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A substantial recrudescent wave of pandemic influenza A/H1N1 that began in December 2011 is ongoing and has not yet peaked in Mexico, following a 2-year period of sporadic transmission. Mexico previously experienced three pandemic waves of A/H1N1 in 2009, associated with higher excess mortality rates than those reported in other countries, and prompting a large influenza vaccination campaign. Here we describe changes in the epidemiological patterns of the ongoing 4th pandemic wave in 2011-12, relative to the earlier waves in 2009. The analysis is intended to guide public health intervention strategies in near real time.
We analyzed demographic and geographic data on all hospitalizations with acute respiratory infection (ARI) and laboratory-confirmed A/H1N1 influenza, and inpatient deaths, from a large prospective surveillance system maintained by the Mexican Social Security medical system during 01-April 2009 to 10-Feb 2012. We characterized the age and regional patterns of A/H1N1-positive hospitalizations and inpatient-deaths relative to the 2009 A/H1N1 influenza pandemic. We also estimated the reproduction number (R) based on the growth rate of the daily case incidence by date of symptoms onset.
A total of 5,795 ARI hospitalizations and 186 inpatient-deaths (3.2%) were reported between 01-December 2011 and 10-February 2012 (685 A/H1N1-positive inpatients and 75 A/H1N1-positive deaths). The nationwide peak of daily ARI hospitalizations in early 2012 has already exceeded the peak of ARI hospitalizations observed during the major fall pandemic wave in 2009. The mean age was 34.3 y (SD=21.3) among A/H1N1 inpatients and 43.5 y (SD=21) among A/H1N1 deaths in 2011-12. The proportion of laboratory-confirmed A/H1N1 hospitalizations and deaths was higher among seniors >=60 years of age (Chi-square test P<0.001) and lower among younger age groups (Chi-square test, P<0.03) for the 2011-2012 pandemic wave, compared to the earlier waves in 2009. The reproduction number of the winter 2011-12 wave in central Mexico was estimated at 1.2-1.3, similar to that reported for the fall 2009 wave, but lower than that of spring 2009.
We have documented a substantial and ongoing increase in the number of ARI hospitalizations during the period December 2011-February 2012 and an older age distribution of laboratory-confirmed A/H1N1 influenza hospitalizations and deaths, relative to 2009 A/H1N1 pandemic patterns. The gradual change in the age distribution of A/H1N1 infections in the post-pandemic period is reminiscent of historical pandemics and indicates either a gradual drift in the A/H1N1 virus, and/or a build-up of immunity among younger populations.
The resurgence of swine-origin pandemic A/H1N1 influenza virus in winter 2011-12 is
causing a sizable epidemic in Mexico, following a 2-year period of sporadic
transmission. Mexico experienced a series of three A/H1N1 pandemic waves in the
spring, summer, and fall of 2009 
, followed by a large pandemic vaccination campaign towards the end of
2009. These 3 waves were together associated with high excess mortality burden
relative to that seen in other countries 
. Because a significant fraction of the population is now protected from
A/H1N1 influenza through natural exposure or vaccination , there is potential for the emergence of drift A/H1N1 influenza
variants, and/or changing age patterns, as typically seen in post-pandemic periods
Here we report on the epidemiology of a recrudescent (4th) wave of pandemic A/H1N1 influenza activity in Mexico from 01-December 2011 to 10-February 2012. Because past pandemic experiences have indicated substantial post-pandemic morbidity and mortality burden may occur months to years after the initial pandemic waves     , we must remain vigilant and continue to monitor the epidemiology and health burden of A/H1N1 influenza. We compared the epidemiological characteristics of laboratory-confirmed A/H1N1 hospitalizations and deaths in winter 2011-12 with those previously reported for the 2009 pandemic waves and show a significant change in the age distribution of cases and deaths.
Individual level hospitalization data were available from a prospective
epidemiological surveillance system that was put in place especially for the
2009 influenza pandemic by the Mexican Institute for Social Security (IMSS) 
. IMSS is a tripartite Mexican health system covering approximately
40% of the Mexican population comprising workers in the private sector and their
families, relying on a network of 1,099 primary health-care units and 259
hospitals nationwide. The age and gender distributions of persons affiliated to
the IMSS medical system are representative of the general Mexican population .
We analyzed information from all hospitalizations and inpatient-deaths among patients admitted with acute respiratory infection (ARI) during 01-December 2011 to 10-February 2012. ARI was defined as any person with respiratory difficulty presenting fever 38°C and cough together with one or more of the following clinical symptoms: confinement to bed, thoracic pain, polypnea, or acute respiratory distress syndrome. Children <5 years with pneumonia or severe pneumonia that required hospitalization were also considered as ARI cases. Respiratory swabs were obtained for about 26% of ARI hospitalizations (ARI) in winter 2011-12 and were tested for the influenza virus by rRT-PCR .
