Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States

Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States
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  Absolute Humidity and the Seasonal Onset of Influenzain the Continental United States Jeffrey Shaman 1 * , Virginia E. Pitzer 2,3,4 , Ce´ cile Viboud 2 , Bryan T. Grenfell 2,4,5 , Marc Lipsitch 6,7,8 1 College of Oceanic and Atmospheric Sciences, Oregon State University, Corvallis, Oregon, United States of America,  2 Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America,  3 Center for Infectious Disease Dynamics, Pennsylvania State University, State College, Pennsylvania, United States of America,  4 Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America,  5 Woodrow Wilson School, PrincetonUniversity, Princeton, New Jersey, United States of America,  6 Center for Communicable Disease Dynamics, Harvard School of Public Health, Harvard University, Boston,Massachusetts, United States of America,  7 Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts, United States of America,  8 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard University, Boston, Massachusetts, United States of America Abstract Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recentreanalysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival andtransmission of the influenza virus. Here, we extend these findings to the human population level, showing that the onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humiditylevels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditionstemper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality. Themodel results indicate that direct modulation of influenza transmissibility by absolute humidity alone is sufficient toproduce this observed seasonality. These findings provide epidemiological support for the hypothesis that absolutehumidity drives seasonal variations of influenza transmission in temperate regions. Citation:  Shaman J, Pitzer VE, Viboud C, Grenfell BT, Lipsitch M (2010) Absolute Humidity and the Seasonal Onset of Influenza in the Continental UnitedStates. PLoS Biol 8(2): e1000316. doi:10.1371/journal.pbio.1000316 Academic Editor:  Neil M. Ferguson, Imperial College London, United Kingdom Received  September 10, 2009;  Accepted  January 20, 2010;  Published  February 23, 2010This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the publicdomain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding:  This work was supported, in part, by the US National Institutes of Health (NIH) Models of Infectious Disease Agent Study program through cooperativeagreements 5U01GM076497 (ML) and 1U54GM088588 (ML and JS). VEP and BG were supported by NIH grant R01GM083983-01, the Bill and Melinda GatesFoundation, the RAPIDD program of the Science and Technology Directorate, US Department of Homeland Security, and the Fogarty International Center, NIH.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests:  The authors have declared that no competing interests exist. Abbreviations:  AH, absolute humidity; P&I, pneumonia and influenza; RH, relative humidity; RMS, root mean square.* E-mail: Introduction In temperate regions, wintertime influenza epidemics are respon-sible for considerable morbidity and mortality [1]. These seasonalepidemics are maintained by the gradual antigenic drift of surfaceantigens, which enables the influenza virus to evade host immuneresponse [2]. Recent influenza epidemics have resulted from thecocirculation of three virus (sub)types, A/H1N1, A/H3N2, and B,with one generally predominant locally in a given winter [3–5]. Incontrast, influenza pandemic activity can occur any time of year,including during spring or summer months, in the rare instanceswhen a novel virus to which humans have little or no immunity jumpsfrom avian or mammalian hosts into the human population, as in theon-going H1N1v pandemic [6–9]. Despite numerous reportsdescribing wintertime transmission of epidemic influenza in temperateregions [10], our understanding of the mechanisms underlying influenza seasonal variation remains very limited.Experimental studies suggest that influenza virus survival withinaerosolized droplets is strongly associated with the absolute humidity(AH) of the ambient air, such that virus survival improves markedlyas AH levels decrease [11]. A similar relationship is observedbetween AH and airborne influenza virus transmission among laboratory guinea pigs, in that transmission increases markedly as AH levels decrease (Figure 1). Within temperate regions of theworld, AH conditions are minimal in winter and maximal insummer (Figure 1D). This seasonal cycle favors a wintertimeincrease of both influenza virus survival