Wladimir J. Alonso

Global Influenza Seasonality: Reconciling Patterns across Temperate and Tropical Regions

Background Despite the significant disease burden of the influenza virus in humans, our understanding of the basis for its pronounced seasonality remains incomplete. Past observations that influenza epidemics occur in the winter across temperate climates, combined with insufficient knowledge about the epidemiology of influenza in the tropics, led to the perception that cool and dry conditions were a necessary, and possibly sufficient, driver of influenza epidemics. Recent reports of substantial levels of influenza virus activity and well-defined seasonality in tropical regions, where warm and humid conditions often persist year-round, have rendered previous hypotheses insufficient for explaining global patterns of influenza. Objective In this review, we examined the scientific evidence for the seasonal mechanisms that potentially explain the complex seasonal patterns of influenza disease activity observed globally. Methods In this review we assessed the strength of a range of hypotheses that attempt to explain observations of influenza seasonality across different latitudes and how they relate to each other. We reviewed studies describing population-scale observations, mathematical models, and ecological, laboratory, and clinical experiments pertaining to influenza seasonality. The literature review includes studies that directly mention the topic of influenza seasonality, as well as other topics we believed to be relevant. We also developed an analytical framework that highlights the complex interactions among environmental stimuli, mediating mechanisms, and the seasonal timing of influenza epidemics and identify critical areas for further research. Conclusions The central questions in influenza seasonality remain unresolved. Future research is particularly needed in tropical localities, where our understanding of seasonality remains poor, and will require a combination of experimental and observational studies. Further understanding of the environmental factors that drive influenza circulation also may be useful to predict how dynamics will be affected at regional levels by global climate change.

Demographic Variability, Vaccination, and the Spatiotemporal Dynamics of Rotavirus Epidemics

Ecology of Diarrhea Rotavirus is an important cause of morbidity and mortality globally, and, although the infection takes a terrible toll on infant lives, its epidemiology is rather poorly known. New vaccines have become available and are being introduced in the United States prior to global rollout, but they may have some unexpected effects on disease dynamics. Pitzer et al. (p. 290; see the Perspective by Medley and Nokes) analyzed data and developed models describing the epidemiology of rotavirus before and during adoption of the vaccine. Ecological analysis showed that the birth rate predicted the timing of epidemics much better than climatic variables and that shifts in birth rates explained changes over the years. But as increasing numbers of infants are vaccinated, the pool of susceptible individuals in the population will be reduced, which will affect the annual waves of geographic spread of rotavirus. Diarrhea-causing rotavirus epidemics can be predicted by shifts in birth rate rather than by seasonal variables. Historically, annual rotavirus activity in the United States has started in the southwest in late fall and ended in the northeast 3 months later; this trend has diminished in recent years. Traveling waves of infection or local environmental drivers cannot account for these patterns. A transmission model calibrated against epidemiological data shows that spatiotemporal variation in birth rate can explain the timing of rotavirus epidemics. The recent large-scale introduction of rotavirus vaccination provides a natural experiment to further test the impact of susceptible recruitment on disease dynamics. The model predicts a pattern of reduced and lagged epidemics postvaccination, closely matching the observed dynamics. Armed with this validated model, we explore the relative importance of direct and indirect protection, a key issue in determining the worldwide benefits of vaccination.

Latitudinal Variations in Seasonal Activity of Influenza and Respiratory Syncytial Virus (RSV): A Global Comparative Review

Background There is limited information on influenza and respiratory syncytial virus (RSV) seasonal patterns in tropical areas, although there is renewed interest in understanding the seasonal drivers of respiratory viruses. Methods We review geographic variations in seasonality of laboratory-confirmed influenza and RSV epidemics in 137 global locations based on literature review and electronic sources. We assessed peak timing and epidemic duration and explored their association with geography and study settings. We fitted time series model to weekly national data available from the WHO influenza surveillance system (FluNet) to further characterize seasonal parameters. Results Influenza and RSV activity consistently peaked during winter months in temperate locales, while there was greater diversity in the tropics. Several temperate locations experienced semi-annual influenza activity with peaks occurring in winter and summer. Semi-annual activity was relatively common in tropical areas of Southeast Asia for both viruses. Biennial cycles of RSV activity were identified in Northern Europe. Both viruses exhibited weak latitudinal gradients in the timing of epidemics by hemisphere, with peak timing occurring later in the calendar year with increasing latitude (P<0.03). Time series model applied to influenza data from 85 countries confirmed the presence of latitudinal gradients in timing, duration, seasonal amplitude, and between-year variability of epidemics. Overall, 80% of tropical locations experienced distinct RSV seasons lasting 6 months or less, while the percentage was 50% for influenza. Conclusion Our review combining literature and electronic data sources suggests that a large fraction of tropical locations experience focused seasons of respiratory virus activity in individual years. Information on seasonal patterns remains limited in large undersampled regions, included Africa and Central America. Future studies should attempt to link the observed latitudinal gradients in seasonality of viral epidemics with climatic and population factors, and explore regional differences in disease transmission dynamics and attack rates.

