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Seasonal variation in host susceptibility and cycles of certain infectious diseases.

Seasonal variation in host susceptibility and cycles of certain infectious diseases. Perspective Seasonal Variation in Host Susceptibility and Cycles of Certain Infectious Diseases Scott F. Dowell Centers for Disease Control and Prevention, Atlanta, Georgia, USA Seasonal cycles of infectious diseases have been variously attributed to changes in atmospheric conditions, the prevalence or virulence of the pathogen, or the behavior of the host. Some observations about seasonality are difficult to reconcile with these explanations. These include the simultaneous appearance of outbreaks across widespread geographic regions of the same latitude; the detection of pathogens in the off-season without epidemic spread; and the consistency of seasonal changes, despite wide variations in weather and human behavior. In contrast, an increase in susceptibility of the host population, perhaps linked to the annual light/dark cycle and mediated by the pattern of melatonin secretion, might account for many heretofore unexplained features of infectious disease seasonality. Ample evidence indicates that photoperiod- driven physiologic changes are typical in mammalian species, including some in humans. If such physiologic changes underlie human resistance to infectious diseases for large portions of the year and the changes can be identified and modified, the therapeutic and preventive implications may be considerable. From 1703 onward, the annual rise and fall of measles deaths in London was recorded in sufficient detail to allow for careful mathematical modeling in 1918 (1). Since then, surveillance for a variety of diseases has established that regular seasonal variation in incidence is the rule, rather than the exception, for acute infections. Seasonal variations should be distinguished from periodic large epidemics, as observed every 2 years for measles (2) or at less frequent and more irregular intervals for meningococcal meningitis (3) and rubella (4). This discussion will focus on the more robust annual cycle, which “locks in” large epidemics to the same time of year (3,4) and persists even after large epidemics have been eliminated by mass vaccination (2). The life cycles of pathogens spread by insect vectors or maintained in animal or environmental reservoirs add complexity because seasonal changes might influence not only the pathogen or human host but also the vector population and animal or environmental reservoir. Therefore, this discussion will focus on bacterial and viral pathogens maintained primarily by person-to- person spread. The regular and predictable pattern of seasonal outbreaks dominates the epidemiology of many exclusively human pathogens (Figure 1). Different infections peak in each of the four seasons, but for each pathogen, the timing and characteristics of the annual outbreak are remarkably consistent from year to year. Other key observations have been made on the seasonality of infectious diseases, including the simultaneous onset of outbreaks in geographically remote areas and the persistence of pathogens in the off-season in the Figure 1. Seasonal variation in the occurrence of three human pathogens in the U.S. A: an annual cycle of rubella activity was absence of epidemic spread (Table). In fact, latitude has a maintained between larger epidemics, which occurred every 6 to 9 clear influence on the timing and magnitude of outbreaks of years. B: percentage of specimens testing positive for influenza viruses rotavirus infection (10), influenza (15), and poliomyelitis among specimens tested by World Health Organization and U.S. National Respiratory and Enteric Virus Surveillance System Address for correspondence: Scott F. Dowell, Centers for Disease collaborating laboratories. C: a consistent pattern of rotavirus Control and Prevention, 1600 Clifton Road NE, Mailstop C12, Atlanta, seasonality is evident in the U.S. National Respiratory and Enteric GA 30333, USA; fax: 404-639-3039; e-mail: sdowell@cdc.gov Virus Surveillance System. Adapted from references 4-6. Vol. 7, No. 3, May–June 2001 369 Emerging Infectious Diseases Perspective Table. Observations on the seasonal occurrence of infectious diseases Observation Examples Pathogens peak at characteristic times in Winter: influenza, pneumococcus, rotavirus all seasons of the year Spring: RSV, measles Summer: polio, other enteroviruses Fall: parainfluenza virus type 1 Timing and duration of peaks for each Measles: regular pattern since 1703 (1) pathogen are similar from year to year Influenza: annual peak varies by only 5 to 10 weeks in the United States (6) Onset of epidemics often occurs simultaneously Influenza: simultaneous outbreaks across North America, 16 European in areas that are geographically dispersed countries, and 6 Chinese provinces (7) and have different weather conditions and Pneumococcus: simultaneous outbreaks in seven surveillance areas (8) diverse populations Latitude is a critical determinant of timing An increasing magnitude of seasonal peaks as distance from the equator and magnitude of peaks increases has been documented for polio (9) and rotavirus (10) and reported for influenza (11). Pathogens can be detected in the off-season Meningococcus: no decrease in carriage in the off-season, despite despite lower incidence of disease and absence of epidemic disease (12) virtual absence of epidemics RSV: sporadic summer viral isolation but no epidemic spread (13) Influenza: sporadic summer isolation, occasional clusters of disease without