We have estimated, using data from two cities on tiered levels of severity and self-reported rates of seeking medical attention, that approximately 1.44% of symptomatic 2009 pH1N1 patients during the spring in the United States were hospitalized; 0.239% required intensive care or mechanical ventilation; and 0.048% died. Within the assumptions made in our model, these estimates are uncertain up to a factor of about 2 in either direction, as reflected in the 95% credible intervals associated with the estimates. These estimates take into account differences in detection and reporting of cases at different levels of severity, which we believe, based on some evidence, to be more complete at higher levels of severity. Without such corrections for detection and reporting, estimates are approximately two-fold higher for each level of severity. Using a second approach, which uses self-reported rates of influenza-like illness in New York City to estimate symptomatic infections, we have estimated rates approximately an order of magnitude lower, with a symptomatic case-hospitalization ratio (sCHR) of 0.16%, a symptomatic case-intensive care ratio of 0.028%, and a symptomatic case-fatality ratio of 0.007%. In both approaches, the sCFR was highest in adults and lowest in school-age children (5-17); data on children 0-4 and adults 65 and older were relatively sparse, making statements about their ordering more difficult. Nonetheless, given the large number of cases in nonelderly adults, this represents a substantial shift in the burden of hospitalization and mortality from those over 65, for whom seasonal influenza is most severe 
, to middle-aged adults, consistent with findings from previous pandemics 
These estimates are valuable for attempting to project, in approximate terms, the possible severity of a fall-winter wave of pH1N1, under the assumption that the virus does not change its characteristics. From the 1957 and 1968 pandemics, it appears that perhaps 40-60% of the population was serologically infected, and that of those, 40-60% were symptomatic ,,,
. Current estimates of the transmission of 2009 pH1N1 range between about 1.4 and about 2.2, consistent with estimates of the reproduction numbers from prior,,,,
. To convert our estimates into population impacts, one needs to make an assumption about the attack rate and its age distribution. For each 10% of the US population symptomatically infected (with the same age distribution observed in the spring wave), our Approach 1 estimates suggest that approximately 7800-29,000 deaths (3-10 per 100,000 population), 40,000-140,000 intensive care admissions (13-46 per 100,000 population), and 250,000-790,000 hospitalizations (170-630 per 100,000 population). These estimates will scale up and down in proportion to the attack rate; for example, they should be doubled if 20% of the population were symptomatic, producing for example 15,000-58,000 deaths, or 6-20 per 100,000 population. Approach 2 suggests much smaller figures (for each 10% of the population symptomatic) of 1500-2700 deaths (0.5-0.9 per 100,000); 6600-11,000 ICU admissions/uses of mechanical ventilation (22-35 per 100,000); and 36,000-78,000 hospitalizations (12-26 per 100,000). Again, these numbers should be scaled in proportion to the attack rate.
Our estimates reflect a level of antiviral treatment and health care capacity that will not be available in all populations. Oseltamivir use was common in Milwaukee (Milwaukee Department of Health, unpublished data), and although the health system was stressed in both cities studied, there was no shortage of intensive care or other life-saving medical resources. In a situation of greater stress on the health system, as has been observed in certain locations in the Southern Hemisphere , http://www.capegateway.gov.za/eng/your_gov/3576/news/2009/aug/185589
, , or in areas that lack a high-quality health system, severity might increase in proportion as adequate medical attention is less available. Worryingly, our estimates of the proportion of symptomatic cases requiring mechanical ventilation or ICU care was approximately 4-5x our estimate of the sCFR. It is possible that a substantial proportion of those admitted to ICUs would have died without intensive care. In populations without widespread access to intensive care, our results suggest that the same burden of disease would lead to a death rate 4-5 times higher. Likewise, a change in the virus to become more virulent or resistant to existing antiviral drugs, or the emergence of more frequent bacterial coinfections could increase the severity of infection compared to that observed so far.
Estimates of severity for an infection such as influenza are fraught with uncertainties 
. Our analysis has accounted for many of these uncertainties, including imperfect detection and reporting of cases, bias due to delays between events (such as the delay from illness onset to death), and the statistical uncertainties associated with limited numbers of cases, hospitalizations and deaths. Another major source of difficulty is the spatial and temporal variation in reporting effort for mild and severe cases; for example, most jurisdictions in the United States stopped reporting mild cases on or before the second week of May, but this change varied by jurisdiction. We have attempted to avoid this difficulty by focusing on individual jurisdictions – New York and Milwaukee – for which the approach to reporting was relatively stable over time. One limitation is that Milwaukee changed its guidance during our surveillance period from testing of all symptomatic cases to testing of all symptomatic health care workers but only moderate to severe cases in non-health care workers. We believe that testing policies did not change dramatically during this period, because the proportion of hospitalized case remained fairly constant; however, the sample size prior to this change in guidance was small. Thus, our estimates should be seen as being the risk of severe outcome among persons with symptoms, possibly biased somewhat toward those with more severe symptoms.
