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Cytokine Response Patterns, Exposure to Viruses, and Respiratory Infections in the First Year of Life

Departments of Pediatrics, Biostatistics and Medical Informatics, and Medicine, University of Wisconsin, and Wisconsin State Laboratory of Hygiene, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to Christopher C. Copenhaver, M.D., K4/910 University of Wisconsin Hospital, 600 Highland Avenue, Madison, WI 53792-9988. Email: cc.copenhaver{at}hosp.wisc.edu

	ABSTRACT

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Daycare attendance and siblings are associated with viral-induced wheezing in children. Preexisting immunologic factors may influence the expression of viral infections in infancy, and in turn, recurrent infections may influence the development of immune responses. A total of 285 children were enrolled in the Childhood Origins of Asthma Project at birth and followed for at least 1 year. Cord blood and 1-year mononuclear cells were stimulated with phytohemagglutinin, and cytokine-response profiles were measured by enzyme-linked immunosorbent assay. Nasal lavage was performed for moderate to severe respiratory illnesses. Daycare attendance and/or siblings significantly increased the likelihood of contracting respiratory syncytial virus (1.5–1.6-fold increase) and rhinovirus (1.8–2.1-fold increase), and increased the risk of rhinovirus-induced wheezing (14–18% vs. 2%, p = 0.011). Cord blood IFN- responses were inversely related to the frequency of viral respiratory infections (r_s = –0.11, p = 0.05), and more significant for subjects with high exposure to other children (r_s = –0.27, p = 0.028). The interval change in infantile IFN- responses correlated positively with the frequency of viral infections in infancy (r_s = 0.12, p = 0.047). These data suggest that neonatal IFN- responses may influence antiviral activity, or may represent a marker of antiviral immunity maturation. Conversely, the frequency of viral infections in infancy can influence IFN- responses.

Key Words: interferon- • respiratory syncytial virus • daycare • sibling

Viral respiratory illnesses, many of which are contracted through contact with siblings or attendance at daycare, are the most common triggers for wheezing and asthma exacerbations among young children. In both the Tucson Children's Respiratory Study (1, 2) and the Italian Studies of Respiratory Disorders in Childhood and the Environment project (3), daycare attendance was shown to be a risk factor for viral infections and viral-associated wheezing in the first 2 years of life, but protective against viral infections and asthma later in life. Celedon and colleagues found that daycare attendance during the first year of life was associated with lower rates of asthma at 6 years of age, but only among children without a maternal history of asthma (4). Similarly, children with older siblings in the home are more likely to experience viral illnesses and wheezing in the first 2 years of life, but have decreased rates of wheezing, and decreased rates of atopic sensitization later in childhood (2, 3, 5, 6). Despite the convincing evidence linking exposure to other children with rates of respiratory illnesses and wheezing, the effects of increased exposure on specific viral infections have not been ascertained.

While exposure is an important determinant of lower respiratory tract illnesses, it does not explain why some children entering daycare experience a dramatic increase in viral infections, while others are relatively healthy. In addition, recent genetic studies suggest that clinical outcomes of viral infections in infancy might also be influenced by polymorphisms in cytokine genes (7–9). These observations suggest the hypotheses that variations and/or subtle defects in the antiviral immune response also affect the clinical expression of viral respiratory infections. Furthermore, stressing the immune system with increased viral exposure may uncover relatively minor immune defects that are not apparent in children with less exposure to viruses. To test these hypotheses, we conducted a prospective birth cohort study to evaluate interactions between exposure to other children, the development patterns of cytokine responses in peripheral blood cells, and the etiology and severity of respiratory viral infections during the first year of life.

Other study results pertinent to this cohort have been previously published as both original articles and abstracts (10–13).

	METHODS

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Study Subjects
After obtaining informed consent, 289 subjects were enrolled in the Childhood Origins of Asthma Study (14) at birth and 285 were followed prospectively for at least 1 year. Details of study design have been described previously (12–14). This study was approved by the University of Wisconsin Human Subjects Committee.

Wheezing Respiratory Illnesses and Daycare
Definitions of wheezing illness and daycare attendance are available in the online supplement.

Collection of Blood Samples
Cord blood and 1-year peripheral blood samples were collected as described previously (13).