epidemic spread (14) RSV = respiratory syncytial virus. RSV peaks in the winter or spring in the United States, depending on location. For simplicity, it is listed here as a spring pathogen. (Figure 2) (9). Reconciling these observations with the Pathogen Appearance and Disappearance consistent seasonality of clinical illness is a continuing Perhaps the most obvious explanation for the absence of challenge. disease during a period is that the pathogen is also absent during the period. However, the regular annual migration of Explanations of Seasonality epidemics of influenza, poliomyelitis, and rotavirus infection Because seasonal cycles of infectious diseases are so from northern latitudes across the equator to southern ones universal and no single theory has proved satisfactory, and back does not necessarily imply that the pathogens explanations about their cause abound. More than one themselves migrate in this way. explanation or combination of explanations may be true. Current theory holds that influenza is maintained only Explanations can be grouped into three types: pathogen by direct spread in a series of chains of transmission from one appearance and disappearance, environmental changes, and ill person to another (16). Some evidence suggests that host-behavior changes. influenza viruses do spread geographically, particularly during pandemics, but whether geographic spread accounts for the patterns observed in annual outbreaks has been questioned (11,17,18). The simultaneous onset of geographi- cally widespread outbreaks is difficult to reconcile with Latitude chains of person-to-person transmission. One hypothesis is that earlier “seeding” of the virus throughout the population must have occurred (17). During an 1826 influenza epidemic, one observer wrote, “...this epidemic affects a whole region in the space of a week, nay, a whole continent as large as North America, together with all the West Indies, in the course of a few weeks, while the inhabitants could not within so short a time have had any communication or intercourse whatever across such a vast extent of country” (11). A more recent hypothesis attributes geographic spread to the atmospheric dispersion of virus from Southeast Asia by trans-Pacific winds across the North American continent (18). Environmental Changes Environmental changes, particularly changes in weath- er, are the explanations most often invoked for the seasonality of infectious diseases. Statistically significant correlations between epidemic cycles and cycles of temperature (19-22), humidity (21-23), rains (24), or winds (24) have been identified. However, correlations may be found with Figure 2. Seasonal variation in the incidence of poliomyelitis by confounders as well as with causes. latitude, 1956-57. As distance from the equator increases, a higher In some cases, the association with weather is supported, proportion of cases are evident in summer and fall months. Adapted from reference 9. but the biologic plausibility appears tenuous. Although the Emerging Infectious Diseases Vol. 7, No. 3, May–June 2001 Monthly % of cases Perspective seasonal incidence of poliomyelitis correlated quite well with typically mediated by changes in the duration of the daily the summer increase in relative humidity in Boston and melatonin pulse. The changes in susceptibility may be Houston from 1942 to 1951 (23), the explanation that distinct for different pathogens and may cover a broad range aerosolized poliovirus survives for a longer time at higher of possibilities, including (but not limited to) changes in the relative humidity is difficult to reconcile with the fecal-oral characteristic of mucosal surfaces, the expression of epithelial route of poliovirus transmission. receptors, the leukocyte numbers or responsiveness, or other In other cases, the correlations are supported by biologic features of specific or nonspecific immunity. plausibility but are not consistently observed. In sub- This hypothesis would predict that pathogens do not Saharan Africa, the onset of meningococcal epidemics closely physically migrate across the equator and that nationwide followed the season of dry winds and ended with the onset of epidemics do not necessarily result from chains of person-to- the rains (25). It has been proposed that drying of mucosal person transmission. Rather, the pathogens may be present surfaces increases the probability of bacteremic spread and in the population year-round, and epidemics occur when the that the rains moisten the mucosa or decrease the spread of susceptibility of the population increases enough to sustain the organism by dust. However, in Oregon and other areas, them. Perhaps the most significant prediction is that people meningococcal disease peaks during the rainy season (26). are relatively resistant to disease if exposed in the off-season Similarly, a significant correlation between the onset of the and that the specific physiologic process leading to seasonal invasive pneumococcal disease season and a drop in mean resistance should be identifiable and perhaps modifiable. C in Houston (19) was not daily temperatures below 24 confirmed in seven other areas with more widely varying Seasonal Changes in Host Physiology weather patterns (8). Respiratory syncytial virus epidemics Many mammalian species undergo seasonal physiologic occur in the colder months of winter and spring in the United changes. The best characterized are changes in reproductive States (13) but paradoxically are significantly correlated with organs and other tissues seen in animals that are seasonal the hotter months in Singapore