The 1918–1919 influenza pandemic in England and Wales: spatial patterns in transmissibility and mortality impact

Spatial variations in disease patterns of the 1918–1919 influenza pandemic remain poorly studied. We explored the association between influenza death rates, transmissibility and several geographical and demographic indicators for the autumn and winter waves of the 1918–1919 pandemic in cities, towns and rural areas of England and Wales. Average measures of transmissibility, estimated by the reproduction number, ranged between 1.3 and 1.9, depending on model assumptions and pandemic wave and showed little spatial variation. Death rates varied markedly with urbanization, with 30–40% higher rates in cities and towns compared with rural areas. In addition, death rates varied with population size across rural settings, where low population areas fared worse. By contrast, we found no association between transmissibility, death rates and indicators of population density and residential crowding. Further studies of the geographical mortality patterns associated with the 1918–1919 influenza pandemic may be useful for pandemic planning.

Global seasonality of rotavirus disease.

Background: A substantial number of surveillance studies have documented rotavirus prevalence among children admitted for dehydrating diarrhea. We sought to establish global seasonal patterns of rotavirus disease before the introduction of widespread vaccination. Methods: We reviewed studies of rotavirus detection in children with diarrhea published since 1995. We assessed potential relationships between seasonal prevalence and locality by plotting the average monthly proportion of diarrhea cases positive for rotavirus according to geography, country development and latitude. We used linear regression to identify variables that were potentially associated with the seasonal intensity of rotavirus. Results: Among a total of 99 studies representing all 6 geographic regions of the world, patterns of year-round disease were more evident in low- and low-middle income countries compared with upper-middle and high-income countries where disease was more likely to be seasonal. The level of country development was a stronger predictor of strength of seasonality (P = 0.001) than geographic location or climate. However, the observation of distinctly different seasonal patterns of rotavirus disease in some countries with similar geographic location, climate and level of development indicate that a single unifying explanation for variation in seasonality of rotavirus disease is unlikely. Conclusion: While no unifying explanation emerged for varying rotavirus seasonality globally, the country income level was somewhat more predictive of the likelihood of having seasonal disease than other factors. Future evaluation of the effect of rotavirus vaccination on seasonal patterns of disease in different settings may help understand factors that drive the global seasonality of rotavirus disease.

The Dilemma of Influenza Vaccine Recommendations when Applied to the Tropics: The Brazilian Case Examined Under Alternative Scenarios

Since 1999 the World Health Organization issues annually an additional influenza vaccine composition recommendation. This initiative aimed to extend to the Southern Hemisphere (SH) the benefits—previously enjoyed only by the Northern Hemisphere (NH)—of a vaccine recommendation issued as close as possible to the moment just before the onset of the influenza epidemic season. A short time between the issue of the recommendation and vaccine delivery is needed to maximize the chances of correct matching between putative circulating strains and one of the three strains present in the vaccine composition. Here we compare the effectiveness of the SH influenza vaccination adopted in Brazil with hypothetical alternative scenarios defined by different timings of vaccine delivery and/or composition. Scores were based on the temporal overlap between vaccine-induced protection and circulating strains. Viral data were obtained between 1999 and 2007 from constant surveillance and strain characterization in two Brazilian cities: Belém, located at the Equatorial region, and São Paulo, at the limit between the tropical and subtropical regions. Our results show that, among currently feasible options, the best strategy for Brazil would be to adopt the NH composition and timing, as in such case protection would increase from 30% to 65% (p<.01) if past data can be used as a prediction of the future. The influenza season starts in Brazil (and in the equator virtually ends) well before the SH winter, making the current delivery of the SH vaccination in April too late to be effective. Since Brazil encompasses a large area of the Southern Hemisphere, our results point to the possibility of these conclusions being similarly valid for other tropical regions.

Cognition in an ever-changing world: climatic variability is associated with brain size in Neotropical parrots.

Research on the conditions favoring the evolution of complex cognition and its underlying neural structures has increasingly stressed the role of environmental variability. These studies suggest that the ability to learn, behave flexibly and innovate would be favored under unpredictable variations in the availability of resources, as it would enable organisms to adjust to novel conditions. Despite the growing number of studies based on the idea that larger-brained organisms would be better prepared to cope with environmental challenges, direct testing of the association between brain size and environmental variability per se remains scant. Here we focus on Neotropical parrots as our model group and test the hypothesis that if relatively larger brains were favored in climatically variable environments, larger-brained species should currently tolerate a higher degree of environmental uncertainty. Although we show that there are also other factors underlying the dynamics of brain size variation in this group, our results support the hypothesis that proportionally larger-brained species are more tolerant to climatic variability, both on a temporal and spatial scale. Additionally, they suggest that the differences in relative brain size among Neotropical parrots represent multiple, recent events in the evolutionary history of the group, and are particularly tied to an increased dependence on more open and climatically unstable habitats. As this is the first study to present evidence of the link between brain size and climatic variability in birds, our findings provide a step towards understanding the potential benefits underlying variation in brain size and the maintenance of highly enlarged brains in this and other groups.