For all ARI hospitalizations, we retrieved demographic information (age in
yrs, and gender), influenza laboratory test result (if tested), reporting state
(including 31 states plus the Federal District), and dates of onset of symptoms
(self-reported). We also obtained population data by state and age group for all
persons affiliated with IMSS in 2009 to calculate incidence
We examined the age distribution of hospitalizations and deaths based on all ARIs and laboratory-confirmed A/H1N1 influenza patients reported from 01-December 2011 to 10-February 2012. We compared the age distribution of hospitalizations and deaths in winter 2011-12 with those described for the three waves of the 2009-10 A/H1N1 pandemic in Mexico, 01-April 2009 to 31-March 2010, using the same IMSS reporting system.
We also calculated preliminary estimates of the in-hospital case fatality rate by
dividing inpatient deaths by hospitalizations, separately for ARI and
laboratory-confirmed A/H1N1. These estimates are preliminary as we likely
underestimate the true fatality ratio due to a delay from symptoms onset to
We analyzed state- and age-specific time series of laboratory-confirmed A/H1N1 influenza hospitalizations by day of symptom onset to analyze the geographic dissemination patterns of ongoing sustained A/H1N1 influenza transmission in Mexico during the early weeks of the wave, 01-December 2011 to 10-February 2012.
Further, we estimated the reproduction number, R, in Central Mexico where the great majority of cases have been reported, based on a simple method previously used in the context of the 2009 A/H1N1 pandemic waves in Mexico . Specifically we estimate the initial epidemic growth rate by fitting an exponential function to the early ascending phase of daily ARI or A/H1N1 hospitalizations by date of symptoms onset . The early ascending phase was determined as the period between the day of pandemic onset and the midpoint between the onset and peak days. We assumed a mean generation interval of three and four days, which are within the range of mean estimates for the 2009 influenza pandemic    . As a sensitivity analysis we also assessed small variations in the length of the ascending epidemic phase used to estimate the exponential growth rate (+/- 4 days).
This study did not need approval from a scientific committee; all individual data
were kept de-identified.
Statistical analyses were performed using SPSS 20.0 and Matlab (The Mathworks,
The characteristics of all ARI and A/H1N1-positive hospitalizations reported to the IMSS medical system between 01-Dec 2011 and 10-February 2012 are given in Table 1. The time series of daily ARI hospitalizations and deaths and laboratory-confirmed influenza hospitalizations are shown in Figures 1 and 2, respectively. An A/H1N1 influenza outbreak began around 01-December 2011 and is ongoing at the time of writing of this report (Figure 3), particularly in central Mexico (Figure 1). The daily number of ARI hospitalizations in winter 2011-12 is exceeding the levels that were observed during the major fall wave of the 2009 A/H1N1 influenza pandemic (Figure 4). In Mexico City the cumulative number of ARI hospitalizations during 01-Dec 2011 to 10-February 2012 represents 37% of all ARI hospitalizations that were reported in Mexico City during the first year of A/H1N1 virus circulation (April 2009 to Mar 2010).
Table 1. Characteristics of all ARI hospitalizations and laboratory-confirmed A/H1N1 influenza hospitalizations, Mexico, 01 December 2011 through 10 February, 2012.
A total of 5,795 ARI hospitalizations and 186 inpatient-ARI deaths (preliminary case fatality rate, 3.2% (95% CI: 2.8, 3.7)) were reported to the IMSS system between 01-December 2011 and 10-February 2012. The preliminary estimate of case fatality rate for laboratory-confirmed A/H1N1 inpatients was 10.9% (95% CI: 8.6, 13.3) over the same period (685 inpatients and 75 deaths).
This preliminary estimate of the case fatality rate for hospitalized A/H1N1
patients in 2011-12 is significantly lower than the CFR measured in 2009 (16.1%
(95% CI: 15.0, 17.2)).
Overall the majority of laboratory-confirmed influenza inpatients during 01-Dec
2011 to 10-Feb 2012 were among persons aged 15-59 years (66.4%) followed by the
0-4 year age group (11.4%) and seniors >=60 years (12.4%) (Table 1). Severity
increased with older age, with an inpatient fatality rate of 18.8% (95% CI:
10.3, 27.3) for persons >=60 years.