and Hong Kong (21,22). breeders. Humans are not seasonal breeders, but fertility has seasonal variations. Seasonal variations have been documented Host-Behavior Changes in other physiologic processes and immunologic features (31,32). Seasonal changes in poliomyelitis, measles, and other Producing offspring in a season during which food is seasonal infectious diseases have been attributed to changes unavailable and the environment is unsuitable for the young in the behavior of the host. Public swimming pools were a is an evolutionary dead-end for some species, leading to source of great concern during the polio epidemics of the carefully regulated breeding seasons for many rodents (33), 1950s, and summer peaks in polio and other enteroviruses sheep (34), other ungulates (35), monkeys (36), and primates were attributed to swimming (23,27,28). Subsequent studies (37). Seasonal physiologic changes involve not just behavior discounted the importance of swimming in the spread of but also the secretion of sex hormones and the size and enterovirus infections (28). function of reproductive organs. In controlled laboratory Crowding of susceptible persons is one of the most conditions, the duration of the light/dark cycle is the key common explanations for seasonal infectious diseases, and it parameter governing these seasonal changes, which can be certainly has biologic plausibility. The seasonal patterns of completely replicated by artificial manipulation of the measles in England and Wales have been attributed to the photoperiod. Photoperiod is most commonly used rather than timing of school holidays (29,30). Although such explanations temperature, humidity, food availability, or other seasonally are plausible, one must also ask why influenza outbreaks do varying parameters, presumably because its invariant nature not occur in crowded international conventions during best prevents accidental breeding at the wrong time of year. summer, and why measles outbreaks are not common at Under constant photoperiod, the physiologic changes can also summer camps. As one authority noted regarding meningo- be reproduced by controlling the duration of the daily coccal seasonality, “The story that African epidemics are melatonin pulse. caused by people crowding together at night during the dry Seasonal physiologic changes have also been documented season is a medical myth which is difficult to kill. Villagers in processes not typically associated with breeding but sleep inside at the height of the rainy season at least as potentially related to susceptibility to infectious agents. For frequently as during the cold part of the dry season...” (24). example, even under constant conditions, red deer have Comprehensive explanations of seasonal changes in distinct seasonal changes in digestive features (35), mice have infectious diseases should identify the means by which seasonal changes in seizure threshold (38), and dairy cattle similar pathogens peak at different seasons (with character- have seasonal changes in the fat and protein content of their istic timing and duration) and explain the prompt regionwide milk (39). In recent years, seasonal changes in immunologic epidemics in geographically dispersed populations, the features have been documented. For example, Siberian variation in epidemic patterns by latitude, and the hamsters exposed to short-day photoperiod demonstrate persistence of the pathogen in the off-season without epidemic increased natural killer-cell activity and lymphocyte disease (Table). blastogenesis but decreased phagocytosis and oxidative burst activity by granulocytes (40); deer mice treated with The Proposed Hypothesis melatonin in constant photoperiod exhibit increased Regular annual variations in the incidence of many lymphocyte response to mitogen stimulation (41). infectious diseases may be due to changes in susceptibility of A series of studies documented that the death rate in mice the human host to the particular pathogen. Like the seasonal experimentally exposed to pneumococcal infection varied physiologic cycles of many mammalian species, these changes with the time of day (42-44). Survival patterns were altered by in susceptibility may be timed to the light/dark cycle, modifying environmental lighting conditions, rather than Vol. 7, No. 3, May–June 2001 371 Emerging Infectious Diseases Perspective feeding or activity, and susceptibility appeared related to the constant temperature and humidity, and observed that 34% daily cycle of cortisone, although the specific physiologic were infected in May to October, compared with 58% in feature responsible for increased susceptibility was not November to April (p <0.001). The photoperiod conditions in identified. Since these findings, understanding of the role of these experiments were not noted. melatonin and its control of circadean and seasonal rhythms It is not clear whether attempts were made to replicate has increased greatly, but further studies of the influence of these provocative experiments or if the potential importance photoperiod on experimental pneumococcal infections in mice of the observations was fully appreciated. The animal appear not to have been pursued. experiments may be relatively easy to confirm or refute, and Seasonal physiologic changes are not as well character- the many live attenuated vaccines currently tested or used ized for humans as for other mammals, but mounting data should provide ample material to evaluate the effects of suggest that changes in photoperiod and the melatonin pulse season on immunogenicity or reactogenicity. The season of may also influence human