Because seasonal cycles of infectious diseases are so universal and no single theory has proved satisfactory, explanations about their cause abound. More than one explanation or combination of explanations may be true. Explanations can be grouped into three types: pathogen appearance and disappearance, environmental changes, and host-behavior changes.

Regular annual variations in the incidence of many infectious diseases may be due to changes in susceptibility of the human host to the particular pathogen. Like the seasonal physiologic cycles of many mammalian species, these changes in susceptibility may be timed to the light/dark cycle, typically mediated by changes in the duration of the daily melatonin pulse. The changes in susceptibility may be distinct for different pathogens and may cover a broad range of possibilities, including (but not limited to) changes in the characteristic of mucosal surfaces, the expression of epithelial receptors, the leukocyte numbers or responsiveness, or other features of specific or nonspecific immunity.

This hypothesis would predict that pathogens do not physically migrate across the equator and that nationwide epidemics do not necessarily result from chains of person-to-person transmission. Rather, the pathogens may be present in the population year-round, and epidemics occur when the susceptibility of the population increases enough to sustain them. Perhaps the most significant prediction is that people are relatively resistant to disease if exposed in the off-season and that the specific physiologic process leading to seasonal resistance should be identifiable and perhaps modifiable.

Many mammalian species undergo seasonal physiologic changes. The best characterized are changes in reproductive organs and other tissues seen in animals that are seasonal breeders. Humans are not seasonal breeders, but fertility has seasonal variations. Seasonal variations have been documented in other physiologic processes and immunologic features (31,32).

Producing offspring in a season during which food is unavailable and the environment is unsuitable for the young is an evolutionary dead-end for some species, leading to carefully regulated breeding seasons for many rodents (33), sheep (34), other ungulates (35), monkeys (36), and primates (37). Seasonal physiologic changes involve not just behavior but also the secretion of sex hormones and the size and function of reproductive organs. In controlled laboratory conditions, the duration of the light/dark cycle is the key parameter governing these seasonal changes, which can be completely replicated by artificial manipulation of the photoperiod. Photoperiod is most commonly used rather than temperature, humidity, food availability, or other seasonally varying parameters, presumably because its invariant nature best prevents accidental breeding at the wrong time of year. Under constant photoperiod, the physiologic changes can also be reproduced by controlling the duration of the daily melatonin pulse.

Seasonal physiologic changes have also been documented in processes not typically associated with breeding but potentially related to susceptibility to infectious agents. For example, even under constant conditions, red deer have distinct seasonal changes in digestive features (35), mice have seasonal changes in seizure threshold (38), and dairy cattle have seasonal changes in the fat and protein content of their milk (39). In recent years, seasonal changes in immunologic features have been documented. For example, Siberian hamsters exposed to short-day photoperiod demonstrate increased natural killer-cell activity and lymphocyte blastogenesis but decreased phagocytosis and oxidative burst activity by granulocytes (40); deer mice treated with melatonin in constant photoperiod exhibit increased lymphocyte response to mitogen stimulation (41).

A series of studies documented that the death rate in mice experimentally exposed to pneumococcal infection varied with the time of day (42-44). Survival patterns were altered by modifying environmental lighting conditions, rather than feeding or activity, and susceptibility appeared related to the daily cycle of cortisone, although the specific physiologic feature responsible for increased susceptibility was not identified. Since these findings, understanding of the role of melatonin and its control of circadean and seasonal rhythms has increased greatly, but further studies of the influence of photoperiod on experimental pneumococcal infections in mice appear not to have been pursued.

Seasonal physiologic changes are not as well characterized for humans as for other mammals, but mounting data suggest that changes in photoperiod and the melatonin pulse may also influence human physiology (32). Blind people, who lack the capability for light to cue their biologic clocks, are often plagued by free-running circadian rhythms. A recent study demonstrated that these free-running rhythms can be entrained to a normal cycle by daily administration of melatonin (45). Although humans are sexually active year-round, a seasonal distribution in conceptions has consistently been demonstrated, and a variation in the ovulation rate has been postulated as the cause (31). Seasonal affective disorder, a well-characterized depression associated with short days and specific genetic defects (46), is treatable with extra hours of exposure to broad-spectrum light (47). Seasonal variations in heart attacks (48), breast cancer (49), and other seemingly noninfectious conditions have also been reported.