Mononuclear Cell Stimulation
Mononuclear cells were stimulated with phytohemagglutin (PHA) (5 µg/ml) or incubated in medium alone, as described previously (13).

Cytokine ELISA
Levels of IFN-, interleukin (IL)-5, IL-10, and IL-13 in supernatants were evaluated by ELISA (Pharmingen, San Diego, CA). The manufacturer's protocol was followed except that the sample volume was reduced to 50 µl. The sensitivities are as follows: IFN- = 4.7 pg/ml, IL-5 = 1.9 pg/ml, IL-10 = 7.7 pg/ml, and IL-13 = 3.1 pg/ml. Duplicate wells were run, and mean values are reported.

Nasal Lavage Samples
Nasopharyngeal mucus specimens were obtained under two circumstances: (1) scheduled clinic visits at 2, 4, 6, 9, and 12 months of age, and (2) during acute respiratory illnesses. Parents contacted a study coordinator when their child developed a respiratory tract infection, and a respiratory symptom scorecard (maximum score = 31, Table 1) was completed. If the child scored a 5 or higher, a nasopharyngeal mucus specimen was obtained within 48 hours. The collection and handling methods of these samples have been described previously (15).

At 1 year of age, an ELISA was performed on serum to detect anti-RSV IgG (see online supplement). RSV fusion protein was generously provided by Dr Gerald Hancock (Wyeth-Lederle Vaccines, Henrietta, NY). RSV infections were diagnosed on the basis of positive serology at age 1 year, or virus detection in nasal secretions. When multiple viruses were recovered, the sample counted as a positive for each virus.

Measurement of Blood Eosinophils and IgE
Total white blood cell counts, and total and allergen-specific IgE were measured, as previously described (13).

Statistical Analysis
SAS (version 8.1; SAS Institute Inc., Cary, NC) was used for all statistical analyses. Rates of viral infection and wheezing in groups based on daycare attendance and/or presence of an older sibling were compared using Pearson's ² test. Frequency of viral infections and wheezing in these groups were compared using two-sample t tests. Associations between cytokine responses, total IgE, and eosinophil counts were assessed using Spearman's rank correlation analyses, both for the entire cohort and for groups defined by daycare attendance and/or presence of an older sibling.

Wilcoxon signed-rank tests were used to compare changes in cytokine responses in cord blood taken during the first year of life. A nominal p value of 0.05 was considered to be statistically significant.

	RESULTS

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Influence of Daycare Attendance and/or Older Siblings on Laboratory-documented Viral Infections
Overall, 556 nasal lavage samples were obtained during a respiratory illness with a symptom score of 5 or higher: viruses were detected in 408 (73%) samples, and 34 of these samples were positive for more than 1 virus. Fifty-three samples were culture positive for RV; and of the 503 samples that were culture-negative for RV, 208 were RV-RNA–positive. We next evaluated the separate and combined effects of daycare attendance, and the presence of at least one older sibling in the home on the risk of developing a moderate to severe viral respiratory infection during the first year of life. Of the 285 children in the study, 66 attended daycare only, 90 had an older sibling only, and 66 had both types of exposure. Children who either attended daycare or had an older sibling had an overall significantly increased rate of developing respiratory viral infections during the first year of life (Table 2) . When evaluating relationships with specific infections, there was a significantly increased rate of both RV (1.8–2.1-fold) and RSV (1.5–1.6-fold) infections for children who either attended daycare only or had a sibling only. The rate of infection with viruses other than RV or RSV was significantly increased only among children with both types of exposure.

Influence of Daycare Attendance and/or Older Siblings on Virus-associated Wheezing
Among our cohort, 25% of children experienced at least one episode of viral-associated wheezing during the first year of life. Overall, greater exposure to other children in the home and daycare was associated with a twofold increase in wheezing with viral infections, and similar trends were noted when individual exposures were considered separately (Table 3) . Different associations were observed, however, according to the specific viral pathogen that caused the wheezing illness. Daycare and siblings were particularly strong risk factors (7–9-fold increase) for RV-induced wheezing. In contrast, although there was a tendency for higher rates of RSV-induced wheezing in high-exposure groups, this trend was relatively small (less than twofold) and was not statistically significant. For viruses other than RSV and RV, the rate of viral-associated wheezing was significantly increased only for children with both sibling and daycare exposure.