Despite our efforts to account for sources of uncertainty, several others remain and have not been accounted for in our analysis. First, we have assumed that for each level of severity (from medically attended up to fatal), case reporting was equal across age groups; for example, we assumed that medically attended cases were as likely to be reported for young children as for adults. It is possible that this is not the case, for example that mild cases were more likely to come to medical attention if they occurred in children than if they occurred in adults. If this were true, our conclusion that severity was higher in adults than children could be partly a result of differential reporting.
Second, the overall estimates of severity (not stratified by age group) reflect the age composition of cases in the sample we studied, especially the age composition of the lowest level of severity examined, medically attended illness. Among medically attended cases in Milwaukee, 60% were in the 5-17 age group, the one in which severe outcomes were the least likely. A preponderance of cases within this age group may be typical of the early part of influenza epidemics, and while it has been argued that there is a shift from younger to older age groups in seasonal influenza 
as the epidemic progresses, there is evidence from at least the 1957 pandemic that attack rates remain higher in children than adults throughout the course of the epidemic 
. Since severity appears to be considerably higher in adults, then a shift in the burden of disease from children to adults as the epidemic progresses would lead to an increase in average severity.
We note that the association between age and severity may also affect observed trends in the characteristics of cases. The World Health Organization has noted worldwide a shift from younger to older mean age among confirmed cases (http://www.who.int/csr/disease/swineflu/notes/h1n1_situation_20090724/en/index.html
). If severity is lowest among children, this upward shift in age distribution may partially reflect a shift toward detection of more severe cases, rather than a true shift in the ages of those becoming infected.
Third, the symptomatic case-fatality, case-ICU admission and case-hospitalization ratios are dependent upon our estimates of the true number of symptomatic cases,
and hence are sensitive to the choice of prior for these, as well as to our prior assumptions on the detection probabilities. In particular, if the probability that symptomatic cases seek medical attention and are confirmed is lower than we assume in our prior distributions, then there are more cases than are inferred by our model, and severity is correspondingly lower than our estimates. If the probability of detecting severe outcomes (hospitalizations, deaths, ICU) is lower than our priors reflect, then there are more severe outcomes than our model infers, so severity is correspondingly higher.
Finally, the small sample sizes in some age groups, the over-65 year olds in particular, lead to large uncertainty about the age-specific estimates. This level of uncertainty is reflected in the wide 95% credible intervals for the estimates.
Our two approaches yield estimates that differ by almost an order of magnitude in the severity of the infection, on each of the three measures considered. How should planners evaluate these contrasting estimates? The lower estimates, using the denominator of self-reported influenza-like illness in New York City, may reasonably be considered lower bounds on the true ratios. Influenza-like illness is thought to be relatively rare in May-June, hence true influenza-like illness was probably largely attributable to pH1N1 during this period in New York. However, self-reported ILI is notoriously prone to various biases, most of which suggest that true rates are probably lower than self-reported rates. A previous telephone survey conducted in New York City found that 18.5% of New Yorkers reported influenza-like illness in the 30 days prior to being surveyed in late March, 2003 
, which represented a period of above-baseline but declining influenza activity nationally and no known influenza outbreaks in New York City 
. The survey was repeated in October-November, 2003, prior to the appearance of significant influenza activity, and 20.8% reported influenza-like illness in the 30 days prior 
. If these surveys represent a baseline level of self-reported ILI in the absence of significant influenza activity, then the approximately 12% self-reported ILI in the telephone survey is substantially lower than this out-of-season baseline, suggesting that it likely overstates the total burden if symptomatic pH1N1 disease. The lower estimates are also broadly consistent with estimates from New Zealand, which has experienced a nearly complete influenza season 
, and from Australia (http://www.health.gov.au/internet/main/publishing.nsf/Content/cda-surveil-ozflu-flucurr.htm/$FILE/ozflu-no14-2009.pdf). The higher estimates, on the other hand, were obtained using ratios of hospitalizations to confirmed medically attended cases and self-reported rates of seeking medical attention for ILI, which have been consistently measured in the range of about 40-60%. It is possible that the special efforts of the New York City health department to identify pH1N1-related fatalities (including those not hospitalized) provides a fuller picture of the total number of deaths from this infection. Interestingly, New York City reports about the same number of hospitalizations for our study period (996) as New Zealand reports up to mid-August (972), but 3.5x as many deaths (53 vs. 16) 
. If this discrepancy reflects more complete ascertainment of deaths in New York City, it may account for much of the difference between our higher estimates of case-fatality ratios and those from New Zealand. Given the number of uncertainties cataloged above (which apply also to other jurisdictions within and outside the USA), we believe that our two approaches probably bracket the reasonable range of severity for the US spring wave.