physiology (32). Blind people, who administration influences seroconversion rates to oral polio lack the capability for light to cue their biologic clocks, are vaccine (57,58) and protection against polio (59), but much of often plagued by free-running circadian rhythms. A recent this seasonal variation may be attributable to competition by study demonstrated that these free-running rhythms can be other enteroviruses during summer (57). Vaccine-associated entrained to a normal cycle by daily administration of paralytic polio among vaccine contacts reflects the seasonal melatonin (45). Although humans are sexually active year- pattern of natural polio (60). round, a seasonal distribution in conceptions has consistently been demonstrated, and a variation in the ovulation rate has Conclusion been postulated as the cause (31). Seasonal affective disorder, Photoperiod-driven changes in host physiology might a well-characterized depression associated with short days explain certain enigmatic observations about seasonality, but and specific genetic defects (46), is treatable with extra hours some observations remain unexplained. For example, the of exposure to broad-spectrum light (47). Seasonal variations west-east movement of rotavirus is not easily attributable to in heart attacks (48), breast cancer (49), and other seemingly host susceptibility changes timed to the light/dark cycle (5). noninfectious conditions have also been reported. The increase in hospitalizations coincident with warm Recent research has focused on seasonal changes in weather and El Nino points to temperature rather than immunologic values in humans. Specific melatonin receptors photoperiod as a key influence on some diarrheal disease coupled with G-protein have been identified on lymphocytes pathogens (20). The sudden appearance and worldwide (50). As in rodents, seasonal variations in lymphocyte spread of a new pandemic strain of influenza virus also argues mitogenic responses and in the quantity of circulating more for chains of transmission than for a crop of outbreaks lymphocytes, neutrophils, CD4 and CD8 cells, and IL-6 have from virus already present in the population. been reported (51-53). Some values, such as lymphocyte aryl Epidemiologists have long puzzled over why seasonal hydrocarbon hydroxylase activity, peak in summer (54), while infectious disease outbreaks occur when they do. Perhaps the others, such as number of circulating B cells, peak in winter more important question is why they do not occur when they (52). Although statistically significant, the functional do not. Is the human population already relatively resistant significance of these variations has not yet been established. for 6 to 9 months each year? If the absence of epidemics of summer influenza or winter polio is attributable to climate or Testing the Hypothesis weather, we may have little power to influence them. On the The above observations lend some biologic plausibility to other hand, if these annual troughs are due to increased host the proposed hypothesis, but direct testing is needed. Several resistance, opportunities abound for studying and modifying observations support the prediction that the host is less these changes. Such opportunities might include reviews of susceptible to infection or disease in the off-season. existing databases, careful evaluation of “experiments of In a double-blind placebo-controlled trial conducted in nature,” and studies in laboratory animals. the Soviet Union during different seasons, nonimmune Databases surely exist that might shed light on this volunteers were given attenuated live influenza vaccine hypothesis. Clinical trials of live attenuated vaccines during intranasally (55). Febrile reactions attributable to vaccine the usual seasonal peak and seasonal trough for that (calculated by subtracting the proportion of participants with particular disease could be reviewed for seasonal differences reactions in the placebo group from the proportion in the in reactogenicity and immunogenicity. Experiments of vaccine group) were observed in 6.7% of 360 volunteers nature, in which groups adapted to summer come into contact inoculated in Leningrad in January, compared with 0.8% of with groups adapted to winter (as in a convention or a cruise 197 inoculated in June (p = 0.003). Fourfold rises in antibody ship with passengers from both Southern Hemisphere and titer were seen in 31% to 40% in Krasnodar in January, Northern Hemisphere countries) and are exposed to a depending on the vaccine strain, compared with 4.3% to 4.8% seasonal pathogen (such as influenza or an enterovirus), given the same strains in May and October (all p <0.001). could be analyzed for differences in attack rate or clinical Similar trends with less significant differences were seen in severity. Laboratory animals housed in photoperiod- three other cities. controlled rooms could be exposed to seasonal pathogens and Some years earlier, in a series of experiments on the evaluated to see if photoperiod or melatonin modifies clinical transmission of influenza virus from infected to susceptible and physiologic responses to infection. If differences are mice, <1% of mice exposed from July to October were infected, documented, the specific physiologic feature governing compared with 22% of those exposed in December or January susceptibility changes could be isolated and identified. (p <0.001) (56). One year later, the investigators repeated the It is time to have a closer look at these possible seasonal experiment with a different strain of mice, now kept under changes in host susceptibility and if they are confirmed, Emerging Infectious Diseases Vol. 7, No. 3, May–June 2001 Perspective 21. Chew F, Doraisingham S, Ling A, Kumarasinghe G, Lee B. identify and modify the physiologic changes underlying Seasonal trends of viral respiratory tract infections in the tropics. annual cycles of infectious diseases. Epidemiol Infect 1998;121:121-8. 22. Sung R, Murray H, Chan R, Davies D, French G. 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Seasonal variation in host susceptibility and cycles of certain infectious diseases.