The cumulative hospitalization and inpatient death rates for the 3 waves of the
2009-10 A/H1N1 pandemic are on average 6.5 and 9.5 times greater than the
corresponding rates for the ongoing 2011-12 A/H1N1 wave in Mexico. Comparison of
the age-specific A/H1N1 hospitalization and death rates reveals an increasing
burden among older populations in 2011-12, relative to the 2009-10 waves (Figure
5). An analysis of the proportionate distribution of A/H1N1 hospitalization and
inpatient deaths reveals a shift in the age distribution of recent cases towards
older ages as well. Specifically, we note a significantly higher proportion of
individuals older than 60 yrs hospitalized with laboratory-confirmed A/H1N1 in
2011-12, relative to the 2009-10 pandemic period (12.4% vs. 6.1%, Chi-square
test P<0.0001, Table 2, Figure 6). We also found a reduction in the
proportion of A/H1N1-positive hospitalizations among persons 5-14 years of age
compared to the 2009 pandemic (9.8% vs. 14.9%, Chi-square test, P=0.0003).
We found a similar change in the age distribution of A/H1N1 inpatient deaths in 2011-12 compared to the 2009 A/H1N1 influenza pandemic (Table 3, Figure 6). Specifically, 21.3% of deaths occurred among persons >=60 years of age in the ongoing 2011-12 epidemic period whereas only 8.9% in the 2009-10 period (Chi-square test, P=0.0006). Similarly to the age shift in hospitalization data, the proportion of A/H1N1 inpatient deaths among individuals aged 15-29 declined, relative to 2009-10 (9.3% vs. 21%, Chi-square test, P=0.02).
Computed using the Chi-square test statistic for differences in
Table 2. Age-specific proportions of total laboratory-confirmed A/H1N1 hospitalizations for the 2009 A/H1N1 influenza pandemic compared to ongoing A/H1N1 outbreaks in Mexico spanning 01-December 2011 to 10-February 2012. We note a significantly different age distribution of A/H1N1 hospitalizations during 01-December 2011 to 10-February 2012 compared to that of the 2009 A/H1N1 influenza pandemic spanning 01-April 2009 to 31-March 2010 (Wilcoxon test, P<0.0001).
* Computed using the Chi-square test statistic for differences in time periods
Table 3. Age-specific proportions of total laboratory-confirmed A/H1N1 inpatient deaths for the 2009 A/H1N1 influenza pandemic and ongoing A/H1N1 outbreaks in Mexico spanning 01-December 2011 to 10-February 2012. We note a significantly different age distribution of A/H1N1 inpatient deaths in the 4th wave, compared to that of the previous 3 waves during 2009 (Wilcoxon test, P=0.001). The age shift is characterized by a doubled proportion of elderly deaths, offset by a halving in deaths in young adults.
The majority of A/H1N1 inpatients during the 4th wave have been
reported in central Mexican states (66.3%) followed by southeastern states
(19.4%) (Table 1), and a higher proportion of A/H1N1 deaths have occurred in
central states compared to other regions (Chi-square test, P=0.04).
Assuming a mean generation interval of 3 (and 4) days, the mean R was estimated
to be 1.2 (1.3) during the period 17-Dec 2011 to 9-Jan 2012, based on daily
A/H1N1-positive hospitalizations. As a sensitivity analysis we also estimated R
using daily ARI hospitalizations; our estimate of R was somewhat lower at 1.1
(1.2). When the length of the epidemic ascending phase was varied (+/- 4 days),
our R estimates changed by 0.1 or less.
We have characterized the epidemiology of a recrudescent 4th wave of
A/H1N1 influenza transmission in Mexico spanning 01-December 2011 to 10-Feberuary
2012, based hospitalizations for acute respiratory infections and
laboratory-confirmed A/H1N1 infections. We compared the impact, severity, age
patterns, and reproduction number of this 4th wave with those of earlier pandemic
waves in spring, summer and fall 2009 in Mexico, 
. We used individual-level patient information collected through a
prospective influenza surveillance system put in place especially for the 2009
pandemic by the largest Mexican Social Security medical system and providing daily
data during 2009-2012  . Our data show that the nationwide peak level of daily ARI
hospitalizations obtained so far in early 2012 (it may not yet have peaked) has
already exceeded the peak of ARI hospitalizations observed during the major fall
pandemic wave in 2009. We have also documented a significant increase in the
proportion of A/H1N1 hospitalizations and deaths among persons >=60 y, relative
to the 2009 pandemic, and a significant reduction in the proportion of A/H1N1
hospitalizations and deaths among school age children.
The observed change in age distribution of hospitalization and deaths in the post
2009 pandemic period is reminiscent of the influenza seasons following the 1918
influenza pandemic 
 and the 1968 pandemic . A quantitative analysis of excess mortality prior to and after
the1918 influenza pandemic found that the age distribution of influenza-related
mortality returned to pre-pandemic mortality levels a few years after the initial
pandemic waves as a result of emerging drift variants 
. Hence the age shift seen in the 2011-12 winter season could signal
either a gradual emergence of drift A/H1N1 variants, and/or a build up of immunity
among younger populations. Both have implications for influenza prevention and
mitigation strategies, which we discuss below.
