We found that pain associated with the initial HZ episode had a clear impact on the patients’ HRQL and interference in ADLs; at day 0, 80.1% of patients had moderate or severe HZ “worst” pain and 46.2% had severe “worst” pain. Acute HZ pain had an impact on the patients’ ADLs, in particular sleep disturbance with 35.3% of patients reporting severe interference on sleep score at day 0 (Fig. 2). For most patients, interference with ADL reduced within 30 days after HZ rash onset, with mean scores between 1 and 2 for all the ZBPI ADL items at this time point. EQ-5D scores were also impacted in the acute HZ phase, with a mean disutility of 0.138 in the first 30 days of the HZ episode in the overall HZ patient cohort, which represents a quality-adjusted life-year (QALY) loss of 0.011 in the first month (and with greater disutility and QALY loss in older patients) (Table 2).
In our cohort, 25 patients (4.6%) developed PHN, and mean ZBPI “worst” pain scores at day 0 in patients who developed PHN were higher than in those who did not (6.9 and 5.4, respectively) and remained above 5.0 during the first 90 days, whereas “worst” pain scores fell below 2.0 after 1 month in patients with HZ without subsequent PHN (Fig. 1). HRQL was also lower in patients who developed PHN, with EQ-5D utility scores at day 0 around 0.2 lower than in patients without PHN, with this difference maintained over the entire 90-day follow-up period (patients without PHN were not followed beyond day 90) (Fig. 3).
Our estimate of 4.6% of patients with HZ developing PHN is lower than that reported in other studies from Spain. An extensive retrospective analysis of primary care records evaluating the risk of HZ in patients aged 50 years or older in the Valencia region reported that 13,658 out of 87,086 patients with HZ (15.7%) developed PHN . In Catalonia, PHN has been reported to occur in 12.3% of patients with HZ aged 50–59 years and in 17.5% in those aged 70 years or older . In our study, the proportion was based on the total number of patients in the overall study cohort (N = 545) rather than the number of patients with an actual pain assessment after day 90 (N = 212). If we limit our estimate to those patients with an assessment on or after day 90, the percentage of patients at least 50 years old with HZ who developed PHN increases to 11.8% which is more in keeping with these previous data from Spain.
Questionnaire compliance (in terms of response rates for completed questionnaires) in this study was lower than observed for other studies which used a similar approach to evaluating HZ impact on HRQL [25, 26]. We had available ZBPI and EQ-5D scores for only around 50% of our cohort at initial assessment, and so our observations on pain and interference in ADLs and impact on HRQL may not be wholly representative of the overall study population. The differential response rate between ZBPI and EQ-5D at subsequent study time points is also unusual; however, one explanation for the greater compliance with the EQ-5D questionnaire may be that this was due to telephone administration . We are uncertain as to the impact of low compliance rates on our overall cohort’s HRQL outcomes and the nature of any potential sampling bias associated with this; our findings on HZ impact on HRQL should be considered in light of these limitations. Nevertheless, our HRQL results are consistent with those of previous studies that used the same ZBPI and EQ-5D instruments for assessing the impact of HZ and PHN on HRQL [5, 8, 9, 27, 38, 39]. Although HRQL data in Spanish patients with HZ are scarce, a recent Italian study using similar methodology reported comparable impact of HZ-related pain on ADLs and EQ-5D scores, with similar disutility during the first month following rash onset, and with the greatest impact observed in those patients subsequently developing PHN . This would suggest that missing data may be missing completely at random.