Emerging Infectious Diseases , Volume 7 (3) – Sep 1, 167

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Perspective Seasonal Variation in Host Susceptibility and Cycles of Certain Infectious Diseases Scott F. Dowell Centers for Disease Control and Prevention, Atlanta, Georgia, USA Seasonal cycles of infectious diseases have been variously attributed to changes in atmospheric conditions, the prevalence or virulence of the pathogen, or the behavior of the host. Some observations about seasonality are difficult to reconcile with these explanations. These include the simultaneous appearance of outbreaks across widespread geographic regions of the same latitude; the detection of pathogens in the off-season without epidemic spread; and the consistency of seasonal changes, despite wide variations in weather and human behavior. In contrast, an increase in susceptibility of the host population, perhaps linked to the annual light/dark cycle and mediated by the pattern of melatonin secretion, might account for many heretofore unexplained features of infectious disease seasonality. Ample evidence indicates that photoperiod- driven physiologic changes are typical in mammalian species, including some in humans. If such physiologic changes underlie human resistance to infectious diseases for large portions of the year and the changes can be identified and modified, the therapeutic and preventive implications may be considerable. From 1703 onward, the annual rise and fall of measles deaths in London was recorded in sufficient detail to allow for careful mathematical modeling in 1918 (1). Since then, surveillance for a variety of diseases has established that regular seasonal variation in incidence is the rule, rather than the exception, for acute infections. Seasonal variations should be distinguished from periodic large epidemics, as observed every 2 years for measles (2) or at less frequent and more irregular intervals for meningococcal meningitis (3) and rubella (4). This discussion will focus on the more robust annual cycle, which “locks in” large epidemics to the same time of year (3,4) and persists even after large epidemics have been eliminated by mass vaccination (2). The life cycles of pathogens spread by insect vectors or maintained in animal or environmental reservoirs add complexity because seasonal changes might influence not only the pathogen or human host but also the vector population and animal or environmental reservoir. Therefore, this discussion will focus on bacterial and viral pathogens maintained primarily by person-to- person spread. The regular and predictable pattern of seasonal outbreaks dominates the epidemiology of many exclusively human pathogens (Figure 1). Different infections peak in each of the four seasons, but for each pathogen, the timing and characteristics of the annual outbreak are remarkably consistent from year to year. Other key observations have been made on the seasonality of infectious diseases, including the simultaneous onset of outbreaks in geographically remote areas and the persistence of pathogens in the off-season in the Figure 1. Seasonal variation in the occurrence of three human pathogens in the U.S. A: an annual cycle of rubella activity was absence of epidemic spread (Table). In fact, latitude has a maintained between larger epidemics, which occurred every 6 to 9 clear influence on the timing and magnitude of outbreaks of years. B: percentage of specimens testing positive for influenza viruses rotavirus infection (10), influenza (15), and poliomyelitis among specimens tested by World Health Organization and U.S. National Respiratory and Enteric Virus Surveillance System Address for correspondence: Scott F. Dowell, Centers for Disease collaborating laboratories. C: a consistent pattern of rotavirus Control and Prevention, 1600 Clifton Road NE, Mailstop C12, Atlanta, seasonality is evident in the U.S. National Respiratory and Enteric GA 30333, USA; fax: 404-639-3039; e-mail: sdowell@cdc.gov Virus Surveillance System. Adapted from references 4-6. Vol. 7, No. 3, May–June 2001 369 Emerging Infectious Diseases Perspective Table. Observations on the seasonal occurrence of infectious diseases Observation Examples Pathogens peak at characteristic times in Winter: influenza, pneumococcus, rotavirus all seasons of the year Spring: RSV, measles Summer: polio, other enteroviruses Fall: parainfluenza virus type 1 Timing and duration of peaks for each Measles: regular pattern since 1703 (1) pathogen are similar from year to year Influenza: annual peak varies by only 5 to 10 weeks in the United States (6) Onset of epidemics often occurs simultaneously Influenza: simultaneous outbreaks across North America, 16 European in areas that are geographically dispersed countries, and 6 Chinese provinces (7) and have different weather conditions and Pneumococcus: simultaneous outbreaks in seven surveillance areas (8) diverse populations Latitude is a critical determinant of timing An increasing magnitude of seasonal peaks as distance from the equator and magnitude of peaks increases has been documented