JS,
    4. et al
    . Epidemiologic and molecular trends of “Norwalk-like viruses” associated with outbreaks of gastroenteritis in the United States. J Infect Dis 2002;186:1-7.
    Abstract/FREE Full Text
  8. 8.
    1. Hedlund KO,
    2. Rubilar-Abreu E,
    3. Svensson L
    . Epidemiology of calicivirus infections in Sweden, 1994–1998. J Infect Dis 2000;181 (Suppl 2):S275-80.
    CrossRefMedline
  9. 9.↵
    1. Koopmans M,
    2. Vinj J,
    3. de Wit M,
    4. Leenen I,
    5. van der Poel W,
    6. van Duynhove Y
    . Molecular epidemiology of human enteric caliciviruses in The Netherlands. J Infect Dis 2000;181 (Suppl 2):S262-9.
    CrossRefMedlineWeb of Science
  10. 10.↵
    1. Phan TG,
    2. Okame M,
    3. Nguyen TA,
    4. et al
    . Human astrovirus, norovirus (GI, GII), and sapovirus infections in Pakistani children with diarrhea. J Med Virol 2004;73:256-61.
    CrossRefMedlineWeb of Science
  11. 11.
    1. Subekti D,
    2. Lesmana M,
    3. Tjaniadi P,
    4. et al
    . Incidence of Norwalk-like viruses, rotavirus and adenovirus infection in patients with acute gastroenteritis in Jakarta, Indonesia. FEMS Immunol Med Microbiol 2002;33:27-33.
    MedlineWeb of Science
  12. 12.↵
    1. Talal AH,
    2. Moe CL,
    3. Lima AAM,
    4. et al
    . Seroprevalence and seroincidence of Norwalk-like virus infection among Brazilian infants and children. J Med Virol 2000;61:117-124.
    CrossRefMedlineWeb of Science
  13. 13.↵
    1. Ko G,
    2. Garcia C,
    3. Jiang ZD,
    4. et al
    . Noroviruses as a cause of traveler's diarrhea among students from the United States visiting Mexico. J Clin Microbiol 2005;43:6126-9.
    Abstract/FREE Full Text
  14. 14.↵
    1. Vinje J,
    2. Green J,
    3. Lewis DC,
    4. Gallimore CI,
    5. Brown DW,
    6. Koopmans MP
    . Genetic polymorphism across regions of the three open reading frames of “Norwalk-like viruses”. Arch Virol 2000;145:223-41.
    CrossRefMedlineWeb of Science
  15. 15.↵
    1. Atmar RL,
    2. Estes MK
    . Diagnosis of noncultivatable gastroenteritis viruses, the human caliciviruses. Clin Microbiol Rev 2001;14:15-37.
    Abstract/FREE Full Text
  16. 16.↵
    1. Lindesmith L,
    2. Moe C,
    3. Lependu J,
    4. Frelinger JA,
    5. Treanor J,
    6. Baric RS
    . Cellular and humoral immunity following Snow Mountain virus challenge. J Virol 2005;79:2900-9.
    Abstract/FREE Full Text
  17. 17.↵
    1. Garcia C,
    2. DuPont HL,
    3. Long KZ,
    4. Santos JI,
    5. Ko G
    . Asymptomatic norovirus infection in Mexican children. J Clin Microbiol 2006;44:2997-3000.
    Abstract/FREE Full Text
  18. 18.↵
    1. Long KZ,
    2. Santos JI,
    3. Rosado JL,
    4. et al
    . Impact of vitamin A on selected gastrointestinal pathogen infections and associated diarrheal episodes among children in Mexico City, Mexico. J Infect Dis 2006;194:1217-25.
    Abstract/FREE Full Text
  19. 19.↵
    1. Long KZ,
    2. Estrada T,
    3. Santos JI,
    4. et al
    . The impact of vitamin A supplementation on the intestinal immune response in Mexican children is modified by pathogen infections and diarrhea. J Nutr 2006;136:1365-70.
    Abstract/FREE Full Text
  20. 20.↵
    1. Long KZ,
    2. Rosado JL,
    3. DuPont HL,
    4. Hertzmark E,
    5. Santos JI
    . Supplementation with vitamin A reduces watery diarrhea and respiratory infections in Mexican children. Br J Nutr 2007;97:337-43.
    CrossRefMedlineWeb of Science
  21. 21.↵
    1. Kojima S,
    2. Kageyama T,
    3. Fukushi S,
    4. et al
    . Genogroup-specific PCR primers for detection of Norwalk-like viruses. J Virol Methods 2002;100:107-14.