Looking at healthcare resource use within our cohort, the mean number of primary care visits per patient due to the HZ episode was 1.7 visits, somewhat lower than that reported by Cebrián-Cuenca et al. in a previous study from Spain which also prospectively evaluated resource use and allied costs of HZ and PHN treated in primary care in Valencia (which reported an average of 2.4 GP visits) , while a later retrospective study from Valencia by Muñoz-Quiles et al. reported data indicating an average of 2.0 cases per patient . The mean number of additional specialist or nursing consultations or emergency room visits (0.09 per patient) is also lower than that reported by Cebrián-Cuenca et al. (where a mean number of 0.29 specialist visits per patient and a further 0.31 nursing or other professional visits per patient were reported) . The proportion of our cohort hospitalized (2.0%) is similar to that reported by Salleras et al. (1.5%) in a previous Spanish study , although others report lower rates: 1.2% in the extensive retrospective analysis from Valencia , whereas in the cohort reported by Cebrián-Cuenca et al., none of the 130 patients were hospitalized for HZ . The proportion of our study cohort receiving systemic antivirals (95%) is broadly comparable to that reported by Cebrián-Cuenca et al. in their cohort (91%) .
Our analysis of the costs of HZ and related complications confirms that HZ presents a substantial economic burden. Note that unlike the HRQL aspect of the study, cost data was recorded by GPs at the initial visit or on subsequent visits, supplemented with data from additional medical providers when relevant and entered into case report forms throughout the study, and so was not dependent on ZBPI and EQ-5D questionnaire completion. We found a mean direct medical cost per patient of €240 from the HCS payer perspective and €266 from a societal perspective, and overall disease costs of €240 from the HCS payer perspective and €296 from a societal perspective. Costs were dependent upon development of complications: the lowest in uncomplicated HZ, greater in patients who developed PHN, and the highest in those with other non-PHN complications (Fig. 4).
Although one should be cautious about making cost comparisons, our costs were lower than those previously reported from Spain. In their study, Cebrián-Cuenca and colleagues estimated total costs per HZ episode (which excluded hospitalizations) of €309 and €378 from the payer and societal perspectives, respectively . In that study, costs also varied depending on PHN status, with mean costs per patient of €821 in those with PHN compared with €307 in those without PHN . In a retrospective study from Catalonia, Salleras and colleagues estimated the direct healthcare costs for patients with HZ presenting in the dermatology outpatient unit of a hospital, where the mean direct medical cost per patient was €302 in cases of HZ that did not evolve to PHN and €917 for those who subsequently PHN . Another primary care retrospective study from Catalonia reported overall (direct and indirect) costs of €1827 for patients with PHN and €457 for patients with uncomplicated HZ . In all these studies, costs were greater in older patients.
Our study was not designed to monitor the evolution of HZ costs over specific time periods, which may be considered a limitation. However, the great majority of resources used and estimated costs we report were incurred within the first 90 days (as only those patients with PHN we followed beyond this point). Furthermore, much of the resource use and allied medical costs relate to services provided the acute HZ episode (initial GP visit, antiviral medication treatment, HZ hospitalization, etc.), and would have been incurred within the first 30 days, although it may be expected that patients with complications and with persistent HZ-associated pain would continue to incur further cumulative costs. This would be consistent with other data. For example, in their resource use and cost analysis, the majority of the primary care services and allied costs reported by Cebrián-Cuenca et al. were incurred within the first month .
From these studies, and as seen in the present study, it seems clear that HZ carries a significant economic burden and that direct medical costs are greater in older patients, with a common finding that PHN development substantially increases direct and societal HZ costs. However, as reported elsewhere, when considering the overall cost of disease at a population level, the overall cost is higher for patients with uncomplicated HZ, primarily a result of the higher incidence rates of uncomplicated HZ .
The study has certain limitations relating to the cost analysis. This study was carried out in a GP setting with data on resource utilization derived from GPs’ own clinical records and from external sources (i.e., information provided by patients or from external clinical institutions and physicians); additional visits to other specialists, prescribed medications, and hospitalizations may have occurred without being reported to the study GP and so not recorded in the database. Our results should be considered in the context of such uncertainty (which on balance may be an underestimation of actual costs). Study strengths include its prospective design which evaluated a relatively large cohort of patients with HZ presenting in primary care.