URTI are commonly caused by viral infection; the majority of viruses enter the body via the respiratory tract where they infect selected cell types, replicate within those cells and are able to infect other cells [48]. The incidence of the common cold and influenza increases during the winter possibly because of a cooling of the nasal passages and associated weakening of immune defences [77].
Over 200 viruses may cause URTIs including: orthomyxoviruses (influenza), paramyxoviruses (respiratory synctial virus), parainfluenza, coronaviruses, picornaviruses, rhinoviruses, herpes viruses and adenoviruses [77]. Mild upper respiratory illness (the common cold) is mostly caused by rhinoviruses (about 50% of all cases [7]) and coronaviruses [78] [79]. The primary site of replication for rhinoviruses is the nasal mucosa and infection appears to be restricted to the upper respiratory tract. Rhinoviruses bind to intercellular adhesion molecule-1 which is on the apical surface of epithelial cells suggesting trans- epithelial transport is not required for infection. Temperatures in the upper respiratory tract (about 33 °C) are also optimal for virus survival and replication [80]. Viral shedding in nasal secretions can reflect the extent of the infection. If swallowed however, rhinoviruses do not survive passage through the gastrointestinal tract because of their sensitivity to reduced pH.
S-IgA as the main effector of mucosal immune protection has a multifunctional role in preventing URTI. In athletes, reduced levels of salivary S-IgA have been observed immediately after prolonged intensive bouts of exercise [81]. If the post-exercise recovery period is inadequate (i.e. short duration, insufficient nutrient replenishment, inadequate sleep) the cumulative effect over a training season can result in S-IgA levels remaining depressed [82]. Increased risk for URTI was observed in elite swimmers with reduced levels of S-IgA which supports the importance of the role of mucosal protection in prevention of URTI [83]. Older adults also experience an increased incidence of URTI thought to be due to immunosenescence. The increased incidence of infectious diseases
such as URTI in older adults is an important health concern because of the associated increased morbidity and mortality rates [84].
Typically upper respiratory symptoms (URS) begin within one to two days after infection and last one to two weeks. Symptoms are experienced as a result of the disturbance of the normal functioning of cells. As a consequence of local inflammation and systemic aches, fever and fatigue can persist long after the URS disappear; actual clearance of the virus can take longer [48]. Confirmation of URS as URTI is difficult and in clinical trials generally occurs by physician diagnosis or through self-recorded wellness records both of which are problematic. Verification requires serological investigation which is very rarely performed as it is expensive and not practical for large numbers of participants [48]. This is a difficulty in determining the effect of an intervention on a specific immune response and associating any effect with a health outcome such as the incidence of URTI. For these reasons some researchers exclude self-recorded URS days if the duration is less than two consecutive days [85, 86]
Reliability and validation of self reporting of URS
In longitudinal studies, when investigating the effect of a nutrition intervention on changes to an immune marker of mucosal immunity (such as salivary S-IgA), monitoring the incidence of URS is important as viral infection of the upper respiratory tract is accompanied by changes in levels of salivary S-IgA. It has been shown that the immune response to a viral infection results in increased salivary S-IgA levels about six days before the first URS appear, and levels remain elevated before returning to previous levels about 10 days later [48]. Independent subjective evaluation of URS by a physician could be helpful in qualifying symptoms but may not be possible in longitudinal studies, therefore the reliability and accuracy of self-recording of URS is important [8]. There is no ‘gold standard’ questionnaire for assessing symptoms of URTI, as they vary considerably between individuals in intensity and duration [8]. The most commonly used severity rating system was developed in the 1960s and is based on a simple sum of severity points (0=absent, 1=mild, 2=moderate, 3=severe) [8]. It has several limitations including lack of assessment of the
effect on quality of life, and for the athlete the impact of URTI on the ability to continue training.
Questionnaires used to evaluate the effect of a nutrition intervention or physical stress on URS have been criticised for the subjective nature of reportage. This is because of the inability of the individual to distinguish between symptoms due to viral infection or due to other factors such as inhalation of air pollutants [4]. A questionnaire with 44 items (including 32 symptom-based items, and 10 functional quality of life items) has been validated by determining the importance of symptoms to patients [8]. While a questionnaire of this length would not be practical in longitudinal nutrition studies it may be useful for validating a shorter questionnaire. A combination of immune parameter measurements and a questionnaire (or daily wellness records) may provide a better understanding of the changes to immune function and health outcomes that may be a result of a nutrition intervention [4].
As the yearly incidence of URTI is between two to four episodes per person, nutrition intervention trials need to be of sufficient length to detect potential differences (e.g. at least six months) [4]. Interventions of this length may be problematic with respect to compliance of consumption of the intervention. In addition large numbers of subjects studied over a long period of time are required to investigate the effects of a nutrition intervention on infection risk. For example Albers et al., 2005, suggest at least 50 participants for a placebo and 50 in a control group [4], but numbers depend on the desired study end point and need to be statistically determined in order to establish a significant difference in effect. Recruitment for intervention studies to reduce incidence of illness may introduce bias as those participants who experience a higher incidence of URTI could be more likely to volunteer making it difficult to recruit a representative sample [8].