    CrossRefMedlineWeb of Science
  22. 22.↵
    1. Gardner W,
    2. Mulvey EP,
    3. Shaw E
    . Regression analyses of counts and rates: Poisson, overdispersed Poisson, and negative binomial models. Psychol Bull 1995;118:392-404.
    CrossRefMedlineWeb of Science
  23. 23.↵
    1. de Wit MA,
    2. Koopmans MP,
    3. Kortbeek LM,
    4. et al
    . Sensor, a populationbased cohort study on gastroenteritis in The Netherlands: incidence and etiology. Am J Epidemiol 2001;154:666-74.
    Abstract/FREE Full Text
  24. 24.↵
    1. Gabbay YB,
    2. Glass RI,
    3. Monroe SS,
    4. et al
    . Prevalence of antibodies to Norwalk virus among Amerindians in isolated Amazonian communities. Am J Epidemiol 1994;139:728-33.
    Abstract/FREE Full Text
  25. 25.↵
    1. Farkas T,
    2. Jiang X,
    3. Guerrero ML,
    4. et al
    . Prevalence and genetic diversity of human caliciviruses (HuCVs) in Mexican children. J Med Virol 2000;62:217-23.
    CrossRefMedlineWeb of Science
  26. 26.↵
    1. Jiang X,
    2. Matson DO,
    3. Velazquez FR,
    4. et al
    . Study of Norwalk-related viruses in Mexican children. J Med Virol 1995;47:309-16.
    MedlineWeb of Science
  27. 27.↵
    1. Matsui SM,
    2. Greenberg HB
    . Immunity to calicivirus infection. J Infect Dis 2000;181(Suppl 2):S331-5.
  28. 28.↵
    1. Mounts AW,
    2. Ando T,
    3. Koopmans M,
    4. Bresee JS,
    5. Noel J,
    6. Glass RI
    . Cold weather seasonality of gastroenteritis associated with Norwalk-like viruses. J Infect Dis 2000;181(Suppl 2):S284-7.
  29. 29.↵
    1. Boga JA,
    2. Melon S,
    3. Nicieza I,
    4. et al
    . Etiology of sporadic cases of pediatric acute gastroenteritis in asturias Spain and genotyping and characterization of norovirus strains involved. J Clin Microbiol 2004;42:2668-74.
    Abstract/FREE Full Text
  30. 30.
    1. Lopman BA,
    2. Reacher M,
    3. Gallimore C,
    4. Adak GK,
    5. Gray JJ,
    6. Brown DW
    . A summertime peak of “winter vomiting disease”: surveillance of noroviruses in England and Wales 1995 to 2002. BMC Public Health 2003;3:13.
    CrossRefMedline
  31. 31.↵
    1. Lopman BA,
    2. Adak GK,
    3. Reacher MH,
    4. Brown DW
    . Two epidemiologic patterns of norovirus outbreaks: surveillance in England and Wales 1992–2000. Emerg Infect Dis 2003;9:71-7.
    MedlineWeb of Science
  32. 32.↵
    1. Lau CS,
    2. Wong DA,
    3. Tong LK,
    4. et al
    . High rate and changing molecular epidemiology pattern of norovirus infections in sporadic cases and outbreaks of gastroenteritis in Hong Kong. J Med Virol 2004;73:113-7.
    CrossRefMedlineWeb of Science
  33. 33.↵
    1. Parks CG,
    2. Moe CL,
    3. Rhodes D,
    4. et al
    . Genomic diversity of “Norwalk like viruses” (NLVs): pediatric infections in a Brazilian shantytown. J Med Virol 1999;58:426-34.
    CrossRefMedlineWeb of Science
  34. 34.↵
    1. Guerrero RA,
    2. Ball JM,
    3. Krater SS,
    4. Pacheco SE,
    5. Clements JD,
    6. Estes MK
    . Recombinant Norwalk virus-like particles administered intranasally to mice induce systemic and mucosal (fecal and vaginal) immune responses. J Virol 2001;75:9713-22.
    Abstract/FREE Full Text
  35. 35.↵
    1. Nicollier-Jamot B,
    2. Ogier A,
    3. Piroth L,
    4. Pothier P,
    5. Kohli E
    . Recombinant virus-like particles of a norovirus (genogroup II strain) administered intranasally and orally with mucosal adjuvants LT and LT(R192G) in BALB/c mice induce specific humoral and cellular Th1/Th2-like immune responses. Vaccine 2004;22:1079-86.