for polio (9) and rotavirus (10) and reported for influenza (11). Pathogens can be detected in the off-season Meningococcus: no decrease in carriage in the off-season, despite despite lower incidence of disease and absence of epidemic disease (12) virtual absence of epidemics RSV: sporadic summer viral isolation but no epidemic spread (13) Influenza: sporadic summer isolation, occasional clusters of disease without epidemic spread (14) RSV = respiratory syncytial virus. RSV peaks in the winter or spring in the United States, depending on location. For simplicity, it is listed here as a spring pathogen. (Figure 2) (9). Reconciling these observations with the Pathogen Appearance and Disappearance consistent seasonality of clinical illness is a continuing Perhaps the most obvious explanation for the absence of challenge. disease during a period is that the pathogen is also absent during the period. However, the regular annual migration of Explanations of Seasonality epidemics of influenza, poliomyelitis, and rotavirus infection Because seasonal cycles of infectious diseases are so from northern latitudes across the equator to southern ones universal and no single theory has proved satisfactory, and back does not necessarily imply that the pathogens explanations about their cause abound. More than one themselves migrate in this way. explanation or combination of explanations may be true. Current theory holds that influenza is maintained only Explanations can be grouped into three types: pathogen by direct spread in a series of chains of transmission from one appearance and disappearance, environmental changes, and ill person to another (16). Some evidence suggests that host-behavior changes. influenza viruses do spread geographically, particularly during pandemics, but whether geographic spread accounts for the patterns observed in annual outbreaks has been questioned (11,17,18). The simultaneous onset of geographi- cally widespread outbreaks is difficult to reconcile with Latitude chains of person-to-person transmission. One hypothesis is that earlier “seeding” of the virus throughout the population must have occurred (17). During an 1826 influenza epidemic, one observer wrote, “...this epidemic affects a whole region in the space of a week, nay, a whole continent as large as North America, together with all the West Indies, in the course of a few weeks, while the inhabitants could not within so short a time have had any communication or intercourse whatever across such a vast extent of country” (11). A more recent hypothesis attributes geographic spread to the atmospheric dispersion of virus from Southeast Asia by trans-Pacific winds across the North American continent (18). Environmental Changes Environmental changes, particularly changes in weath- er, are the explanations most often invoked for the seasonality of infectious diseases. Statistically significant correlations between epidemic cycles and cycles of temperature (19-22), humidity (21-23), rains (24), or winds (24) have been identified. However, correlations may be found with Figure 2. Seasonal variation in the incidence of poliomyelitis by confounders as well as with causes. latitude, 1956-57. As distance from the equator increases, a higher In some cases, the association with weather is supported, proportion of cases are evident in summer and fall months. Adapted from reference 9. but the biologic plausibility appears tenuous. Although the Emerging Infectious Diseases Vol. 7, No. 3, May–June 2001 Monthly % of cases Perspective seasonal incidence of poliomyelitis correlated quite well with typically mediated by changes in the duration of the daily the summer increase in relative humidity in Boston and melatonin pulse. The changes in susceptibility may be Houston from 1942 to 1951 (23), the explanation that distinct for different pathogens and may cover a broad range aerosolized poliovirus survives for a longer time at higher of possibilities, including (but not limited to) changes in the relative humidity is difficult to reconcile with the fecal-oral characteristic of mucosal surfaces, the expression of epithelial route of poliovirus transmission. receptors, the leukocyte numbers or responsiveness, or other In other cases, the correlations are supported by biologic features of specific or nonspecific immunity. plausibility but are not consistently observed. In sub- This hypothesis would predict that pathogens do not Saharan Africa, the onset of meningococcal epidemics closely physically migrate across the equator and that nationwide followed the season of dry winds and ended with the onset of epidemics do not necessarily result from chains of person-to- the rains (25). It has been proposed that drying of mucosal person transmission. Rather, the pathogens may be present surfaces increases the probability of bacteremic spread and in the population year-round, and epidemics occur when the that the rains moisten the mucosa or decrease the spread of susceptibility of the population increases enough to sustain the organism by dust. However, in Oregon and other areas, them. Perhaps the most significant prediction is that people meningococcal disease peaks during the rainy season (26). are relatively resistant to disease if exposed in the off-season Similarly, a significant correlation between the onset of the and that the specific physiologic process leading to seasonal invasive pneumococcal disease season and a drop in mean resistance should be identifiable and perhaps modifiable. C in Houston (19) was not daily temperatures below 24 confirmed in seven other areas with more widely varying Seasonal