There was an inverse correlation between cord blood PHA-induced IFN- responses of mononuclear cells and the number of moderate to severe (symptom score 5) viral infections during the first year of life (r_s = –0.11, p = 0.05 (Figure 1) ; vigorous secretion of IFN- was associated with fewer infections. This correlation was stronger (r_s = –0.27, p = 0.028) among children who both attended daycare and had a sibling, and, thus, had the greatest exposure to other children. There were no significant correlations between symptomatic viral infections during infancy and other PHA-induced responses (IL-5, IL-10, and IL-13) from cord blood cells.

View larger version (14K): [in this window] [in a new window]   Figure 1. Relationship of cord blood phytohemagglutin (PHA)-induced IFN- secretion to number of viral infections in the first year of life. The data demonstrate a correlation between cord blood PHA-induced IFN- secretion and the number of viral infections documented by positive culture or rhinovirus (RV)-specific polymerase chain reaction (PCR) from nasal lavage samples obtained when children had symptoms scores of 5 or higher; n = 285.

There were no significant relationships between the cytokine response profiles at birth and the frequency of virus detection at scheduled visits.

Association between Viral Infections and Developmental Changes in Immune Responses
For the entire cohort, PHA-induced IFN- responses showed a small but significant reduction by one year of age (57–26 pg/ml, p < 0.001), as previously reported. (13) A significant positive correlation was observed between the number of viral respiratory infections and the change in PHA-induced IFN- responses (r_s = 0.12, p = 0.047) (Figure 2) . In contrast, there was no correlation between the frequency of viral infections and changes in other PHA-induced cytokine responses, cytokine responses, total IgE levels, or blood eosinophil counts at age 1 year.

View larger version (12K): [in this window] [in a new window]   Figure 2. Relationship of viral infections to the change in PHA-induced IFN- secretion between birth and 1 year of age. The data demonstrate a correlation between the number of viral infections documented by positive culture or RV-specific PCR from nasal lavage samples obtained when children presented with symptoms scores of 5 or higher, and the change in PHA-induced mononuclear cell IFN- secretion in the first year of life. The changes in IFN- responses were calculated by subtracting the IFN- secreted by cord blood samples from the values obtained from peripheral blood mononuclear cells at 1 year of age.

	DISCUSSION

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Infancy is a time of rapid immunologic development, and theoretically, the development of innate and adaptive immune responses could influence the clinical expression of respiratory viral infections, or conversely, be influenced by recurrent infections. In this study, we were able to test these hypotheses by prospectively evaluating cytokine responses and exposure to other children, and relating these factors to the number and severity of respiratory infections with specific viral pathogens. We were able to quantify the magnitude of the effects of exposure to other children on the number of children who had symptomatic infections with RV (1.8–2.1-fold increase) and RSV infections (1.5–1.6-fold increase). In addition, the correlation between exposure and viral-associated wheezing varied with specific pathogen. While the rate of RV-associated wheezing was greatly increased by exposure to daycare and/or siblings, there was relatively little effect on RSV-associated wheezing. Furthermore, we have found an association between cytokine responses at birth and infections in the first year of life, inversely relating IFN- responses to the number of symptomatic respiratory viral infections. Finally, in accordance with the hygiene hypothesis, there was a small but measurable effect of frequent infections being associated with a smaller decline of IFN- responses (13) during the first year of life.

The rate of viral-associated wheezing among our cohort during the first year of life (25%) is similar to findings published by the Tuscon Children's Respiratory Study, in which 21% of children experienced at least one wheezing-lower respiratory tract infection during a similar time period (17). Among our cohort, children who attended daycare and had a sibling were more likely to contract an RV infection. Furthermore, for a yet undefined reason, children who contract an RV infection from either daycare or a sibling are more likely to wheeze. This is in contrast to the relatively consistent rate of RSV-associated wheezing among all exposure categories. It is possible that children who contract RV from a sibling or daycare receive a larger inoculum, either due to poor hygiene practices or exposure to multiple-infected children, and the net result is a more virulent illness. An alternative possibility is that recurrent infections caused by close contact with other children may, in a stepwise fashion, promote airway changes, such as goblet cell hyperplasia and increased responsiveness that predispose to wheezing.