and transmission, and mayexplain the observed seasonal peak of influenza morbidity andmortality during winter. Annual wintertime mortality peaks areevident in the long-term mortality records of excess pneumonia andinfluenza (P&I) in the US, a robust indicator of the timing andimpact of epidemics at national and local scales [4] (Figure S1).Here, we develop epidemiological support for these previouslaboratory-based findings implicating AH as a driver of seasonalinfluenza transmission. First, we analyze the spatial and temporal variation of epidemic influenza onset across the continental US,1972–2002, and correlate this observed variability with records of  AH for the same period and locations. Second, we show that amathematical model of influenza transmission in the US canreproduce the spatial and temporal variation of epidemic influenzawhen daily AH conditions within each state are used to modulatethe basic reproductive number,  R  0 (  t   ), of the influenza virus. Results AH and the Onset of Wintertime Influenza Outbreaks Our first test of the hypothesis that low AH drives wintertimeincreases of influenza transmission is to assess whether the onset of  PLoS Biology | 1 February 2010 | Volume 8 | Issue 2 | e1000316  the influenza epidemic each winter—which shows substantialannual variation (Figure S1)—corresponds to a period of unusuallylow AH. We define the onset of wintertime influenza as the date atwhich, for the 2 wk prior, the observed excess P&I mortality ratehad been at or above a prescribed threshold level (e.g., 0.01deaths/100,000 people/day). This onset date was identifiedseparately for each of the 30 winters in the 1972–2002observational record at each of the 48 contiguous states plus theDistrict of Columbia (DC). We then examined the anomalous AH(   AH  9  ) conditions prior to and following these onset dates.  AH  9  isthe local daily deviation of AH from its 31-y mean for each day (asshown for five states in Figure 1D), defined as: AH  ’ ~ AH  { AH   ð 1 Þ where  AH   denotes the 1972–2002 daily average value. Attemperate latitudes, such as in the US, wintertime AH levels arealready much lower than summer (Figure 1D). By using   AH  9 , wecan determine whether the onset of wintertime influenza occurswhen AH is above or below typical local daily AH levels.Negative  AH  9  values are typically observed beginning 4 wk prior to the onset of influenza epidemics (Figure 2), with the largestexcursion occurring 17 d prior to onset. This result is robust to thechoice of the mortality threshold level used to define onset date(from 0.001 to 0.02 excess P&I deaths/100,000 people/day). Toassess the statistical significance of the association betweennegative wintertime  AH  9  and epidemic onset, we bootstrappedthe distribution of observed wintertime  AH  9  records and foundstrong statistical support (   p , 0.0005, see Text S1). Depending onthe threshold used to define onset, 55%–60% of onset datesdemonstrate negative  AH  9 averaged over the 4 wk prior to onset. Although highly statistically significant, this shift from theexpected 50% likelihood is small. These findings indicate thatnegative  AH  9 are not necessary for wintertime influenza onset butinstead presage an increased likelihood of these onset events. Ineffect, negative  AH  9  in the weeks prior to onset provide anadditional increase of influenza virus survival and transmissionover typical local wintertime levels and may further facilitate thespread of the virus.Regional differences in the association of negative  AH  9  withonset date are also evident. The association is strongest in theeastern US, in particular the Gulf region and the northeast(Figures S2, S3, and S4). Although the association does not reachstatistical significance in much of the western US,  AH  9 are typicallynegative during the weeks prior to onset in this region as well.Next, we used the same approach to examine whether otherpotential environmental drivers of influenza are associated withwintertime influenza onset. The findings indicate that negativerelative humidity (RH) and temperature anomalies, as well aspositive solar insolation anomalies, are also associated with onsetdate (Table 1). However, the direction of the associations of thedaily wintertime anomalies of solar insolation and RH withepidemic onset are contrary to the association between theseenvironmental factors and epidemic activity at the seasonal timescale. Decreased solar insolation during the winter months isposited to increase influenza activity by decreasing host melatoninand vitamin D levels and thus host resistance [12,13]; however,our findings indicate that influenza onset is associated with  increased  daily solar insolation