Changes in Host Physiology weather patterns (8). Respiratory syncytial virus epidemics Many mammalian species undergo seasonal physiologic occur in the colder months of winter and spring in the United changes. The best characterized are changes in reproductive States (13) but paradoxically are significantly correlated with organs and other tissues seen in animals that are seasonal the hotter months in Singapore and Hong Kong (21,22). breeders. Humans are not seasonal breeders, but fertility has seasonal variations. Seasonal variations have been documented Host-Behavior Changes in other physiologic processes and immunologic features (31,32). Seasonal changes in poliomyelitis, measles, and other Producing offspring in a season during which food is seasonal infectious diseases have been attributed to changes unavailable and the environment is unsuitable for the young in the behavior of the host. Public swimming pools were a is an evolutionary dead-end for some species, leading to source of great concern during the polio epidemics of the carefully regulated breeding seasons for many rodents (33), 1950s, and summer peaks in polio and other enteroviruses sheep (34), other ungulates (35), monkeys (36), and primates were attributed to swimming (23,27,28). Subsequent studies (37). Seasonal physiologic changes involve not just behavior discounted the importance of swimming in the spread of but also the secretion of sex hormones and the size and enterovirus infections (28). function of reproductive organs. In controlled laboratory Crowding of susceptible persons is one of the most conditions, the duration of the light/dark cycle is the key common explanations for seasonal infectious diseases, and it parameter governing these seasonal changes, which can be certainly has biologic plausibility. The seasonal patterns of completely replicated by artificial manipulation of the measles in England and Wales have been attributed to the photoperiod. Photoperiod is most commonly used rather than timing of school holidays (29,30). Although such explanations temperature, humidity, food availability, or other seasonally are plausible, one must also ask why influenza outbreaks do varying parameters, presumably because its invariant nature not occur in crowded international conventions during best prevents accidental breeding at the wrong time of year. summer, and why measles outbreaks are not common at Under constant photoperiod, the physiologic changes can also summer camps. As one authority noted regarding meningo- be reproduced by controlling the duration of the daily coccal seasonality, “The story that African epidemics are melatonin pulse. caused by people crowding together at night during the dry Seasonal physiologic changes have also been documented season is a medical myth which is difficult to kill. Villagers in processes not typically associated with breeding but sleep inside at the height of the rainy season at least as potentially related to susceptibility to infectious agents. For frequently as during the cold part of the dry season...” (24). example, even under constant conditions, red deer have Comprehensive explanations of seasonal changes in distinct seasonal changes in digestive features (35), mice have infectious diseases should identify the means by which seasonal changes in seizure threshold (38), and dairy cattle similar pathogens peak at different seasons (with character- have seasonal changes in the fat and protein content of their istic timing and duration) and explain the prompt regionwide milk (39). In recent years, seasonal changes in immunologic epidemics in geographically dispersed populations, the features have been documented. For example, Siberian variation in epidemic patterns by latitude, and the hamsters exposed to short-day photoperiod demonstrate persistence of the pathogen in the off-season without epidemic increased natural killer-cell activity and lymphocyte disease (Table). blastogenesis but decreased phagocytosis and oxidative burst activity by granulocytes (40); deer mice treated with The Proposed Hypothesis melatonin in constant photoperiod exhibit increased Regular annual variations in the incidence of many lymphocyte response to mitogen stimulation (41). infectious diseases may be due to changes in susceptibility of A series of studies documented that the death rate in mice the human host to the particular pathogen. Like the seasonal experimentally exposed to pneumococcal infection varied physiologic cycles of many mammalian species, these changes with the time of day (42-44). Survival patterns were altered by in susceptibility may be timed to the light/dark cycle, modifying environmental lighting conditions, rather than Vol. 7, No. 3, May–June 2001 371 Emerging Infectious Diseases Perspective feeding or activity, and susceptibility appeared related to the constant temperature and humidity, and observed that 34% daily cycle of cortisone, although the specific physiologic were infected in May to October, compared with 58% in feature responsible for increased susceptibility was not November to April (p <0.001). The photoperiod conditions in identified. Since these findings, understanding of the role of these experiments were not noted. melatonin and its control of circadean and seasonal rhythms It is not clear whether attempts were made to replicate has increased greatly, but further studies of the influence of these provocative experiments or if the potential importance photoperiod on experimental pneumococcal infections in mice of the observations was fully appreciated. The animal appear not to have been pursued. experiments