Based on primary data of patients with confirmed diagnosis of 2009 pandemic influenza A (H1N1) 2009, we have estimated the pattern of healthcare resources utilization as well as patient and caregiver work absenteeism. Derivate cost per patient and the economic impact on healthcare services were described. Mean length of hospital stay was almost fourfold for patients requiring critical care (ICU) than for patients treated at the general ward only. As expected, inpatients needed more time to recover and their mean length of work sick leave was 30.5 days, in comparison with the 9 days observed for outpatients. Loss of productivity was also important for caregivers, since 21.7% and 8.5% of inpatients and outpatients respectively had caregivers who had to be absent from work. From an economic point of view, at an individual level, inpatients had a greater cost (€ 6,236 per inpatient) than outpatients (€ 940 per outpatient). From the healthcare provider's perspective, the 86% of economic national burden was the result of outpatients' resource utilization. The healthcare economic burden of patients with confirmed diagnosis of influenza A (H1N1) 2009 was estimated in €144,773,577, and €256,530,812 when considering clinical cases.
The description of healthcare utilization is essential for the healthcare provider's administration, the economic evaluation of health technologies and the estimation of the burden of a disease. In agreement with previous studies, length of hospital stay of general-ward inpatients doubled that observed for seasonal flu 
. It has been described that the risk of serious complications was not elevated in patients with pandemic influenza (H1N1) 2009 compared with recent seasonal strains 
. Thus, longer hospitalizations might be attributed to differences in medical practice during a pandemic outbreak when clinical evolution was uncertain.
Regarding ambulatory healthcare, several economic evaluation studies have included in their models evidence of previous seasonal surges or from patients with influenza-like illness 
. Our study adds a detailed description of ambulatory healthcare resource utilization, including less frequently used medical assistance (such as home medical visits or occupational care visits) also relevant for the health services organization.
As in previous studies of seasonal influenza, antibiotics were more frequently used than antiviral drugs outside the hospital 
. Since influenza is a viral infection, the antibiotic prescription was probably inappropriate in most cases. Nevertheless, neither has the existing evidence demonstrated a clear benefit of antiviral drugs in reducing influenza complications 
Productivity losses represented the most important impact of the pandemic outbreak. Compared with estimations for seasonal influenza, length of work sick leave was almost ten times higher in the case of inpatients, and at least two times higher in the case of outpatients 
. Moreover, length of work absenteeism during the pandemic in Spain exceeded that reported in other European countries 
. This was not an exclusive feature of the pandemic influenza A (H1N1), since it was also observed in other pathologies 
Costs per patient derived from our study did not differ much from previous estimates for seasonal influenza in our country. If we consider that 99.8% of clinical cases were outpatients, 0.15% were general-ward inpatients and 0.06% were ICU-inpatients, the mean cost per pandemic influenza A (H1N1) patient in Spain would be €954 
. In the same country, Badia et al. calculated the mean cost per patient with seasonal influenza-like illness to be €542.1 (95%CI
487.1–597.1). This cost and their reported cost due to work leave resembled our results, considering that their study was conducted one decade ago 
. Also, our estimated direct costs per pandemic inpatient were also similar to those reported for seasonal influenza in the US, which ranged from US$ 2,785 and US$ 13,159 
The economic burden of health services estimated here was considerably low in comparison with previous reports for seasonal influenza in the United States 
. Molinari et al estimated the direct costs of the annual medical treatment for influenza in U$S 10.4 billion. Although they considered also non-medically attended cases, the cost of these patients accounted for less than 1% of the medical expenditures. In contrast to our results, they calculated that 52% of the expenditures on influenza were attributable to hospitalizations 
. These differences might be due to the mildness of the influenza H1N1 pandemic, the higher cost per patient considered in their analysis and the methodology used. Another study that included only hospital and emergency costs, estimated the annual cost burden at $44 to $163 million 
. Also, costs of pandemic influenza A (H1N1) 2009 were clearly lower than direct medical costs associated to other pathologies in Spain, such as metabolic syndrome (€1,900 million) and knee and hip osteoarthritis costs (€4,075 million) 
The results of this study should be interpreted taking into account several limitations. First, the study population was a subsample of patients recruited for a case-control study. This is important for outpatients who were selected to be matched with inpatient rather than a representative sample of the outpatient Spanish population. Therefore, external validity could be compromised. However, patient's were temporally representative of the pandemic surge in Spain 
, and the prevalence of comorbidities among our inpatient's was similar to that reported before 
. Also, although follow-up response was not 100%, demographic characteristics of lost patients and those who stayed in the study were not statistically different. Second, none of the patients included died during the influenza infection. Consequently, our estimates underestimate the actual impact of the pandemic. Nevertheless, most patients who died during the pandemic were either old or had previous severe chronic conditions, thus not affecting much our estimation of indirect costs 
. Third, we could only analyse flu cases that had contact with health services and were laboratory confirmed. This might have prevented us from overestimating costs due to over diagnosis of influenza. However, it could have lead us underestimate productivity costs among specific populations (housekeepers, or non-contracted individuals, for instance) 
. Fourth, even though there is evidence regarding possible differences in mean cost by social class 
, comparisons stratifying by this variable could not be performed due to many missing values. Also, we need to indicate that the number of cases that were used to estimate the costs per ICU-inpatient was small (n
20). Finally, the limitations related with the sources of data used in our study deserve a comment. Although some of the information was directly gathered from the patient during an interview (to patients or proxies) and in some cases several months after the flu, memory bias was probably minor due to the influenza pandemic's important mass media repercussion 
. We had to consider alternative sources of information for unit costs, as there is no accepted common information source for the Spanish national healthcare system. While the source of unit costs for hospital and day absenteeism were reliable, many ambulatory unit costs were probable overestimated because they were obtained from the list of prices of health services provision to third parties. It is worth mentioning that several of the limitations listed above were addressed by the sensitivity analyses performed, because variations in unit costs, hospitalization length of stay in each area and days of work absenteeism were introduced as inputs of the model. The resulting confidence intervals of estimates represent the degree of uncertainty introduced by these limitations.
In conclusion, this paper provides information for health service providers and society during the pandemic influenza A (H1N1) 2009 which might be of interest for sizing the costs and needs of care in such episode, and in future outbreaks of similar epidemiological characteristics. Work absenteeism of patients and caregivers accounted for the majority of costs per outpatient. Interventions such as home-care provided by health services should be explored to reduce parents' and other relatives' productivity losses. Clinical Practice Guidelines for general practitioners might reduce economic impact on health services by minimizing unnecessary health resource utilization in a pandemic scenario. In addition, the evidence given by this study, together with other global expenses, such as prevention campaigns, massive vaccine purchase and other economy costs of reduced productivity, should be useful to evaluate the global impact of the pandemics.