Temporal Trends and Climatic Factors Associated with Bacterial Enteric Diseases in Vietnam, 1991–2001

Objective In Vietnam, shigellosis/dysentery, typhoid fever, and cholera are important enteric diseases. To better understand their epidemiology, we determined temporal trends, seasonal patterns, and climatic factors associated with high risk periods in eight regions across Vietnam. Methods We quantified monthly cases and incidence rates (IR) for each region from national surveillance data (1991–2001). High- and low-disease periods were defined from the highest and lowest IRs (1 SD above and below the mean) and from outbreaks from positive outliers (4 SDs higher in 1 month or 2 SDs higher in ≥ 2 consecutive months). We used general linear models to compare precipitation, temperature, and humidity between high- and low-risk periods. Results Shigellosis/dysentery was widespread and increased 2.5 times during the study period, with the highest average IRs found between June and August (2.1/100,000–26.2/100,000). Typhoid fever was endemic in the Mekong River Delta and emerged in the Northwest in the mid-1990s, with peaks between April and August (0.38–8.6). Cholera was mostly epidemic along the central coast between May and November (0.07–2.7), and then decreased dramatically nationwide from 1997 onward. Significant climate differences were found only between high- and low-disease periods. We were able to define 4 shigellosis/dysentery, 14 typhoid fever, and 8 cholera outbreaks, with minimal geotemporal overlap and no significant climatic associations. Conclusions In Vietnam, bacterial enteric diseases have distinct temporal trends and seasonal patterns. Climate plays a role in defining high- and low-disease periods, but it does not appear to be an important factor influencing outbreaks.

Spatio-temporal tracking and phylodynamics of an urban dengue 3 outbreak in São Paulo, Brazil.

The dengue virus has a single-stranded positive-sense RNA genome of ∼10.700 nucleotides with a single open reading frame that encodes three structural (C, prM, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. It possesses four antigenically distinct serotypes (DENV 1–4). Many phylogenetic studies address particularities of the different serotypes using convenience samples that are not conducive to a spatio-temporal analysis in a single urban setting. We describe the pattern of spread of distinct lineages of DENV-3 circulating in São José do Rio Preto, Brazil, during 2006. Blood samples from patients presenting dengue-like symptoms were collected for DENV testing. We performed M-N-PCR using primers based on NS5 for virus detection and identification. The fragments were purified from PCR mixtures and sequenced. The positive dengue cases were geo-coded. To type the sequenced samples, 52 reference sequences were aligned. The dataset generated was used for iterative phylogenetic reconstruction with the maximum likelihood criterion. The best demographic model, the rate of growth, rate of evolutionary change, and Time to Most Recent Common Ancestor (TMRCA) were estimated. The basic reproductive rate during the epidemics was estimated. We obtained sequences from 82 patients among 174 blood samples. We were able to geo-code 46 sequences. The alignment generated a 399-nucleotide-long dataset with 134 taxa. The phylogenetic analysis indicated that all samples were of DENV-3 and related to strains circulating on the isle of Martinique in 2000–2001. Sixty DENV-3 from São José do Rio Preto formed a monophyletic group (lineage 1), closely related to the remaining 22 isolates (lineage 2). We assumed that these lineages appeared before 2006 in different occasions. By transforming the inferred exponential growth rates into the basic reproductive rate, we obtained values for lineage 1 of R0 = 1.53 and values for lineage 2 of R0 = 1.13. Under the exponential model, TMRCA of lineage 1 dated 1 year and lineage 2 dated 3.4 years before the last sampling. The possibility of inferring the spatio-temporal dynamics from genetic data has been generally little explored, and it may shed light on DENV circulation. The use of both geographic and temporally structured phylogenetic data provided a detailed view on the spread of at least two dengue viral strains in a populated urban area.

Comparative dynamics, morbidity and mortality burden of pediatric viral respiratory infections in an equatorial city.

Background: Although acute respiratory infections (ARIs) are the global leading cause of pediatric morbidity and mortality, the relative impact of viral pathogens on pediatric ARIs is still poorly understood, especially in equatorial settings. Long-term studies of multiple viruses concurrently circulating in these regions are still lacking. Here, we report the results of a systematic prospective surveillance of multiple respiratory viruses conducted every weekday for nearly a decade in an equatorial city in Brazil. Methods: We analyzed the relative burden of influenza, parainfluenza, respiratory syncytial virus (RSV), adenovirus, and metapneumovirus, their seasonality, and their association with climatic and demographic factors, ARI diagnosis, and pediatric mortality. Results and Conclusions: RSV was the primary driver of severe childhood respiratory infections, including pneumonia. RSV was also the virus most strongly associated with respiratory-associated deaths, with RSV circulation and pediatric mortality being in phase. Annual circulation of influenza peaked much earlier than annual mortality due to respiratory causes. The results also show that viral circulation can be strongly seasonal even in equatorial regions, which lack seasons with low temperatures: RSV and influenza were concentrated in the rainy season, whereas parainfluenza predominantly circulated in the dry season. The consistent epidemiologic patterns observed can be used for an effective adjustment of the timing of therapeutic and prophylactic interventions in this and potentially in other equatorial regions.