may be relatively easy to confirm or refute, and Seasonal physiologic changes are not as well character- the many live attenuated vaccines currently tested or used ized for humans as for other mammals, but mounting data should provide ample material to evaluate the effects of suggest that changes in photoperiod and the melatonin pulse season on immunogenicity or reactogenicity. The season of may also influence human physiology (32). Blind people, who administration influences seroconversion rates to oral polio lack the capability for light to cue their biologic clocks, are vaccine (57,58) and protection against polio (59), but much of often plagued by free-running circadian rhythms. A recent this seasonal variation may be attributable to competition by study demonstrated that these free-running rhythms can be other enteroviruses during summer (57). Vaccine-associated entrained to a normal cycle by daily administration of paralytic polio among vaccine contacts reflects the seasonal melatonin (45). Although humans are sexually active year- pattern of natural polio (60). round, a seasonal distribution in conceptions has consistently been demonstrated, and a variation in the ovulation rate has Conclusion been postulated as the cause (31). Seasonal affective disorder, Photoperiod-driven changes in host physiology might a well-characterized depression associated with short days explain certain enigmatic observations about seasonality, but and specific genetic defects (46), is treatable with extra hours some observations remain unexplained. For example, the of exposure to broad-spectrum light (47). Seasonal variations west-east movement of rotavirus is not easily attributable to in heart attacks (48), breast cancer (49), and other seemingly host susceptibility changes timed to the light/dark cycle (5). noninfectious conditions have also been reported. The increase in hospitalizations coincident with warm Recent research has focused on seasonal changes in weather and El Nino points to temperature rather than immunologic values in humans. Specific melatonin receptors photoperiod as a key influence on some diarrheal disease coupled with G-protein have been identified on lymphocytes pathogens (20). The sudden appearance and worldwide (50). As in rodents, seasonal variations in lymphocyte spread of a new pandemic strain of influenza virus also argues mitogenic responses and in the quantity of circulating more for chains of transmission than for a crop of outbreaks lymphocytes, neutrophils, CD4 and CD8 cells, and IL-6 have from virus already present in the population. been reported (51-53). Some values, such as lymphocyte aryl Epidemiologists have long puzzled over why seasonal hydrocarbon hydroxylase activity, peak in summer (54), while infectious disease outbreaks occur when they do. Perhaps the others, such as number of circulating B cells, peak in winter more important question is why they do not occur when they (52). Although statistically significant, the functional do not. Is the human population already relatively resistant significance of these variations has not yet been established. for 6 to 9 months each year? If the absence of epidemics of summer influenza or winter polio is attributable to climate or Testing the Hypothesis weather, we may have little power to influence them. On the The above observations lend some biologic plausibility to other hand, if these annual troughs are due to increased host the proposed hypothesis, but direct testing is needed. Several resistance, opportunities abound for studying and modifying observations support the prediction that the host is less these changes. Such opportunities might include reviews of susceptible to infection or disease in the off-season. existing databases, careful evaluation of “experiments of In a double-blind placebo-controlled trial conducted in nature,” and studies in laboratory animals. the Soviet Union during different seasons, nonimmune Databases surely exist that might shed light on this volunteers were given attenuated live influenza vaccine hypothesis. Clinical trials of live attenuated vaccines during intranasally (55). Febrile reactions attributable to vaccine the usual seasonal peak and seasonal trough for that (calculated by subtracting the proportion of participants with particular disease could be reviewed for seasonal differences reactions in the placebo group from the proportion in the in reactogenicity and immunogenicity. Experiments of vaccine group) were observed in 6.7% of 360 volunteers nature, in which groups adapted to summer come into contact inoculated in Leningrad in January, compared with 0.8% of with groups adapted to winter (as in a convention or a cruise 197 inoculated in June (p = 0.003). Fourfold rises in antibody ship with passengers from both Southern Hemisphere and titer were seen in 31% to 40% in Krasnodar in January, Northern Hemisphere countries) and are exposed to a depending on the vaccine strain, compared with 4.3% to 4.8% seasonal pathogen (such as influenza or an enterovirus), given the same strains in May and October (all p <0.001). could be analyzed for differences in attack rate or clinical Similar trends with less significant differences were seen in severity. Laboratory animals housed in photoperiod- three other cities. controlled rooms could be exposed to seasonal pathogens and Some years earlier, in a series of experiments on the evaluated to see if photoperiod or melatonin modifies clinical transmission of influenza virus from infected to susceptible and physiologic responses to infection. 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