We found a weak but statistically significant inverse relationship between IFN- responses in cord blood and symptomatic viral respiratory infections. This relationship was stronger among children with greater exposure to viruses, suggesting that infants with mild impairment of antiviral responses are more likely to be symptomatic when placed in a high-exposure environment. Although cord blood IFN- responses were inversely related to symptomatic infections, there was no correlation between IFN- and viral detection at scheduled visits. This suggests that strong IFN- responses are not necessarily associated with fewer infections, but may instead lessen the severity of viral infections during infancy.

Guerra and colleagues in the Tucson Children's Respiratory Study recently reported that infants with reduced mitogen-induced IFN- response at 3 months of age have a significantly increased risk of recurrent wheezing in the first year of life (18). This new information, when considered together with our findings, supports the hypothesis that IFN- plays an important role in limiting the severity of respiratory illnesses in infancy. Furthermore, this effect could be especially important when the environmental exposure to other children is high.

The relationship between IFN- responses and viral infections may be explained by its role in innate and acquired antiviral responses. IFN- plays a critical role in stimulating macrophages to kill phagocytosed microbes through induction of nitric oxide, and enhances antigen presentation as well as antiviral effects of CD8 T cells and natural killer cells (19). This hypothesis is supported by case reports of children with deficiencies of IFN- production or receptors who experience more severe clinical manifestations during viral infections (20–22). Alternatively, reduced IFN- responses may also represent a nonspecific marker of an immature immune response that does not have adequate antiviral activity.

Epidemiologic studies have demonstrated a link between frequent infections in infancy and reduced allergies and asthma later in childhood (23, 24), and it has been suggested that this may be due to stimulation of T helper cell type 1 immune responses. In support of this hypothesis, we found a positive relationship between the number of symptomatic infections and changes in IFN- responses during infancy. Alternatively, children who had high IFN- at birth were shown to experience fewer viral infections during the first year of life. This group also had a more dramatic decline in production based on their initial high value. Consequently, the decline in IFN- production may be secondary to an elevated cord blood level rather than the lower rate of viral infections.

The major outcome measure of the Childhood Origins of Asthma Study is to determine the relationship between cytokine dysregulation, viral infections, and the initiation of childhood asthma. The foundation for this study was based on work performed in a rodent model of asthma inception (25–28). In this model, infection with a paramyxovirus in an atopic strain of rats at a critical time period during their development (susceptible as weanlings, but not as adults) induces an asthma phenotype that in many ways parallels human asthma both histologically and physiologically. In relationship to the current findings, the development of the asthma phenotype appears to involve, at least in part, a dysregulation of natural killer cell IFN- responses in the responder strain of rats. Although the children in the Childhood Origins of Asthma Study are presently too young to label definitively as having asthma, the findings reported here related to IFN- response profiles and viral infections during infancy may be even more informative once asthma phenotypes are affirmed in the Childhood Origins of Asthma Study children.

In summary, these findings help to clarify relationships among exposure to viruses, specific viral illnesses, wheezing, and cytokine responses in infancy. In particular, the demonstration that viral-stimulated IFN- response profiles may both influence and be influenced by the frequency of viral respiratory tract infections during infancy raises the possibility of a new therapeutic approach to these common infections. Although treatments directed at boosting IFN- responses may not prevent viral respiratory infections, these findings suggest that this approach could be helpful in moderating the severity of infections with common respiratory pathogens (29).