    CrossRefMedlineWeb of Science
  36. 36.↵
    1. Tacket CO,
    2. Sztein MB,
    3. Losonsky GA,
    4. Wasserman SS,
    5. Estes MK
    . Humoral, mucosal, and cellular immune responses to oral Norwalk viruslike particles in volunteers. Clin Immunol 2003;108:241-7.
    CrossRefMedlineWeb of Science
  37. 37.↵
    1. Ball JM,
    2. Graham DY,
    3. Opekun AR,
    4. Gilger MA,
    5. Guerrero RA,
    6. Estes MK
    . Recombinant Norwalk virus-like particles given orally to volunteers: phase I study. Gastroenterology 1999;117:40-8.
    CrossRefMedlineWeb of Science
  38. 38.↵
    1. Ko G,
    2. Jiang ZD,
    3. Okhuysen PC,
    4. DuPont HL
    . Fecal cytokines and markers of intestinal inflammation in international travelers with diarrhea due to noroviruses. J Med Virol 2006;78:825-8.
    CrossRefMedlineWeb of Science
  39. 39.↵
    1. Bowman TA,
    2. Goonewardene IM,
    3. Pasatiempo AM,
    4. Ross AC,
    5. Taylor CE
    . Vitamin A deficiency decreases natural killer cell activity and interferon production in rats. J Nutr 1990;120:1264-73.
    Abstract/FREE Full Text
  40. 40.↵
    1. Sijtsma SR,
    2. Rombout JH,
    3. West CE,
    4. van der Zijpp AJ
    . Vitamin A deficiency impairs cytotoxic T lymphocyte activity in Newcastle disease virus-infected chickens. Vet Immunol Immunopathol 1990;26:191-201.
    CrossRefMedlineWeb of Science
  41. 41.↵
    1. Pasatiempo AM,
    2. Kinoshita M,
    3. Taylor CE,
    4. Ross AC
    . Antibody production in vitamin A-depleted rats is impaired after immunization with bacterial polysaccharide or protein antigens. FASEB J 1990;4:2518-27.
    Abstract
  42. 42.↵
    1. Braciak TA,
    2. Gallichan WS,
    3. Graham FL,
    4. et al
    . Recombinant adenovirus vectors expressing interleukin-5 and -6 specifically enhance mucosal immunoglobulin A responses in the lung. Immunology 2000;101:388-96.
    CrossRefMedlineWeb of Science
  43. 43.↵
    1. Long KZ,
    2. Haas M,
    3. Firestone M,
    4. et al
    . Vitamin A supplementation reduces the monocyte chemoattractant protein-1 intestinal immune response of Mexican children. J Nutr 2006;136:2600-5.
    Abstract/FREE Full Text
  44. 44.↵
    1. Lindesmith L,
    2. Moe C,
    3. Marionneau S,
    4. et al
    . Human susceptibility and resistance to Norwalk virus infection. Nat Med 2003;9:548-53.
    CrossRefMedlineWeb of Science
  45. 45.↵
    1. Rockx BH,
    2. Vennema H,
    3. Hoebe CJ,
    4. Duizer E,
    5. Koopmans MP
    . Association of histo-blood group antigens and susceptibility to norovirus infections. J Infect Dis 2005;191:749-54.
    Abstract/FREE Full Text
  46. 46.↵
    1. Hutson AM,
    2. Atmar RL,
    3. Estes MK
    . Norovirus disease: changing epidemiology and host susceptibility factors. Trends Microbiol 2004;12:279-87.
    CrossRefMedlineWeb of Science
  47. 47.↵
    1. Farkas T,
    2. Thornton SA,
    3. Wilton N,
    4. Zhong W,
    5. Altaye M,
    6. Jiang X
    . Homologous versus heterologous immune responses to Norwalk-like viruses among crew members after acute gastroenteritis outbreaks on 2 US Navy vessels. J Infect Dis 2003;187:187-93.
    Abstract/FREE Full Text
  48. 48.↵
    1. Rockx B,
    2. Baric RS,
    3. de Grijs I,
    4. Duizer E,
    5. Koopmans MP
    . Characterization of the homo- and heterotypic immune responses after natural norovirus infection. J Med Virol 2005;77:439-46.
    CrossRefMedlineWeb of Science
  49. 49.↵
    1. Villalpando S,
    2. Montalvo-Velarde I,
    3. Zambrano N,
    4. et al
    . Vitamins A, and C and folate status in Mexican children under 12 years and women 12–49 years: a probabilistic national survey. Salud Publica Mex 2003;45 (Suppl 4):S508-19.
    Medline
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  1. J Infect Dis. (2007) 196 (7): 978-985. doi: 10.1086/521195
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