Recent research has focused on seasonal changes in immunologic values in humans. Specific melatonin receptors coupled with G-protein have been identified on lymphocytes (50). As in rodents, seasonal variations in lymphocyte mitogenic responses and in the quantity of circulating lymphocytes, neutrophils, CD4 and CD8 cells, and IL-6 have been reported (51-53). Some values, such as lymphocyte aryl hydrocarbon hydroxylase activity, peak in summer (54), while others, such as number of circulating B cells, peak in winter (52). Although statistically significant, the functional significance of these variations has not yet been established.

The above observations lend some biologic plausibility to the proposed hypothesis, but direct testing is needed. Several observations support the prediction that the host is less susceptible to infection or disease in the off-season.

In a double-blind placebo-controlled trial conducted in the Soviet Union during different seasons, nonimmune volunteers were given attenuated live influenza vaccine intranasally (55). Febrile reactions attributable to vaccine (calculated by subtracting the proportion of participants with reactions in the placebo group from the proportion in the vaccine group) were observed in 6.7% of 360 volunteers inoculated in Leningrad in January, compared with 0.8% of 197 inoculated in June (p = 0.003). Fourfold rises in antibody titer were seen in 31% to 40% in Krasnodar in January, depending on the vaccine strain, compared with 4.3% to 4.8% given the same strains in May and October (all p <0.001). Similar trends with less significant differences were seen in three other cities.

Some years earlier, in a series of experiments on the transmission of influenza virus from infected to susceptible mice, <1% of mice exposed from July to October were infected, compared with 22% of those exposed in December or January (p <0.001) (56). One year later, the investigators repeated the experiment with a different strain of mice, now kept under constant temperature and humidity, and observed that 34% were infected in May to October, compared with 58% in November to April (p <0.001). The photoperiod conditions in these experiments were not noted.

It is not clear whether attempts were made to replicate these provocative experiments or if the potential importance of the observations was fully appreciated. The animal experiments may be relatively easy to confirm or refute, and the many live attenuated vaccines currently tested or used should provide ample material to evaluate the effects of season on immunogenicity or reactogenicity. The season of administration influences seroconversion rates to oral polio vaccine (57,58) and protection against polio (59), but much of this seasonal variation may be attributable to competition by other enteroviruses during summer (57). Vaccine-associated paralytic polio among vaccine contacts reflects the seasonal pattern of natural polio (60).

Photoperiod-driven changes in host physiology might explain certain enigmatic observations about seasonality, but some observations remain unexplained. For example, the west-east movement of rotavirus is not easily attributable to host susceptibility changes timed to the light/dark cycle (5). The increase in hospitalizations coincident with warm weather and El Nino points to temperature rather than photoperiod is a key influence on some diarrheal disease pathogens (20). The sudden appearance and worldwide spread of a new pandemic strain of influenza virus also argues more for chains of transmission than for a crop of outbreaks from virus already present in the population.

Epidemiologists have long puzzled over why seasonal infectious disease outbreaks occur when they do. Perhaps the more important question is why they do not occur when they do not. Is the human population already relatively resistant for 6 to 9 months each year? If the absence of epidemics of summer influenza or winter polio is attributable to climate or weather, we may have little power to influence them. On the other hand, if these annual troughs are due to increased host resistance, opportunities abound for studying and modifying these changes. Such opportunities might include reviews of existing databases, careful evaluation of "experiments of nature," and studies in laboratory animals.

Databases surely exist that might shed light on this hypothesis. Clinical trials of live attenuated vaccines during the usual seasonal peak and seasonal trough for that particular disease could be reviewed for seasonal differences in reactogenicity and immunogenicity. Experiments of nature, in which groups adapted to summer come into contact with groups adapted to winter (as in a convention or a cruise ship with passengers from both Southern Hemisphere and Northern Hemisphere countries) and are exposed to a seasonal pathogen (such as influenza or an enterovirus), could be analyzed for differences in attack rate or clinical severity. Laboratory animals housed in photoperiod-controlled rooms could be exposed to seasonal pathogens and evaluated to see if photoperiod or melatonin modifies clinical and physiologic responses to infection. If differences are documented, the specific physiologic feature governing susceptibility changes could be isolated and identified.

It is time to have a closer look at these possible seasonal changes in host susceptibility and if they are confirmed, identify and modify the physiologic changes underlying annual cycles of infectious diseases.