Age-specific severity patterns as estimated here are largely consistent with those one would obtain by simply comparing the incidence of confirmed cases, hospitalizations, and deaths in the United States as a whole for a similar period 
, although the estimates for persons over 65 are highly uncertain, with 95% credible intervals spanning several orders of magnitude, due to the very small number of individuals in our sample from that age group.
The estimates provided here may be compared to those for seasonal influenza. Compared to seasonal influenza, these estimates (assuming a 25% symptomatic attack rate) suggest a number of deaths in the United States that could range from about half the number estimated for an average year to nearly twice the number estimated for an average year 
(Approach 1), or a range about 10-fold lower than that (Approach 2); however, the deaths would be expected to occur in younger age groups, compared to the preponderance of deaths in persons over 65 in seasonal influenza. Such a shift in age distribution is typical for pandemics and the years that follow them 
. Under Approach 1, and assuming a typical pandemic symptomatic attack rate of 25%, the estimated number of hospitalizations for an autumn-winter pandemic wave is considerably more than the approximately 300,000 estimated for typical seasonal influenza 
, whereas Approach 2 suggests a number between 1/3 and 2/3 of that observed in typical seasonal influenza. It should be noted that most hospitalizations, and about 90% of deaths attributed to seasonal influenza are categorized as respiratory and circulatory, not including the more specific diagnoses of pneumonia and influenza; that is, they are due to myocardial infarction, stroke, and other proximate causes, but are nonetheless likely caused initially by influenza infection 
. The deaths included in this may have reflected more directly influenza-related causes and may not reflect these indirect causes of influenza-related death. Indeed, it is unclear whether the proportion of indirect respiratory and circulatory causes of death and hospitalization will be so high in this pandemic year, given the younger ages involved in most severe cases. Given these differences between the estimates here based on virologically confirmed deaths and the ecological statistical approach to estimating influenza-attributable deaths and hospitalizations for seasonal influenza, it will be difficult to interpret comparisons between the two types of estimates until (after the pandemic has passed) comparisons can be made between the ecological and the confirmed-case approach to estimating burden of hospitalization and deaths.
Our estimate of the symptomatic case-fatality ratio is lower than those provided by Garske et al. 
, which ranges from 0.11% to 1.47% overall, and between 0.59% and 0.78% in the US, but which was based on confirmed plus probable (rather than symptomatic) cases. Garske et al. do not account for differences in reporting by level of severity; when we ignore such differences in our “naïve” analysis, we get approximately a 2-fold increase in the estimated sCFR. This suggests that the differences in detection of mild and severe cases may have been greater in the data sets used by Garske et al. than in those we have examined. Nishiura et al 
estimate that between 0.16% and 4.48% of confirmed cases in the United States and Mexico were fatal. Wilson and Baker 
, on the other hand, use a denominator of infections (rather than symptomatic or confirmed cases) and estimate a range of CFR from 0.0004% up to 0.6%. Our estimates fall in the middle part of this range. More recently, Baker et al. 
used their estimates of the total incidence of symptomatic disease in New Zealand to estimate a sCFR of 0.005%, equal to the lower end of the credible interval for our Approach 2 estimate, and considerably below our Approach 1 estimate. The generally downward trend in the estimates of severity reflects early ascertainment of more severe cases (e.g., mainly hospitalized cases in the early Mexican outbreak); the issue of ascertainment and its potential biasing effect on severity estimates has been discussed by each of these earlier reports.
While we have been careful to highlight uncertainties in the estimates of severity, our results are sufficiently well-resolved to have important implications for ongoing pH1N1 pandemic planning. The estimated severity indicates that a reasonable expectation for the autumn pandemic wave in the United States is a death toll less than or equal to that which is typical for seasonal influenza, though possibly with considerably more deaths in younger persons. If attack rates in the autumn match those of prior pandemics and hospitalization rates are comparable to our estimates using Approach 1, the surge of ill individuals and subsequent burden on hospitals and intensive care units could be large. However, using Approach 2, estimates of hospitalizations and intensive care admissions are considerably lower. Either set of estimates places the epidemic within the lowest category of severity considered in pandemic planning conducted prior to the appearance of pH1N1 in the United States, which considered case-fatality ratios up to 0.1% (http://www.flu.gov/professional/community/community_mitigation.pdf).
Continued close monitoring of severity of pandemic H1N1 disease is needed to assess how patterns of hospitalization, intensive care utilization, and fatality are varying in space and time, and across age groups. Increases in severity might reflect changes in the host population – for example, infection of persons with conditions that predispose them to severe outcomes, or increased severity might reflect changes in the age distribution of cases, for example a shift toward adults, in whom infection is more severe. Changes in severity might also reflect changes in the virus or variation in the access and quality of care available to infected persons.