	Acknowledgments

 
The authors thank the following health care professionals for their support and cooperation: Gail Allen, Conrad Andringa, Candye Andrus, Richard Anstett, Maribeth Baker, Robert Baker, Adam Balin, Ann Behrmann, Patricia Bellissimo, Arnold Benardette, George Benton, Tom Best, Gregory Bills, John Bohn, Connie Brandt, Don Breckbill, Don Buckstein, Rebecca Bull, Renee Burk, Deirdre Burns, Robert Cape, Colleen Calvy, Michael Cardwell, Susan Carson, Cally Christiansen, R. Christmann, Timothy Chybowski, Marcus Cohen, Robert Cole, Alison Craig, Alison Dahlrymple, James Davis, Nancy Deaton, Patricia Deffner-Valley, Jean Demopolous, Gregory DeMuri, Kathleen DeSantes, Sherri DeVries, Klaus Diem, Karla Dickmeyer, Sabine Droste, Bruce Drummond, Paul Dvorak, Rebecca Eckland, M. Bruce Edmonson, Anne Eglash, Susan Ehrlich, Lawrence Elfman, Marguerite Elliott, Richard Ellis, Dolores Emspak, Sue Engelbaugh, Aida Evans, Gordon Faulkner, Christopher Federman, Ellen Flannery, Joseph Fok, Nadine French, Carolyn Fruehling, Ann Ganch, Claire Gervais, Michelle Gigot, Jenny Hackforth-Jones, Nancy Hagan, David Hann, Mark Hansen, Thomas Hartjes, Jean Haughwout, William Heifner, Russell Hermus, Russell Hess, Karen Hillery, Sherry Holtzmann, Barbara Hostetler, Catherine James, Brenda Jenkin, Sandy Kamnetz, Peter Karofsky, Jennifer Kaufman, Helen Kay, Holly Keevil, Jeffrey Keil, Catherine Kelley, Jeanine Kies, Steve Kincaid, Gretchen Kind, Kristen Knoepke, J. Brendt Kooistra, Paul Kornaus, Steven Koslov, Jeff Krawcek, Dean Kresge, Ann Krigbaum, Robert Kriz, Karen Kronman, Gordon Kronquist, Randy Krszjzaniek, Greg Landry, Mary Landry, Martha Lauster, Karen Lentfer, Joanne Leovy, Stephen Lo, David Lonsdorf, Allan Luskin, Francois Luyet, Joseph Mahoney, Dimitria Manesis, Daniel Marley, Edward McCabe, Gwen McIntosh, Anne Means, Thomas Meier, Frederic Melius, Theresa Mendoza, J. Michael, Eileen Michaels, Bernard Micke, Kaye Mickelson, James Milford, Angie Miller, Julie Mokhtar, Jonathan Morey, Vickie Mulkerin, Maureen Murphy-Greenwood, Thomas Murwin, Eric Nagle, Elizabeth Neary, Paul Neary, James Nettum, Susan Nondahl, Carolyn Ogland, David Okada, Mark Olinger, Reid Olson, Kathleen Oriel, Sandra Osborn, John Ouellette, Meg Parker, Daniel Paulson, Karen Pletta, Amy Plumb, Beth Potter, Peter Pryde, William Ranum, Richard Rice, David Ringdahl, Michael Ritter, Richard Roberts, Everett Roley, Meriel Ronstadt, Karl Rudat, Sherwin Rudman, Jerry Ryan, Julie Saxton, William Scheibel, Ben Schmidt, Rosemarie Schumacher, Julie Schurr, Gerald Shay, Debra Shenoi, James Shropshire, Charles Shutt, Elma Sia, Linda Siewart, Theresa Sizer, Susan Skochelak, Jeffrey Sleeth, Greg Smith, Sheryl Spitzer-Resnick, Patricia Staats, Jennifer Stevens, Katherine Stewart, Mary Stoffel, Joanne Taylor, Jonathan Temte, Stephen Thomas, Mark Timmerman, Ordean Torstenson, Mary-Anne Urtes, Thomas Varley, Eleanor Vita, Lisa Wacholz, David Weber, Bonny Whalen, Margaret Wilcots, Gary Williams, W. Michael Wilson, Robin Wright, Michael Yaffe and Kok-Peng Yu. The support and participation of the following hospitals and clinics has been key to the success of the project: the obstetrical nursing staff at Meriter Hospital, St. Mary's Medical Center, Fort Atkinson Memorial Health Services, Inc., St. Clare Hospital, Reedsburg Area Medical Center, Sauk Prairie Memorial Hospital, as well as the clinic staff of Physicians Plus, Associated Physicians, Dean Medical Center, Group Health Cooperative, and other clinics in southwestern Wisconsin seeing individual Childhood Origins of Asthma Study families.

	FOOTNOTES

 
Supported by National Institutes of Health grants 1R01HL61879–01 and 1P01HL70831–01.

This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: C.C.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; J.E.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; Z.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; P.A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; L.A.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; L.D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; C.J.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; K.A.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; E.L.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; C.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; D.F.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; H.J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; K.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; R.E.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; R.F.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this article.

Received in original form December 3, 2003; accepted in final form April 11, 2004

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