anomalies. Similarly, RH is highest in winter[11], but influenza onset is associated with  low   RH anomalies.Specific weather patterns may explain the observed correlationsbetween these meteorological anomalies and influenza onset. Anomalously low AH over the continental US is typicallyassociated with excursions of colder air masses from the north.These air masses, which often follow a cold front, bring cloud-freeskies (i.e., increased solar insolation) and reduced surfacetemperature and humidity levels. As the air mass movessouthward, it slowly warms; however, unless it traverses a largeopen water source, AH does not increase substantially. As aconsequence, anomalously low RH levels can develop within theseair masses as well. Thus, the anomalies of solar insolation and RHcould be noncausally linked with influenza outbreaks through theirassociation with weather conditions that bring negative  AH  9  to aregion.Temperature and AH are strongly correlated (Table S1); bothare minimal in winter when influenza transmission is maximal andhave negative anomalies associated with influenza onset, tenden-cies which agree with the associations determined from laboratorydata [11,14,15]. To establish which of these variables is mostcritical for onset, we rely on previous laboratory analyses exploring the impact of both environmental factors that indicate AH is theessential determinant of influenza virus survival and transmission[11]. Furthermore,  AH  9  is the only anomaly variable whoseassociation with onset is significant at  p , 0.00002 for all four onsetthreshold levels (Table 1).In addition, it should be noted that seasonal temperatureconditions are often highly managed indoors, where most of theUS population spends the bulk of its time. Average daily outdoortemperatures can differ over 20  u C from winter to summer, butseasonal heating and air conditioning greatly reduce thistemperature cycle indoors. In contrast, AH possesses a largeseasonal cycle both outdoors and indoors [11]. Model Simulations of Influenza Seasonality To further assess the hypothesis that AH is a fundamental driverof influenza seasonality, we examined whether a population-levelmodel of influenza transmission forced by AH conditions couldreproduce the observed seasonal patterns of P&I mortality. Wesimulated influenza transmission for five states representative of different climates within the US: Arizona, Florida, Illinois, NewYork, and Washington. The model considers three disease classes:susceptible, infected, recovered; to integrate the impact of waning immunity following antigenic drift, we allow individuals to go back  Author Summary The srcin of seasonality in influenza transmission is bothof palpable public health importance and basic scientificinterest. Here, we present statistical analyses and amathematical model of epidemic influenza transmissionthat provide strong epidemiological evidence for thehypothesis that absolute humidity (AH) drives seasonalvariations of influenza transmission in temperate regions.We show that the onset of individual wintertime influenzaepidemics is associated with anomalously low AH condi-tions throughout the United States. In addition, we use AHto modulate the basic reproductive number of influenzawithin a mathematical model of influenza transmissionand compare these simulations with observed excesspneumonia and influenza mortality. These simulationscapture key details of the observed seasonal cycle of influenza throughout the US. The results indicate that AHaffects both the seasonality of influenza incidence and thetiming of individual wintertime influenza outbreaks intemperate regions. The association of anomalously low AHconditions with the onset of wintertime influenza out-breaks suggests that skillful, short-term probabilisticforecasts of epidemic influenza could be developed. Absolute Humidity and Wintertime InfluenzaPLoS Biology | 2 February 2010 | Volume 8 | Issue 2 | e1000316  Figure 1. Analyses of laboratory data, environmental data, and SIRS model simulations.  (A) Log-linear regression of guinea pig airborneinfluenza virus transmission data [14,15] on specific humidity (a measure of AH); (B) log-linear regression of 1-h influenza virus survival data [28] onspecific humidity; (C) functional relationship between  R 0 ( t  ) and  q ( t  ) per Equation 4; (D) 1972–2002 daily climatology of 2-m above-ground NCEP-NCARreanalysis specific humidity [23] for Arizona, Florida, Illinois, New York state, and Washington state; (E) 1972–2002 average daily values of   R 0 ( t  ) derivedAbsolute Humidity and Wintertime InfluenzaPLoS Biology | 3 February 2010 | Volume 8 | Issue 2 | e1000316  to the susceptible class at a defined rate (SIRS model). Observed1972–2002 daily AH conditions within each state are used tomodulate the basic reproductive number,  R  0 (  t   ), of the influenza virus, i.e., the per generation transmission rate in a fully susceptiblepopulation. These daily fluctuations of   R  0 (  t   ) alter the transmissionprobability per contact within the SIRS model and thus affectinfluenza transmission dynamics. The SIRS model contains fourfree parameters: two (  R  0max  and  R  0min  ) that define the range of  from the specific humidity climatology using the best-fit parameter combination from SIRS simulations ( R 0max =3.52;  R 0min =1.12) and the functionalform (Figure 1C and Equation 4); (F) average  R E ( t  ) for all wintertime outbreaks in the ten best-fit simulations at each state shown for 100 d prior tothrough 150 d post outbreak onset (minimum 400 infections/day during 2 wk prior; minimum 5,000 infections/day at least 1 d during subsequent30 d). Figure 1A and 1B are redrawn from Shaman and Kohn [11] using specific humidity as the measure of AH.doi:10.1371/journal.pbio.1000316.g001 Figure 2.  AH  9    associated with the observed onset of epidemic influenza.  Top, plots of   AH  9 averaged for the site-winters with an influenzaoutbreak showing the 6 wk prior to and 4 wk following outbreak onset. The conditions at each of the site-winters are defined based on the onsetdate for that site-winter. The onset dates are defined as the date at which wintertime observed excess P&I mortality had been at or above aprescribed threshold level for two continuous weeks (e.g., 0.01 deaths/100,000 people/day). Not every site-winter produced an outbreak as definedby a particular onset threshold. Depending on the threshold level used, 1,181–1,420 epidemics were identified among 1,470 possible (30 winters eachfor the 48 contiguous states plus the District of Columbia). Each solid line is the averaged  AH  9  associated with influenza onset as defined by adifferent threshold mortality rate. The dashed line shows  AH  9 =0. Bottom, plot of   R 0 ( t  ) anomalies using the above  AH  9 values. The  R 0 ( t  ) anomalies arecalculated using the best combined-fit estimates of   R 0max  and  R 0min  (Table 1). The dashed line shows  R 0 ( t  ) 9 =0.doi:10.1371/journal.pbio.1000316.g002Absolute Humidity and Wintertime InfluenzaPLoS Biology | 4 February 2010 | Volume 8 | Issue 2 | e1000316  R  0 (  t   ), one for the duration of immunity (   D   ), and one for theduration of infectiousness (  L   ).If absolute humidity controls influenza seasonality, best-fitsimulations with the AH-driven transmission model should meetthe following criteria: 1) the mean annual model cycle of infectionshould match observations in each state; 2) these simulationsshould converge to similar parameter values, i.e., the virusresponse to AH should be consistent among states; and 3) AHmodulation of transmission rates (  R  0 (  t   )) within the model mustmatch the large range implied by the laboratory data (Figure 1).Multiple 31-y (1972–2002) simulations were run at each of thefive states with randomly chosen parameter combinations. We thencompared the mean annual cycle of daily infection from eachsimulation with a similar average of 1972–2002 observed excess P&Imortality rates [3,4]. Best-fit model simulations at each site capturethe observed seasonal cycle of influenza (Figure 3). Thesesimulations produce not only the late-year rise in transmission andinfection, but also the wintertime peak during early January,typically followed by a secondary peak during late February/earlyMarch. In both models and observations, the dual winter peaks arenot typically seen in individual years; rather these epidemictrajectories reflect the averaging of individual wintertime outbreaksthat peak anytime between December and April (Figure S5).We also searched for the best-fit parameter combinations forall five sites evaluated together. The parameter combinations of these best ‘‘combined fits’’ are characterized by high  R  0max (generally . 2.8), high  R  0min  (  . 