During the first year of circulation of the 2009 A/H1N1 influenza pandemic virus,
protection from influenza-related morbidity and mortality rates was reported in
people over 60 years. This phenomenon of “senior sparing” in age cohorts born prior
to the 1957 pandemic is consistent with first exposure to antigenically-related
A/H1N1 viruses in childhood, a pattern consistent with the antigen recycling and
original antigenic sin hypotheses 
. A high fraction of the Mexican population is now protected against
the 2009 A/H1N1 influenza virus through natural exposure in 2009 (children and young
adults) or prior immunity (seniors)  and by pandemic vaccines. Over 7 million of seasonal influenza vaccine
(featuring a good match for the H1N1-pdm vaccine component) were administered in
2011-12 winter (35% vaccination coverage among IMSS-affiliated seniors >=60
years; 70% among <5 years; 40% among 50-59 years; and 24% among 5-9 years).
Although we saw evidence of a shift in the age distribution of 2011-12 cases
towards seniors, the absolute risk of getting hospitalized was still relatively low
in this age group, relative to those in younger adults. The declining rates of
severe cases in younger age groups is most consistent with build-up of immunity.
Overall the age distribution of recent A/H1N1 influenza hospitalizations and deaths
in Mexico is relatively flat and not quite back to the normal “J-shaped” age risk
profile that characterizes seasonal influenza. In the long run, we expect the
pandemic A/H1N1 virus to drift genetically to escape mounting population immunity –
perhaps with the result that seniors are no longer protected . Hence the epidemiological evidence is consistent with the genetic and
antigenic information published on circulating influenza virus, suggesting a lack
antigenic drift in A/H1N1 viruses in Mexico or elsewhere in winter 2011-12, a season
associated with relatively low A/H1N1 activity globally .
Since transmission of the A/H1N1 influenza virus was sporadic in the winter of
2010-2011 in Mexico, we cannot rule out the possibility of some loss of population
immunity since 2009. We estimated a reproduction number for the ongoing A/H1N1
epidemic to be significantly lower to that of the spring (R~1.8-2.1) and summer
(R~1.6-1.9) pandemic waves in 2009 in Mexico, but in close agreement with estimates
of the fall (3rd) 2009 wave (R~ 1.2-1.3).
Perhaps the most surprising finding of this analysis is the occurrence of a
substantial 4th wave of pandemic A/H1N1 activity in Mexico, a country
which has already experienced severe excess mortality impact during 3 waves of
transmission in 2009 
. Although we are just beginning to assess the global mortality burden
of the 2009 A/H1N1 virus in the pandemic and post-pandemic period, important
geographical variations in the number, timing, transmissibility and impact of
sequential pandemic waves are obvious. For instance, the UK experienced 2 waves in
spring and fall 2009, to be followed by a relatively severe recrudescent wave in
2010-11, not seen in other European countries . The US experienced the brunt of the pandemic burden in the first year
of A/H1N1 circulation. To our knowledge, the 4-wave pattern seen in
Mexico in 2009-12 has not been reported in other countries. Whether these
differences can be explained by geographical variation in prior immunity, seasonal
drivers, control strategies, connectivity, health and healthcare, is unclear and
remains a key area for future research.
In summary our findings indicate a changing age distribution of laboratory-confirmed A/H1N1 influenza hospitalizations and deaths in winter 2011-12, relative to 2009-10 A/H1N1 pandemic patterns. The proportion of hospitalizations and deaths is increasing in seniors >=60 years, an age group that was largely protected during the early pandemic waves in 2009. In contrast, rates of A/H1N1 hospitalizations and deaths are declining among younger population groups, consistent with a gradual build up of immunity. This gradual change in the age distribution A/H1N1 influenza in 2011-12 in Mexico is reminiscent of post-pandemic patterns in past influenza pandemic. As the 4th wave is still ongoing, it is too early to determine whether it is more severe than the previous waves in terms of mortality – something that occurred in the 1889 pandemic in which a 3rd wave occurring in the winter of 1891-92 was far more deadly than previous waves  .
Whether other countries will eventually experience similar severe recrudescent waves
of A/H1N1 activity remains to be seen. A multinational comparison of the
epidemiology of pandemic and post-pandemic waves would be useful to shed light on
the long-term transmission dynamics and build up of immunity to pandemic viruses,
and inform control strategies.
The authors declare no relevant competing interests.
This research was conducted in the context of the MISMS (Multinational Influenza Seasonal Mortality Study), an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). The MISMS study is funded by the International Influenza Unit, Office of Global Health Affairs, Department of Health and Human Services. LS acknowledges support from the RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center.
Dr. Víctor H. Borja-Aburto
Coordinación de Vigilancia Epidemiológica y Apoyo en Contingencias,
Instituto Mexicano del Seguro Social,
Mier y Pesado 120, México, DF 03100 México