1), and low mean infectious period(2 ,  D  , 4.2 d) (Figure S6; Table 2). Best-fit simulations at each of the five sites individually occupy a similar parameter space(Figures S7, S8, S9, S10, and S11; Table S2). In particular, thesesimulations converge to high  R  0max , which indicates a similarresponse to AH variability (see Text S1).There is some correlation among SIRS model parameter valuesin simulations that fit the observed excess P&I mortality well. Forinstance, among better-fit simulations,  L   and  D   tend to be inverselyrelated (Figures S6, S7, S8, S9, S10, and S11). In addition, broadregions of parameter space appear capable of producing high-quality, low root mean square (RMS) error simulations (Figure S6).The stochastic components of the SIRS model may contribute inpart to this behavior. The flat goodness-of-fit within modelparameter space indicates that no one parameter combination isstrictly ‘‘best,’’ rather, a range of parameter combinations mayproduce good simulations of influenza transmission. Theseparameter ranges are:  L  =3–8 y,  D  =2–3.75 d,  R  0max =2.6–4,and  R  0min =1.05–1.30. We reran the SIRS model repeatedlysampling this approximate subset range of parameter space. Best-fit simulations from this subset range of parameter space (TableS3) were of similar quality and exhibited the same flat goodness-of-fit within model parameter space as the best-fit simulationspresented in Table 2.Because the SIRS model simulates only influenza-relatedinfections, not deaths, a scaling factor is needed to comparemodel-simulated rates of infection with the observed excess P&Imortality rates. This scaling factor can be understood as the casefatality ratio, i.e., the probability of mortality given infection.Reassuringly, all best-fit simulations produce a scaling factor of thesame order of magnitude and roughly consistent with the expected value of the case fatality ratio for P&I-related deaths (see Text S1).The model also explains regional variations in influenza dynamics.Due to the modeled nonlinear relationship between  R  0 (  t   ) and AH(Figure 1C), the seasonal cycle of   R  0 (  t   ) is sensitive to both AH seasonalcycle amplitude and mean AH levels (Figure 1D and 1E). In Florida,mean AH levels are higher than for the other four states, but theseasonal AH cycle remains large and produces a seasonal  R  0 (  t   ) cycle of sufficient amplitude to generate an effective reproductive number, R  E (  t   )= R  0 (  t   ) * S  (  t   )/  N  , greater than 1 (Figure 1F) and organize influenzaepidemics preferentially during winter. Outbreak dynamics reinforcethis phase organization in that wintertime epidemics confer immunityto a large proportion of the model population, which then reducespopulation-level susceptibility during the following summer when  R  0 (  t   )is low. In Arizona and Washington state, the seasonal AH cycle is lessthan for the other three states, but average AH levels are lower, at arange where laboratory findings indicate sensitivity to variation in AHis greater; consequently  R  0 (  t   ) retains a sizeable seasonal cycle(Figure 1E). For all five states, the AH-driven seasonal variation of  R  0 (  t   ) is large enough that  R  E (  t   ) is strongly modulated by AH conditionsand exceeds 1 during winter as outbreaks develop (Figure 1F).The humidity-driven SIRS simulations satisfy our three criteriafor supporting the hypothesis that AH controls influenza seasonalityin temperate regions. The simulations produce a consistent responsein the five climatologically diverse US states using similar parameter values. The large sensitivity of simulated influenza transmission to AH is consistent with the analysis of laboratory experiments thatshow large changes in influenza virus survival and transmission inresponse to AH variability (Figure 1A and 1B). Cross-Validation of the Model Findings To further validate the SIRS model findings, we determinedwhether the best-fit simulations derived from the five selectedstates could reproduce the seasonal cycles of influenza elsewhere inthe US. The ten best combined-fit parameter combinations(Table 2) were used to perform 31-y (1972–2002) SIRS simulationsat each of the contiguous 48 states plus DC.The results of this cross-validation demonstrate good simula-tions of observed excess P&I mortality for a majority of states(average  r  . 0.7, minimum  r  . 0.5, see Methods and Table 3). Some Table 1.  Association of daily anomalies in various environmental variables with wintertime influenza onset during 1972–2002 forthe contiguous US. Onset Threshold (Deaths/100,000/Day) AH 9  (1,000*kg/kg) RH 9  (%) Temperature 9  (Kelvin) Solar Radiation 9  (W/m 2 ) 0.005  2 0.138 ( , 0.00002)  2 0.420 (0.00166)  2 0.221 (0.00004) 0.431 (0.0397)0.01  2 0.124 ( , 0.00002)  2 0.586 (0.00006)  2 0.212 (0.00044) 0.547 (0.0068)0.015  2 0.114 ( , 0.00002)  2 0.709 ( , 0.00002)  2 0.178 (0.00398) 0.594 (0.0051)0.02  2 0.107 ( , 0.00002)  2 0.639 ( , 0.00002)  2 0.184 (0.00402) 0.316 (NS)Four different onset thresholds are shown. Average values for each variable are for the period 4 to 0 wk prior to onset. Significance estimates based on bootstrappingare also shown in parentheses.NS=not significant.doi:10.1371/journal.pbio.1000316.t001 Absolute Humidity and Wintertime InfluenzaPLoS Biology | 5 February 2010 | Volume 8 | Issue 2 | e1000316
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